COMPUTER ASSISTED METHOD FOR THE EVALUATION OF CARDIAC METABOLISM

20240266069 · 2024-08-08

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Abstract

The invention relates to a computation based method for determining an individual cardiac metabolic profile in a subject and related materials, devices and mathematical model usage. The present invention therefore relates to a computation-based method for determining an individual metabolic cardiac profile of a subject comprising provision of a heart tissue sample from said subject, quantifying proteins in said sample from said subject, and applying information about quantities of said proteins to a mathematical model. In some embodiments, individual cardiac parameters and/or the metabolites of the subject are additionally introduced into the mathematical model, wherein individual cardiac parameters are determined for a plurality of cardiac workloads, including rest, stress or cardiac pacing. The invention also relates to the individual cardiac metabolic profile comprising a substrate uptake rate, a myocardial ATP consumption, a myocardial ATP production reserve, a myocardial ATP production at said cardiac workload, and a myocardial ATP production at maximal workload, wherein the myocardial ATP production reserve is calculated as the difference between the myocardial ATP-production at said cardiac workload and the myocardial ATP production at maximal workload. The invention further relates to the medical use and corresponding therapeutic methods based on the individual metabolic cardiac profile of the invention in the treatment, prevention, ascertainment, prognosis, of a medical condition associated with a cardiovascular disorder, in addition to detect a perturbation of a normal biological state of the heart from the subject. The invention further relates to the medical use and corresponding therapeutic methods based on the individual metabolic cardiac profile of the invention for the heart at physiological state and/or at pathological state. In further aspects, the invention relates to a computer program adapted to execute a mathematical modelling algorithm that will be performed by a computing device/module to produce outputs given data provided as inputs according to preceding claims, wherein said computer program, preferably MATLAB, is written in a programming language selected from a group comprising Fortran, C #, C/C++, High Level Shading Language, or Python.

Claims

1. A computer-implemented method for determining an individual metabolic cardiac profile of a subject comprising a) providing a heart tissue sample from said subject, b) quantifying proteins in said sample to obtain protein quantities of the heart tissue sample, and c) applying information about the protein quantities from b) to a mathematical model.

2. The computer-implemented method according to claim 1, wherein said heart tissue sample is a left ventricle, a right ventricle, a septum, a left atrium, and/or a right atrium heart tissue sample obtained from said subject during a myocardium examination or cardiac surgery.

3. The computer-implemented method according to claim 1, wherein said method further comprises quantitatively determining metabolites in a plasma, blood, or serum sample from said subject, wherein said metabolites are selected from the group consisting of glucose, lactate, pyruvate, glycerol, fatty acids, glutamate, glutamine, leucin, isoleucine, valine, acetate, B-hydroxybutyrate, catecholamines, insulin and combinations thereof.

4. The computer-implemented method according to claim 1, wherein the method further comprises quantitatively determining of an individual cardiac parameter of the subject comprising heart rate, blood pressure, pressure-volume loops, and/or heart power.

5. The computer-implemented method according to claim 1, wherein the protein quantities of the heart tissue sample from the subject are determined using a protein quantification method selected from the group consisting of mass spectrometry, large scale mass spectrometry, immunoassay, Western blot, microfluidics/nanotechnology sensor, and aptamer capture assay, wherein said method comprises: a) solubilizing the heart tissue sample to obtain a solubilized heart tissue sample, b) extracting proteins from the solubilized heart tissue sample of a) according to the protein quantification method, wherein said proteins are optionally fragmented into peptides, c) transferring said extracted proteins and/or peptides from b) to a device of said protein quantification method and identifying and quantifying the proteins and/or peptides in said sample, wherein said protein quantification method provides a protein profile of said sample from the subject.

6. The computer-implemented method according to claim 5, wherein the protein profile, individual cardiac parameters and/or the metabolites of the subject are introduced into the mathematical model.

7. The computer-implemented method according to claim 1, wherein said individual cardiac metabolic profile comprises a substrate uptake rate, a myocardial ATP consumption, a myocardial ATP production reserve, a myocardial ATP production at a cardiac workload, and a myocardial ATP production at maximal workload, wherein the myocardial ATP production reserve is calculated as a difference between the myocardial ATP-production at said cardiac workload and the myocardial ATP production at said maximal workload.

8. The computer-implemented method according to claim 5, wherein the mathematical model of the individual metabolic cardiac profile of the subject comprises inputing a cardiac kinetic model and providing metabolic parameters relating to the cardiac kinetic model, and/or providing individual cardiac parameters at cardiac workload, parametrizing said mathematical model to the heart tissue sample of said subject by calculating a maximal activity V.sub.max of said subject, and computing a cardiac energy expenditure profile of said subject at cardiac workload, wherein said individual metabolic cardiac profile of said subject is optionally compared to a non-diseased subject at cardiac workload.

9. The computer-implemented method according to claim 8, wherein computing the maximal activity V.sub.max for model parametrization for the heart tissue sample of the subject comprises a) input of the protein profile of the subject, and b) loading at least one reference data set, wherein said reference data set comprises a reference data set containing the quantities of data entries, wherein each data entry of the quantity contains at least one correlated compatible protein label and/or metabolite label, and c) computing the maximal enzyme activity V.sub.max of the subject, wherein V.sub.max is calculated by the formula V max subject = V max ref E subject E ref by applying the protein quantities of the subject to E.sup.subject and by applying V.sub.max.sup.ref and protein quantities to E.sup.ref of any of the reference data sets.

10. The computer-implemented method according to claim 1, wherein said individual metabolic cardiac profile is calculated for a plurality of cardiac workloads, including rest, stress or cardiac pacing, wherein individual cardiac parameter including heart rate, blood pressure, heart power are determined at said cardiac workloads.

11. The computer-implemented method according to claim 1, wherein a plurality of said mathematical models are used in said computations for the heart at physiological state, including normal post-absorptive, post prandial, and fasted, and for the heart at pathological state, including ischemic or diabetic.

12. The computer-implemented method according to claim 1, and calculating, via the computer-implemented method, prognosis of a cardiovascular related disorder, an effect of a change in nutritional interventions, activity and/or therapeutic interventions on protein expression and on the time variation of a metabolic parameter in the heart tissue sample of the subject.

13. The computer-implemented method according to claim 1, and preventing, ascertaining, prognosing or treating, via the computer-implemented method, a cardiovascular related disorder or detecting a perturbation of a normal biological state of the heart from a subject.

14. The computer-implemented method according to claim 1, and, via the computer-implemented method, (i) selecting a nutritional or a therapeutic intervention, and (ii) evaluating or preventing a therapeutic intervention.

15. A computer program adapted to execute a mathematical modelling algorithm that will be performed by a computing device/module to produce outputs of given data provided as inputs according to claim 1, wherein said computer program, is written in a programming language selected from the group consisting of Fortran, C #, C/C++, High Level Shading Language, and Python.

16. The computer-implemented method according to claim 2, wherein said heart tissue sample is obtained during a cardiac catheter examination.

17. The computer-implemented method according to claim 3 wherein the metabolites are quantitively determined in the plasma sample from said subject.

18. The computer-implemented method according to claim 5, wherein the protein quantification method is large scale mass spectrometry, said proteins are fragmented into peptides, the extracted peptides from b) are transferred to a mass spectrometer and the peptides in said sample are quantified.

19. The computer program according to claim 15, said computer program is MATLAB.

Description

SHORT DESCRIPTION OF THE FIGURES

[0228] FIG. 1: Reaction scheme of the metabolic model

[0229] FIG. 2: Simulated and measured myocardial substrate uptake rates in vivo

[0230] FIG. 3: MV.sub.ATP(rest) and MV.sub.ATP(max) for controls and patients with mitral valve disease and aortic stenosis

[0231] FIG. 4: Contribution of energy delivering substrates

[0232] FIG. 5: Correlation between tMVATP(rest) as well as tMVATP(max) and internal myocardial power (iMP) as well as cardiac output (CO) for MI patients (A-D) and AS patients (E-H)

[0233] FIG. 6: Metabolic characterization of three patients with AS

DETAILED DESCRIPTION OF THE FIGURES

[0234] FIG. 1: Reaction scheme of the metabolic model. FIG. 1.1 represents an overview of FIG. 1 for all parts shown in FIG. 1.2:A to FIG. 1.9:H. Arrows symbolize reactions and transport processes between compartments. 1) glycogen metabolism, (2) glycolysis, (3) oxidative pentose phosphate pathway in the endoplasmic reticulum and cytosol, (4) non-oxidative pentose phosphate pathway, (5) triglyceride synthesis, (6) synthesis and degradation of lipid droplets, (7) tricarbonic acid cycle, (8) respiratory chain and oxidative phosphorylation, (9) B-oxidation of fatty acids, (10) ketone body utilization, (11) glutamate metabolism, (12) mitochondrial electrophysiology (membrane transport of ions, (13) Utilization of branched-chain amino acids. Small cylinders and cubes symbolize ion channels and ion transporters. Double-arrows indicate reversible reactions, which according to the value of the thermodynamic equilibrium constant and cellular concentrations of their reactants may proceed in both directions. Reactions are labeled by the short names of the catalyzing enzyme or membrane transporter given in the small boxes attached to the reactions arrow. Metabolites are denoted by their short names. Full names and kinetic rate laws of reaction rates are outlined in Table 8. Full names of metabolites and a comparison of experimentally determined and calculated cellular metabolite concentrations are given in Table 9.

[0235] FIG. 2: Simulated and measured myocardial substrate uptake rates in vivo. (A) Substrate uptake rates at rest and at moderate pacing (50% maxV.sub.O2). The experimental data represent the mean of various studies [40-46]. They were computed from reported extraction rates (=1?arterial concentration/concentration in coronary sinus) putting the coronary blood flow to 0.8 ml/min/g and heart weight to 300 g. (B) Dependence of the glucose uptake rate from the plasma concentration of FFAs. The solid line represents model values, squares symbolize in vivo data taken from Nuutila et al. [38].

[0236] FIG. 3: MV.sub.ATP(rest) and MV.sub.ATP(max) for controls and patients with mitral valve disease and aortic stenosis. MV.sub.ATP(rest) and MV.sub.ATP(max) for controls and patients with mitral valve disease and aortic stenosis (A) Bottom values of the bars refer to MV.sub.ATP(rest), top values refer to MV.sub.ATP(max). The bar length indicates the myocardial ATP production reserve, MAPR=MV.sub.ATP(max)?MV.sub.ATP(rest), of the subject. (B-D) Box plots showing mean values, upper and lower quartiles and total span of MV.sub.ATP(rest), MV.sub.ATP(max) and MAPR for controls and patients with MI and AS.

[0237] FIG. 4: Contribution of energy delivering substrates. The panels A and B show the relative contribution of the energy delivering substrates to total energy expenditure at MV.sub.ATP(rest) and MV.sub.ATP(max) for the control group for 60 min pacing. Area of the pie charts represent total energy expenditure. Changes of substrate uptake rates of MI and AS patients relative to controls are shown at rest (C) and during maximal pacing (D). Bar plots represent the relative change of substrate uptake rates of glucose (1), lactate (2), fatty acids (3) and ketone bodies (4) for patients with MI and AS during rest and at maximal ATP production rate after 60 min of pacing. Relative uptake rates are normalized to control values (i.e. all control values are equal to 1).

[0238] FIG. 5: Correlation between tMV.sub.ATP(rest) as well as tMV.sub.ATP(max) and internal myocardial power (iMP) as well as cardiac output (CO) for MI patients (A-D) and AS patients (E-H). Correlation between tMV.sub.ATP(rest) as well as tMV.sub.ATP(max) and internal myocardial power (iMP) as well as cardiac output (CO) for MI patients (A-D) and AS patients (E-H).

[0239] FIG. 6: Metabolic characterization of three patients with AS. Relative substrate utilization rates compared to healthy controls at rest (A) and at maximal load (C) as well as the relative contribution of the different substrates (glucose (1), lactate (2), fatty acids (3) and ketone bodies (4)) to overall ATP production rate at rest (B) and maximal load (D). Area of pie diagrams represent total ATP production rate.

EXAMPLES

[0240] The invention is demonstrated through the examples disclosed herein. The examples provided represent particular embodiments and are not intended to limit the scope of the invention. The examples are to be considered as providing a non-limiting illustration and technical support for carrying out the invention.

[0241] The examples below present a physiology-based mathematical model of the myocardial energy metabolism. The model encompasses all pathways along which the possible energy-delivering substrates glucose, long-chain fatty acids, ketone bodies (KBs), acetate (AC) and branched-chain amino acids (BCAAs) are utilized. The method described herein allows to assess the capability of the left ventricular septum of patients and controls to increase MV.sub.ATP in response to an increase of the ATP demand. Based on LV samples from controls and patients with MI and AS, it is shown that the ATP production capacity of the LV is reduced in patients and correlates positively with mechanical energy demand and cardiac output and is consistent with the clinical data.

Methods

Patient Characteristics

[0242] We investigated 75 human left ventricular myocardial biopsies. In patients, myocardial samples from the LV septum were collected during surgical aortic or mitral valve replacement from 41 patients with aortic valve stenosis (AS) and 17 patients with mitral valve insufficiency (MI). Patient characteristics are described in Table 1. For the controls (n=17), samples were taken from 44?15 year-old donors without cardiac diseases but whose hearts were not used for transplantation. All samples were frozen immediately in liquid nitrogen until further processing.

[0243] The study protocol was in agreement with the principles outlined in the Declaration of Helsinki and was approved by the Medical Ethics Review Committee. All patients gave written informed consent prior to inclusion.

TABLE-US-00001 TABLE 1 Patients Characteristics Data are presented as total numbers and percentage in case of categorical and as mean and standard deviation (SD) in case of numeric values. Parameter differences between the two patient groups were evaluated by means of two-sided, two-sample Wilcoxon-rank test in case of numeric data and via Chi-squared test with Yates' continuity correction in case of categorical data (p-values given in the right column). ACE-inhibitor = angiotensin converting enzyme-inhibitor, AS = aortic stenosis, BMI = body mass index, MI = mitral valve insufficiency Patient characteristic and SD/ SD/ p- preoperative function parameters AS % MI % value Age at Surgery in years 68 9 60 14 0.032 BMI 28 4 27 3 0.343 Gender female 23 56% 6 35% 0.414 NYHA (stage I, II, III, IV) (5, 17, n.a. (2, 7, n.a. 0.593 15, 1) 6, 2) Blood pressure systolic in mm[Hg] 140 19 131 16 0.123 Blood pressure diastolic in mm[Hg] 74 11 75 13 0.675 EDVi in ml/m2 73 17 108 34 <0.001 ESVi in ml/m2 30 11 40 14 0.015 EF in % 60 7 62 9 0.048 Cl in l/min/m2 3 1 5 2 <0.001 CO in l/min 6 2 9 4 <0.001 Internal myocardial power 13 7 13 5 1 Myocardial mass (i) in g/m2 71 20 67 15 0.484 Mean pressure gradient 56 15 4 8 <0.001 aortic valve, mm[Hg] Mitral valve insufficiency (41, n.a. (0, n.a. (none/mild, moderate, severe) 0, 0) 10, 7) Aortic valve insufficiency (36, n.a. (17, n.a. (none/mild, moderate, severe) 5, 0) 0, 0) Serum Creatinine [mg/dl] 0.91 0.15 1.0 0.20 0.065 Hypertension 27 66% 11 65% 0.826 Dyslipidemia 8 20% 3 18% 0.839 Diabetes type 2 7 17% 2 12% 0.913 Coronary Artery Disease 1 2% 2 12% 0.419 Atrial fibrillation paroxysmal 2 5% 2 12% 0.709 Atrial fibrillation permanent 0 0% 2 12% 0.149 Medication ACE inhibitor 15 37% 5 29% 0.826 Medication beta blocker 20 49% 10 59% 0.683 Medication diuretics 12 29% 5 29% 0.760

Quantitative Proteomics of Tissue Samples

[0244] Heart biopsies were taken from patients admitted in need for aortic or mitral valve replacement surgery or from healthy donor heart control subjects. Left ventricular septum biopsies were extracted at time of surgery, frozen directly in liquid nitrogen and kept at ?80? C. For protein extraction, biopsies were lysed in 200 ?l lysis buffer containing: 2% SDS, 50 mM ammonium bicarbonate buffer and EDTA-free Protease Inhibitor Cocktail (Complete, Roche). Samples were homogenized at room temperature using FastPrep-24? 5G Homogenizer (MP Biomedicals) with 10 cycles of 20 s and 5 s pause between cycles. After heating the samples for 5 min at 95? C., 5 freeze-thaw cycles were applied. 25 U of Benzonase (Merck) was added to each sample and after an incubation for 30 min the lysates were clarified by centrifugation at 16,000 g for 40 min at 4? C. Protein concentration was measured (Bio-Rad DC Protein assay) and 100 ?g of each sample was further processed using the SP3 clean-up and digestion protocol as previously described [20]. Briefly, each sample was reduced with dithiothreitol (10 mM final, Sigma) for 30 min, followed by alkylation with chloroacetamide (40 mM final, Sigma) for 45 min and quenching with dithiothreitol (20 mM final, Sigma). Beads (1 mg) and acetonitrile (70% final concentration) were added to each sample and after 20 min of incubation on an over-head rotor bead-bound protein were washed with 70% ethanol and 100% acetonitrile. 2 ?g sequence-grade Trypsin (Promega) and 2 ?g Lysyl Endopeptidase LysC (Wako) in 50 mM HEPES (pH 8) were added and after an overnight incubation at 37? C. peptides were collected, acidified with trifluoroacetic acid and cleaned up using StageTips protocol [21].

Heart Reference Sample for Matching Library

[0245] A peptide mix for each experimental group (Control, AS and MI) was generated by collecting 10 ?g peptides from each individual sample belonging to the corresponding group. Equal peptide amounts from each group mixture were combined, desalted using a C18 SepPak column (Waters, 100 mg) and dried down using a SpeedVac instrument. Peptides were reconstituted in 20 mM ammonium formate (pH 10) and 2% acetonitrile, loaded on a XBridge C18 4.6 mm?250 mm column (Waters, 3.5 ?m bead size) and separated on an Agilent 1290 HPLC instrument by basic reversed-phase chromatography, using a 90 min gradient with a flow rate of 1 ml/min, starting with solvent A (2% acetonitrile, 5 mM ammonium formate, pH 10) followed by increasing concentration of solvent B (90% acetonitrile, 5 mM ammonium formate, pH 10). The 96 fractions were collected and concatenated by pooling equal interval fractions. The final 26 fractions were dried down and resuspended in 3% acetonitrile/0.1% formic acid for LC-MS/MS analyses.

LC-MS/MS Analyses

[0246] Peptide samples were eluted from stage tips (80% acetonitrile, 0.1% formic acid), and after evaporating organic solvent peptides were resolved in sample buffer (3% acetonitrile/0.1% formic acid). Peptide separation was performed on a 20 cm reversed-phase column (75 ?m inner diameter, packed with ReproSil-Pur C18-AQ; 1.9 ?m, Dr. Maisch GmbH) using a 200 min gradient with a 250 nl/min flow rate of increasing Buffer B concentration (from 2% to 60%) on a High Performance Liquid Chromatography (HPLC) system (ThermoScientific). Peptides were measured on an Orbitrap Fusion (individual samples) and Q Exactive HF-X Orbitrap instrument (reference sample) (ThermoScientific). On the Orbitrap Fusion instrument, peptide precursor survey scans were performed at 120K resolution with a 2?10.sup.5 ion count target. MS.sup.2 scans were performed by isolation at 1.6 m/z with the quadrupole, HCD fragmentation with normalized collision energy of 32, and rapid scan analysis in the ion trap. The MS.sup.2 ion count target was set to 2?10.sup.3 and the max injection time was 300 ms. The instrument was operated in Top speed mode with 3 s cycle time, meaning the instrument would continuously perform MS.sup.2 scans until the list of non-excluded precursors diminishes to zero or 3 s. On the Q Exactive HF-X Orbitrap instrument, full scans were performed at 60K resolution using 3?10.sup.6 ion count target and maximum injection time of 10 ms as settings. MS.sup.2 scans were acquired in Top 20 mode at 15K resolution with 1?10.sup.5 ion count target, 1.6 m/z isolation window and maximum injection time of 22 ms as settings. Each sample was measured twice, and these two technical replicates were combined in subsequent data analyses.

[0247] Data were analyzed using MaxQuant sofware package (v1.6.2.6) [22]. The internal Andromeda search engine was used to search MS.sup.2 spectra against a decoy human UniProt database (HUMAN.2019-01, with isoform annotations) containing forward and reverse sequences. The search included variable modifications of oxidation (M), N-terminal acetylation, deamidation (N and Q) and fixed modification of carbamidomethyl cysteine. Minimal peptide length was set to six amino acids and a maximum of three missed cleavages was allowed. The FDR (false discovery rate) was set to 1% for peptide and protein identifications. Unique and razor peptides were considered for quantification. Retention times were recalibrated based on the built-in nonlinear time-rescaling algorithm. MS.sup.2 identifications were transferred between runs with the Match between runs option, in which the maximal retention time window was set to 0.7 min. The integrated LFQ quantitation algorithm was applied. Gene Symbols assigned by MaxQuant were substituted with gene symbols of the reported UniProt IDs from the FASTA file used.

Description of the Mathematical Model (CARDIOKIN1)

[0248] For the quantification of the metabolic changes caused by the abundance changes of metabolic enzymes, we developed a mathematical model of the cardiac energy metabolism, which comprises all pathways involved in the catabolism of the energy-delivering substrates glucose, lactate, fatty acids, KBs and BCAAs as well as the synthesis of endogenous energy stores (glycogen, triacylglycerol) (see FIG. 1). The model also takes into account the short-term regulation of metabolic enzymes and transporters by the hormones insulin and catecholamines and key electrophysiological processes at the inner mitochondrial membrane including the generation of the proton gradient by the respiratory chain, the synthesis of ATP by the FoF1-ATPase and the membrane transport of various ions.

[0249] The time course of model variables (=concentration of metabolites and ions) is governed by first-order differential equations. Time-variations of small ions are modeled by kinetic equations of the Goldman-Hodgkin-Katz type as used in our previous work [13]. The rate laws for enzymes and membrane transporters were either taken from the literature or constructed based on published experimental data for the mammalian heart.

[0250] Model calibration for individual hearts We used the proteomics-derived protein profiles of enzymes and transporters for model calibration by computing the maximal activities (V.sub.max) of the enzymes by the relation

[00010] V max subject = V max normal E subject .Math. E control .Math. ( 1 )

[0251] where custom-characterE.sup.controlcustom-character is the average protein intensity of the enzyme in the group of control hearts and E.sup.Subject is the protein concentration of the enzyme in the individual (control or patient). The maximal activities v.sub.max.sup.normal of the reference model for the average normal heart were obtained by fitting of the model to experimental data. Equation (1) follows from the fact that the maximal enzyme activity is proportional to the abundance of the protein.

Energetic Capacities of Controls and Patients with Valve Diseases

[0252] We used the model to compute the specific uptake rates of substrates and the specific ATP production rate at rest, MV.sub.ATP(rest), and at maximal ATP workload, MV.sub.ATP(max), for the LV of controls (N=17) and patients with MI (N=17) or AS (N=41). As third parameter to characterize the capacity of the LV to increase the ATP production with increasing workload, we used the span between MV.sub.ATP(max) and MV.sub.ATP(rest), which we will refer to as myocardial ATP production reserve, MAPR (MAPR=MV.sub.ATP(max)?MV.sub.ATP(rest)). In the following, we will distinguish between specific energy parameters MV.sub.ATP(rest), MV.sub.ATP(max) and MAPR quantifying the energetic capacity per mass unit of the LV (given in ?mol/g/h) and total energy parameters tMV.sub.ATP(rest), tMV.sub.ATP(max) and tMAPR quantifying the energetic capacity of the LV (given in mmol/h), i.e. tMV.sub.ATP(rest)=MV.sub.ATP(rest)?LV mass/1000 etc.

[0253] The computations were performed for a normal post-absorptive state (overnight fast) characterized by the following metabolite and hormone concentrations: glucose 5.8 mM [23], fatty acids 0.5 mM [24], lactate 0.8 mM [23], glutamine 0.5 mM [25, 26], valine 0.2 mM [25, 26], leucine 0.15 mM [25, 26], isosleucine 0.06 mM [25, 26], ?-hydroxybutyrate 0.08 mM [27, 28], acetoacetate 0.04 mM. The concentration of catecholamines at rest was 0.75 nM [29, 30] and increased with growing workload (Example 2).

[0254] The myocardial ATP consumption of the stationary resting state, MV.sub.ATP(rest), was chosen in a way that the computed oxygen consumption (MV.sub.O2) was identical with the subject's MV.sub.O2, which we estimated by the 2-factor approximation

[00011] MV O 2 = ? .Math. HR .Math. BP ( 7 )

[0255] HR and BP are the heart rate and the peak systolic blood pressure and ? is a proportionality factor. Resting MV.sub.O2 of normal hearts was found in the range of 0.8-1.2 ml/min/g [2-4]. Thus, with a mean MV.sub.O2=0.1 ml/min/g, HR=70/min and normal BP=125 mm, we set ? to 1.143?10-5 ml/mmHg/g.

[0256] The metabolic response of the ventricle to an additional workload (pacing) was evaluated by computing the temporal changes of the metabolic state elicited by an increase of the ATP consumption rate above the resting value. The ATP consumption rate was modeled by a generic hyperbolic rate law

[00012] v ATP = k load .Math. ATP ATP + K m ( 8 )

[0257] The parameter k.sub.load was stepwise increased until MV.sub.ATP converged to the maximum, MV.sub.ATP(max).

[0258] To evaluate the mechanical burden of the heart, we calculated the internal myocardial power, which describes the energy required for cardiac contraction for the individual hearts (see methods used in Lee et al. [32]).

[0259] All model simulations were performed using MATLAB, Release R2011b, The MathWorks, Inc., Natick, Massachusetts, United States.

Example 1: A Novel Method to Assess the Myocardial ATP Producing Capacity

[0260] Currently, no method is available to measure MV.sub.ATP in vivo. Invasive techniques, such as the determination of substrate extraction rates from coronary sinus, arterial concentration differences or the oxidation rates of 14C-labeled substrates from the rates of 14C.sub.O2, have been applied in healthy subjects and patients with heart diseases [45, 47, 49]. However, such data cannot be directly converted into rates of ATP production. The same holds true for the measurement of the myocardial oxygen consumption rate MV.sub.O2 reflecting the overall myocardial oxidative metabolism. The MV.sub.O2 does not capture the glycolytic ATP contribution, which is low under normoxic conditions but may increase 5-fold during development of heart failure or even 20-fold during the transition from aerobic to anaerobic energy production [51]. Moreover, the ATP/.sub.O2 ratio may change considerably with increasing workload owing to increasing cardiac preference for carbohydrates. This makes it difficult to convert O2 consumption rates into ATP consumption rates. In addition, the maximal MV.sub.O2 can be low due to restrictions imposed to heart performance by the non-metabolic factors. To close this methodological gap, we applied here a novel approach to assess to energetic capacity of the LV of the human heart by combining kinetic modelling with protein abundance data of metabolic enzymes determined in cardiac tissue.

[0261] Except for the maximal enzyme activities (V.sub.max values), which may vary owing to variable gene expression, the numerical values for all other parameters of the enzymatic rate laws were taken from reported kinetic studies of the isolated enzymes. Numerical values for the V.sub.max values were estimated by the same procedure that was used for the calibration of our metabolic liver model [19]: Calculated metabolite profiles and fluxes were adjusted to experimental data from independent experiments with perfused hearts and in vivo measurements (see Table 2) while the metabolite concentrations were constrained to experimentally determined ranges. Short-term regulation of key regulatory enzymes by the hormones insulin and catecholamines (epinephrine, nor-epinephrine) was included into the model by phenomenological mathematical functions relating the enzyme's phosphorylation state and the abundance of the GLUT4 transporter in the sarcolemma to the plasma concentrations of glucose (insulin) and the exercise level (catecholamines) (see Example 2).

TABLE-US-00002 TABLE 2 Model simulations, which correctly recapitulate metabolic measurements obtained with perfused hearts and in human in vivo studies FFAs = free fatty acids, KBs = ketone bodies, BCAAs = branched-chain amino acids Measurements Data source Glucose utilization at varying [33, 34] exogenous glucose concentrations Lactate utilization and lactate/O.sub.2 ratio at varying [35] exogenous lactate concentrations Utilization of FFAs at varying [36, 37] exogenous FFA concentrations Glucose utilization in response to varying exogenous [38] concentration of FFAs (glucose-FFA-competition) KBs utilization at varying exogenous ?- [39] hydroxybutyrate concentrations Utilization rates of glucose, lactate, FFAs, KBs and [40-46] BCAAs under post-absorptive resting conditions Utilization rates of glucose, lactate, FFAs, KBs and [40, 43, 44] BCAAs at moderate pacing

[0262] Details of all validation simulations listed in Table 2 are given in below. As the heart switches its substrate uptake rates in dependence of substrate availability, we performed different simulations with variable substrate availability.

Glucose Uptake:

[0263] First, we simulated the glucose uptake of cardiac muscle in dependence of glucose availability. To match experimental conditions, we assumed that glucose and oxygen are the only available substrates, assumed that there are no hormones present and that the ATP demand is constant with a moderate demand. All external conditions are given in the Table 3.

TABLE-US-00003 TABLE 3 External conditions for simulation of cardiac glucose uptake Glucose [mM] 0.5-25 Valine [mM] 0 Lactate [mM] 0 Leucine [mM] 0 Fatty acids [mM] 0 Isoleucine [mM] 0 B-hydroxybuterate [mM] 0 Insulin [nM] 0-1500 Acetoacetate [mM] 0 TF (Example 2) k-load 5

Lactate Uptake:

[0264] The next most abundant carbohydrate available to the heart is lactate. Therefore, we used the model to investigate the utilization of this important fuel, when the supply with alternative substrate is limited. We varied the external availability of lactate between 0 mM and 12 mM, keeping the glucose concentration at a low value of 2 mM and putting the fatty acid concentration to 0.1 mM (Table 4). Lactate to oxygen consumption rate (OCR) ratio increases up to 4 mM plasma lactate concentration when saturation is reached. This means that in the physiological range (<2 mM) lactate uptake is limited by substrate availability.

TABLE-US-00004 TABLE 4 External conditions for simulation of cardiac lactate uptake Glucose [mM] 2 Valine [mM] 0 Lactate [mM] 0.2-12 Leucine [mM] 0 Fatty acids [mM] 0.1 Isoleucine [mM] 0 B-hydroxybuterate [mM] 0 Insulin [nM] 1 Acetoacetate [mM] 0 TF (Example 2) k-load 0

Fatty Acid Uptake:

[0265] Next, we checked the ability of the model to recapitulate fatty acid uptake. We monitored the fatty acid uptake when systematically varying the plasma fatty acid concentrations between 0 and 2 mM while assuming a moderate ATP demand (Table 5). As the majority of fatty acids in the plasma are bound to albumin, but only free fatty acids are taken up by the heart, we used the transfer function depicted in Example 2 to calculate the free fatty acid concentration from the plasma fatty acid concentration.

TABLE-US-00005 TABLE 5 External conditions for simulation of cardiac fatty acid uptake Glucose [mM] 7.63 Valine [mM] 0 Lactate [mM] 1 Leucine [mM] 0 Fatty acids [mM] 0-2 Isoleucine [mM] 0 B-hydroxybuterate [mM] 0 Insulin [nM] 757 Acetoacetate [mM] 0 TF (Example 2) k-load 5

Suppression of Glucose Uptake by Plasma Fatty Acids:

[0266] After checking that the model correctly recapitulates the substrate utilization for glucose and fatty acids in the absence of the other substrate, the next step was to investigate the interplay of the different substrates. Therefore, we simulated the uptake of glucose in the presence of varying fatty acid concentrations in the plasma. With increasing fatty acid availability, the model correctly recapitulates the replacement of glucose with fatty acids. This strongly supports the view that fatty acids are the preferred substrate for the heart, and that glucose is used only when fatty acid availability is limited. (Table 6)

TABLE-US-00006 TABLE 6 External conditions for simulation of the uptake of glucose in the presence of varying fatty acid concentrations in the plasma. Glucose [mM] 5.8 Valine [mM] 0 Lactate [mM] 0.8 Leucine [mM] 0 Fatty acids [mM] 0-1.2 Isoleucine [mM] 0 B-hydroxybuterate [mM] 0 Insulin [nM] 257 Acetoacetate [mM] 0 TF (Example 2) k-load 2

Ketone Body Utilization:

[0267] Ketone bodies represent an important substrate for the heart especially during fasting conditions when glucose and lactate are not available or need to be saved for the utilization by other organs (i.e. gluconeogenesis form lactate in the liver or glycolysis in the brain). Assuming moderate glucose levels and moderate load, we systematically varied the plasma ketone body concentration (B-hydroxybuterate) from 0 to 5.5 mM and monitored the ketone body uptake rates. (Table 7)

TABLE-US-00007 TABLE 7 External conditions for simulation of the ketone body uptake. Glucose [mM] 4 Valine [mM] 0 Lactate [mM] 0.8 Leucine [mM] 0 Fatty acids [mM] 0-5 Isoleucine [mM] 0 B-hydroxybuterate [mM] 0 Insulin [nM] 36 Acetoacetate [mM] 0 TF (Example 2) k-load 3

Substrate Utilization in the Human Heart:

[0268] Next, we tested whether the model correctly recapitulates substrate uptake of the human heart under physiological conditions when all substrates (glucose, lactate, fatty acids, ketone bodies and branched chain amino acids) are present at the same time. We simulated the substrate utilization rates of the human heart at rest and moderate pacing in an overnight fasted state and compared the simulated rates to experimental data for the human heart (Table 7). FIG. 2 shows that the model calculations recapitulate the substrate uptake profile of the normal human heart as reported in several in vivo studies [8-14] (FIG. 2A). At rest, lactate is utilized with the highest rate, followed by fatty acids and ketone bodies. Increased energy demand during pacing is predominantly fueled by increased uptake by carbohydrates (glucose, lactate, pyruvate), while fatty acid utilization remains almost constant. Branched chain amino acids do not contribute significantly to the energy expenditure of the heart (<1%).

TABLE-US-00008 TABLE 7 External conditions for simulation of the substrate utilization rates of the human heart. Glucose [mM] 5.8 Valine [mM] 0.2 Lactate [mM] 0.8 Leucine [mM] 0.15 Fatty acids [mM] 0.5 Isoleucine [mM] 0.06 B-hydroxybuterate [mM] 0.08 Insulin [nM] 100 Acetoacetate [mM] 0.04 TF (Example 2) k-load 0.5/3

[0269] FIG. 2 shows two model validations highlighting the good concordance of model predictions with experimental data. The examples demonstrate the ability of the heart to ensure cardiac functionality at varying cardiac workload and varying plasma concentrations of energy substrates. In FIG. 2A, the computed substrate uptake profile of the normal human heart is compared with the mean of experimental data taken from several in vivo studies [41-48]. At rest, lactate is utilized with the highest rate, followed by free fatty acids (FFAs) and KBs. Counted in moles ATP per moles substrate (glucose38, lactate18, palmitate138, text book values), FFAs represent the dominating energy source. At moderate pacing, the uptake of the carbohydrates is more than doubled whereas the uptake of FFAs remains essentially unaltered. The energetic contribution of BCAAs was less than 1% at rest and pacing. FIG. 2B shows the relationship between glucose uptake and plasma FFA concentration. The uptake rate of glucose is suppressed with increasing levels of plasma FFAs by inhibition of glucose uptake ensuring the preferential utilization of fatty acids (FIG. 2B).

[0270] For patient-specific model calibration, we used protein intensity profiles (defined through LFQ intensities, see Methods) of 17 control hearts, 41 patients with AS and 17 patients with MI. Using two dimensional liquid chromatography prior to tandem mass spectrometry analysis we identified, in total, 9.133 distinct protein groups, from which a subset of 321 proteins was used for model calibration.

Example 2: External Conditions and Transfer Functions

[0271] Glucose-Insulin: The plasma concentrations of the hormone insulin determine the phosphorylation state of the inter-convertible enzymes. Insulin is secreted by the pancreas into the portal vein and the secretion rate is mainly controlled by the glucose concentration of the blood. Therefore, we used the empirical glucose hormone transfer function (GHT), which describes the relationship between the plasma level of glucose and the plasma levels of insulin established in Bulik et al., 2016 [63]:

[00013] Ins = 1.55 nM * ( Glc ext ) 5.7 ( Glc ext ) 5.7 + ( 7.7 mM ) 5.7

[0272] Enzyme phosphorylation state: The concentration of insulin determines the phosphorylation state of the interconvertible enzymes [63]. The phosphorylation state ? of interconvertible enzymes is given by:

[00014] ? = 1 - Ins 0.65 Ins 0.65 + ( 0.4 nM ) 0.65

[0273] AMP-dependent phosphorylation: In addition to hormone dependent phosphorylation, phosphorylation in dependence of the energetic state of the cell is achieved by the AMP-dependent kinase. Therefore, we introduced AMP dependent phosphorylation by

[00015] ? AMP = AMP AMP + 0.04

[0274] Glucose-fatty acids: The plasma concentration of fatty acids (FA) is largely determined by the rate of triglyceride lipolysis in the adipose tissue, which is mainly controlled by insulin and glucagon through the activity of the hormone sensitive lipases (HSL). Based on measured relations between the plasma levels of plasma and FA we constructed an empirical glucose-FA transfer function (GFT):

[00016] tfa plasma = 1.2 mM - 1.1 mM Glc ext 4 Glc ext 4 + ( 6.5 mM ) 4

[0275] Conversion of total plasma fatty acids to free plasma fatty acids: Plasma fatty acids are largely bound to plasma albumin or lipoproteins, but only free fatty acids are taken up by the heart. We calculated the free fatty acid concentration (ff?.sub.plasma) from total plasma fatty acid concentration (tf?.sub.plasma) assuming a linear relationship between the two. In this way, we can recapitulate hyperbolic saturation kinetics in the cardiac fatty acid uptake rates when depicted against total plasma fatty acid concentration or against free fatty acid plasma concentration:

[00017] ffa plasma = 3.125 .Math. 10 - 4 .Math. tfa plasma

[0276] Epinephrine: The plasma concentrations of the hormone epinephrine is an important determinant for the activity of glucose transport capacity in cardiomyocytes. As epinephrine increases cardiac pacing [64], we describe epinephrine levels in dependence of cardia pacing (load) by a transfer function.

Example 3: Energetic Capacities of the LV of Controls and Patients with Valve Diseases

[0277] FIG. 3 depicts the specific energetic parameters MV.sub.ATP(rest), MV.sub.ATP(max) and MAPR for each subject after 60 min pacing. Compared with controls, the individual variations of these parameters were much larger for the two patient groups (see box plots in FIG. 3 B-D). For MI patients, the mean value of the parameter MV.sub.ATP(rest) was significantly higher (890?292 versus 761?10 ?mol/g/h), while MV.sub.ATP(max) was significantly lower when compared to control values (1713?245 versus 1941?238 ?mol/g/h) (two-sample Kolmogorov-Smirnov test). For AS patients, the mean value of the parameter MV.sub.ATP(rest) was also significantly higher (800?270 versus 761?10 ?mol/g/h) and MV.sub.ATP(max) was also significantly lower (1513?257 versus 1941?238 ?mol/g/h). For both groups of patients, the parameter MAPR was on the average significantly lower compared to the control (826?448 in MI and 904?340 in AS versus 1180?245 ?mol/g/h). Hence, both groups of patients had on the average a reduced ATP production reserve, which was caused by increased MV.sub.ATP(rest) and decreased MV.sub.ATP(max).

[0278] MV.sub.ATP(rest) was significantly increased in the MI and AS group and MV.sub.ATP(max) was significantly decreased in both groups, resulting in a significant reduction of the specific ATP production reserve MAPR (see FIG. 3). The general decrease of MV.sub.ATP(max) in both groups of patients can be accounted for by a decrease of the oxidative phosphorylation capacity as none of the investigated LVs showed excessive glycolytic activity. A decreased expression of the PGC-1?/PPAR? transcription cascade has been identified as an important mechanism responsible for the downregulation of the oxidative phosphorylation in the failing myocardium [3].

Example 4: Substrate Uptake of Patients at Rest and at Maximal Workload

[0279] Next, we investigated changes in the substrate preference of the LV accompanying altered metabolic capacity (see FIG. 4). In the resting state, the largest differences occurred for the uptake rates of glucose and lactate for patients with MI. Especially glucose uptake was increased by more than 20%. At rest, there was a significant decrease in lactate utilization in patients with AS. In general, variances in substrate utilization rates were large, again pointing to individually differing metabolic phenotypes. The reduction in lactate utilization was significant also at maximal load in MI and AS patients, while glucose rates were significantly reduced for patients with AS only. FIG. 4 also shows how the different substrates contribute to overall energy production. The contribution of fatty acids accounts for up to two third, while BCAAs always account for <1% of total energy expenditure and are therefore not shown.

[0280] Both groups of patients exhibited significant changes in the myocardial utilization of the main energy substrates. Generally, there was a trend towards higher uptake rates for glucose and decreased uptake rates for lactate in patients with MI, and a decrease in glucose as well as lactate utilization for AS patients. Ketone body utilization rates showed a high variability, but were in general increased in AS patients. This is in line with recent studies suggesting that increased reliance on ketone body metabolism offers a metabolic advantage in the failing heart and an ergogenic aid for exercise performance [55, 56].

Example 5: Association of MV.SUB.ATP .with Clinical Parameters Evaluating the Mechanical Work and the Systolic Performance of the LV

[0281] In valve disease, the LV is exposed to chronic pressure load (AS) and/or volume overload (MI). This results in a higher mechanical workload, which can be quantified by the surrogate internal myocardial power estimating the power of the LV required for cardiac contraction [32]. Our analysis provided evidence for a strong correlation between tMV.sub.ATP at rest and at maximal pacing and the internal myocardial power (see FIG. 5). Importantly, a significant correlation of the energy parameters has also been found with the cardiac output (see FIG. 5). Taken together, these findings demonstrate a close association between increased ATP production capacity, increased mechanical work of the pressure/volume overloaded LV and cardiac output.

[0282] The central findings of our approach are that even in patients with valvular dysfunction but preserved systolic function and no sign of heart failure, the energy metabolism is already deteriorated (see FIG. 3) and closely associated with mechanical power and systolic performance (see FIG. 5). The first finding is in line with several studies (reviewed in [52]) which have established that a reduction in the ATP production capacity already occurs in early phases of heart failure development. The second finding identifies the capability of the cardiac metabolic network to generate ATP as the key link between systolic function and energy metabolism of the LV rather than the intracellular transport capacity of energy-rich phosphates by the CK shuttle, which was found to not be significantly different in AS patients with preserved and reduced systolic function [10].

Example 6: Metabolic Profiling of Individual Patients

[0283] Despite the general trend of the energy parameters in the patients' LV outlined in the preceding section, substantial differences in the metabolic profiles of individual patients occur. As an example, FIG. 6 depicts the individual energetic profiles of three patients with AS with largely differing values of their cardiac energy parameters (see FIG. 3A). Patients A2 and A4 are characterized by impaired MAPR, while patient A13 has a MAPR comparable to healthy hearts (see FIG. 3). The impaired MAPR of patient A2 results from an increased MV.sub.ATP(rest) with a normal MV.sub.ATP(max), while the impaired MAPR of patient A4 results from an increased MV.sub.ATP(rest) and a decreased MV.sub.ATP(max). Patient A13 with a normal MAPR has normal MV.sub.ATP(rest) and normal MV.sub.ATP(max). The individual alterations in the energetics of the LV are also associated with marked differences in substrate utilization rates. For example, while A13 has normal MV.sub.ATP(rest), its resting carbohydrate utilization rates (glucose and lactate) are strongly decreased and compensated by an increase KB utilization rate. This increased KB utilization is also maintained at MV.sub.ATP(max) and is even more pronounced in A2. In contrast, patient A4 shows a decreased utilization rate for all substrates at MV.sub.ATP(max).

[0284] Our analysis revealed in both groups of patients a large variability of the energy parameters (see FIGS. 3 and 6), likely reflecting larger differences in the patient-specific functional and structural response of the LV to pressure/volume overload. Whereas some patients present with signs of hypertrophy, myocardial thickening and ventricular dilation, others may show alterations in contraction time or only modest signs of remodeling [53, 54]. The large intra-individual variability of cardiac energetics in patients with valvular dysfunction necessitates an individual assessment of the metabolic status (see FIG. 6).

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TABLE-US-00009 TABLE 8 Information to Kinetic rate laws (Table 8 uses separate reference numbering) Fatty acid uptake Carrier mediated FATP [00018] v CD 36 = V max CD 36 .Math. ( ffa ext - c 16 cyt ) 1 + ffa ext K m ffa ext + c 16 cyt K m c 16 cyt V.sub.max.sup.CD36 for numerical value see Table 10 K.sub.m.sup.ffa.sup.ext = 0.000085 [1] K.sub.m.sup.c16.sup.cyt = 0.004 [2] (Long-chain) acyl-coa synthetase [00019] v ACS 1 = V max ACS 1 .Math. c 16 cyt c 16 cyt + K m c 16 cyt .Math. atp cyt atp cyt + K m atp cyt .Math. coa cyt coa cyt + K m coa cyt V.sub.max.sup.ACS1 for numerical value see Table 10 K.sub.m.sup.c16.sup.cyt = 0.033 [3] K.sub.m.sup.atp.sup.cyt = 0.320 [3] K.sub.m.sup.coa.sup.cyt = 0.0064 [3] [00020] v FATP 1 = V max FATP 1 .Math. c 16 cyt c 16 cyt + K m c 16 cyt .Math. atp cyt atp cyt + K m atp cyt .Math. coa cyt coa cyt + K m coa cyt [00021] V max FATP 1 = V max ACS 1 27 [ 3 ] K m c 16 cyt = 0.021 [ 3 ] K m atp cyt = 0.85 [ 3 ] K m coa cyt = 0.0083 [ 3 ] [00022] v FATP 4 = V max FATP 4 .Math. c 16 cyt c 16 cyt + K m c 16 cyt .Math. atp cyt atp cyt + K m atp cyt .Math. coa cyt coa cyt + K m coa cyt V.sub.max.sup.FATP4 = 1.3 .Math. V.sub.max.sup.ASC1 [4] K.sub.m.sup.c16.sup.cyt = 0.013 [4] K.sub.m.sup.atp.sup.cyt = 1.4 [4] K.sub.m.sup.coa.sup.cyt = 0.047 [4] Beta-oxidation Carnitine palmitoyltransferase I (muscle isoform) [00023] v CPT 1 = V max CPT 1 .Math. c 16 coa cyt .Math. car cyt ( c 16 coa cyt + K m c 16 coa cyt ) .Math. ( car cyt + K m car cyt ) V.sub.max.sup.CPT1 for numerical value see Table 10 [00024] K m c 16 coa cyt = K 0 c 16 coa cyt .Math. ( 1 + malcoa 2 imm K i malcoa 2 imm ) K.sub.0.sup.c16coa.sup.cyt = 0.073 [5] K.sub.i.sup.malcoa2.sup.imm = 0.0001 [6] K.sub.m.sup.car.sup.cyt = 0.19 [7] Carnitine acylcarnitine translocase [00025] v CACT = V max CACT .Math. ( car mito .Math. c 16 car cyt - 1 / K eq CACT .Math. car cyt .Math. c 16 car mito ( 1 + car mito K m car mito ) ( 1 + c 16 car cyt K m c 16 coa cyt ) + ( 1 + car cyt K m car cyt ) ( 1 + c 16 car mito K m c 16 car mito ) - 1 ) V.sub.max.sup.CACT for numerical value see Table 10 K.sub.eq.sup.CACT = 1.6 [8] K.sub.m.sup.car.sup.mito = 5.8 [9] K.sub.m.sup.c16car.sup.cyt = 0.001 [10] K.sub.m.sup.car.sup.cyt = 1.3 [11] K.sub.m.sup.c16car.sup.mito = 0.0051 [12] Carnitine palmitoyltransferase 2 [00026] v CPT 2 = V max CPT 2 .Math. ( c 16 car mito .Math. coa mito - 1 / K eq CPT 2 .Math. c 16 coa mito .Math. car mito ( 1 + c 16 car mito K m c 16 car mito ) ( 1 + coa mito K m coa mito ) + ( 1 + c 16 coa mito K m c 16 coa mito ) ( 1 + car mito K m car mito ) - 1 ) V.sub.max.sup.CPT2 for numerical value see Table 10 K.sub.eq.sup.CPT2 = 2 [13] Km.sup.c16car.sup.mito = 0.12 [14] K.sub.m.sup.coa.sup.mito = 0.0055 [15] K.sub.m.sup.c16coa.sup.mito = 0.191 [16] K.sub.m.sup.car.sup.mito = 0.46 [17] Short chain acyl-coa dehydrogenase (c4) (identical to liver enzyme [18]) [00027] v c 4 coa - scdh = V max c 4 coa - dh .Math. ( c 4 coa mito c 4 coa mito + K m c 4 coa mito ) .Math. ( etffad mito etffad mito + K m etffad mito ) V.sub.max.sup.c4coa-dh for numerical value see Table 10 K.sub.m.sup.c4coa.sup.mito = 0.0107 [19] K.sub.m.sup.etffad.sup.mito = 0.0038 [19] Short chain acyl-coa dehydrogenase (c5) (identical to liver enzyme [18]) [00028] v c 5 coa - scdh = V max c 5 coa - dh .Math. ( c 5 coa mito c 5 coa mito + K m c 5 coa mito ) .Math. ( etffad mito etffad mito + K m etffad mito ) V.sub.max.sup.c5coa-dh for numerical value see Table 10 K.sub.m.sup.c5coa.sup.mito = 0.01 K.sub.m.sup.etffad.sup.mito = 0.0038 [19] Medium chain acyl-coa dehydrogenase (c6) (identical to liver enzyme [18]) [00029] v c 6 coa - mcdh = V max c 6 coa - dh .Math. ( c 6 coa mito c 6 coa mito + K m c 6 coa mito ) .Math. ( etffad mito etffad mito + K m etffad mito ) V.sub.max.sup.c6coa-dh for numerical value see Table 10 [00030] K m c 6 coa mito = 0 . 0 0 9 4 [ 19 ] K m etffad mito = 0 . 0 045 [ 19 ] Medium chain acyl-coa dehydrogenase (c8) (identical to liver enzyme [18]) [00031] v c 8 coa - mcdh = V max c 8 coa - dh .Math. ( c 8 coa mito c 8 coa mito + K m c 8 coa mito ) .Math. ( etffad mito etffad mito + K m etffad mito ) V.sub.max.sup.c8coa-dh for numerical value see Table 10 K.sub.m.sup.c8coa.sup.mito = 0.004 [19] K.sup.metffad.sup.mito = 0.0045 [19] Medium chain acyl-coa dehydrogenase (c10) (identical to liver enzyme [18]) [00032] v c 10 coa - mcdh = V max c 10 coa - dh .Math. ( c 10 coa mito c 10 coa mito + K m c 10 coa mito ) .Math. ( etffad mito etffad mito + K m etffad mito ) V.sub.max.sup.c10coa-dh for numerical value see Table 10 K.sub.m.sup.c10coa.sub.mito = 0.0054 [19] K.sub.m.sup.etffad.sup.mito = 0.0045 [19] Medium chain acyl-coa dehydrogenase (c12) (identical to liver enzyme [18]) [00033] v c 12 coa - mcdh = V max c 12 coa - dh .Math. ( c 12 coa mito c 12 coa mito + K m c 12 coa mito ) .Math. ( etffad mito etffad mito + K m etffad mito ) V.sub.max.sup.c12coa-dh for numerical value see Table 10 K.sub.m.sup.c12coa.sup.mito = 0.0057 [19] K.sub.m.sup.etffad.sup.mito = 0.0045 [19] Long chain acyl-coa dehydrogenase (c10) (identical to liver enzyme [18]) [00034] v c 10 coa - lcdh = V max c 10 coa - dh .Math. ( c 10 coa mito c 10 coa mito + K m c 10 coa mito ) .Math. ( etffad mito etffad mito + K m etffad mito ) [00035] V max c 10 coa - dh for numerical value see Table 10 K m c 10 coa mito = K 0 c 10 coa mito .Math. ( 1 + kc 16 coa mito K i kc 16 coa mito ) K.sub.i.sup.kc16coa.sup.mito = 0.00047 [20] K.sub.0.sup.c10coa.sup.mito = 0.0243 [19] K.sub.m.sup.etffad.sup.mito = 0.0083 [19] Long chain acyl-coa dehydrogenase (c12) (identical to liver enzyme [18]) [00036] v c 12 coa - lcdh = V max c 12 coa - dh .Math. ( c 12 coa mito c 12 coa mito + K m c 12 coa mito ) .Math. ( etffad mito etffad mito + K m etffad mito ) [00037] V max c 12 coa - dh for numerical value see Table 10 K m c 12 coa mito = K 0 c 12 coa mito .Math. ( 1 + kc 16 coa mito K i kc 16 coa mito ) k.sub.i.sup.kc16coa.sup.mito = 0.00047 [20] K.sub.0.sup.c12coa.sup.mito = 0.009 [19] K.sub.m.sup.etffad.sup.mito = 0.0083 [19] Long chain acyl-coa dehydrogenase (c14) (identical to liver enzyme [18]) [00038] v c 14 coa - lcdh = V max c 14 coa - dh .Math. ( c 14 coa mito c 14 coa mito + K m c 14 coa mito ) .Math. ( etffad mito etffad mito + K m etffad mito ) V.sub.max.sup.c14coa-dh for numerical value see Table 10 [00039] K m c 14 coa mito = K 0 c 14 coa mito .Math. ( 1 + kc 16 coa mito K i kc 16 coa mito ) K.sub.i.sup.kc16coa.sup.mito = 0.00047 [20] K.sub.0.sup.c14coa.sup.mito = 0.0074 [19] K.sub.m.sup.etffad.sup.mito = 0.0083 [19] Long chain acyl-coa dehydrogenase (c16) (identical to liver enzyme [18]) [00040] v c 16 coa - lcdh = V max c 16 coa - dh .Math. ( c 16 coa mito c 16 coa mito + K m c 16 coa mito ) .Math. ( etffad mito etffad mito + K m etffad mito ) V.sub.max.sup.c16coa-dh for numerical value see Table 10 [00041] K m c 16 coa mito = K 0 c 16 coa mito .Math. ( 1 + kc 16 coa mito K i kc 16 coa mito ) K.sub.i.sup.kc16coa.sup.mito = 0.00047 [20] K.sub.0.sup.c16coa.sup.mito = 0.0025 [19] K.sub.m.sup.etffad.sup.mito = 0.0083 [19] Enoyl-coa hydratase (Crontonase) (ec4) [00042] v ehyd - ec 4 = V max ehyd - ec 4 .Math. ( ec 4 coa mito - 1 / K eq ehyd - ec 4 .Math. lc 4 coa mito ec 4 coa mito + K m ec 4 coa mito ) V.sub.max.sup.ehyd-ec4 for numerical value see Table 10 [00043] K eq ehyd - ec 4 = 0.25 [ 21 ] K m ec 4 coa mito = K 0 ec 4 coa mito .Math. ( 1 + kc 4 coa mito K i kc 4 coa mito ) K.sub.0.sup.ec4coa.sup.mito = 0.013 [22] K.sub.i.sup.kc4coa.sup.mito = 0.025 [23] Enoyl-coa hydratase (Crontonase) (ec6) [00044] v ehyd - ec 6 = V max ehyd - ec 6 .Math. ( ec 6 coa mito - 1 / K eq ehyd - ec 6 .Math. lc 6 coa mito ec 6 coa mito + K m ec 6 coa mito ) [00045] V max ehyd - ec 6 = V max ehyd - ec 4 .Math. 1280 1 6 7 0 [ 22 ] K eq ehyd - ec 6 = 2 [ 21 ] [00046] K m ec 6 coa mito = K 0 ec 6 coa mito .Math. ( 1 + kc 4 coa mito K i kc 4 coa mito ) K.sub.0.sup.ec6coa.sup.mito = 0.029 [22] K.sub.i.sup.kc4coa.sup.mita = 0.025 [23] Enoyl-coa hydratase (Crontonase) (ec8) [00047] v ehyd - ec 8 = V max ehyd - ec 8 .Math. ( ec 8 coa mito - 1 / K eq ehyd - ec 8 .Math. lc 8 coa mito ec 8 coa mito + K m ec 8 coa mito ) [00048] V max ehyd - ec 8 = V max ehyd - ec 4 .Math. 910 1 6 7 0 [ 22 ] K eq ehyd - ec 8 = 2 [ 21 ] [00049] K m ec 8 coa mito = K 0 ec 8 coa mito .Math. ( 1 + kc 4 coa mito K i kc 4 coa mito ) k.sub.0.sup.ec8coa.sup.mito = 0.029 [22] K.sub.i.sup.kc4coa.sup.mito = 0.025 [23] Enoyl-coa hydratase (Crontonase) (ec10) [00050] v ehyd - ec 10 = V max ehyd - ec 10 .Math. ( ec 10 coa mito - 1 / K eq ehyd - ec 10 .Math. lc 10 coa mito ec 10 coa mito + K m ec 10 coa mito ) [00051] V max ehyd - ec 10 = V max ehyd - ec 4 .Math. 540 1670 [ 22 ] K eq ehyd - ec 10 = 2 [ 21 ] [00052] K m ec 10 coa mito = K 0 ec 10 coa mito .Math. ( 1 + kc 4 coa mito K i kc 4 coa mito ) K 0 ec 10 coa mito = 0.029 [ 22 ] K i kc 4 coa mito = 0.025 [ 23 ] Enoyl-coa hydratase (Crontonase) (ec12) [00053] v ehyd - ec 12 = V max ehyd - ec 12 .Math. ( ec 12 coa mito - 1 / K eq ehyd - ec 12 .Math. lc 12 coa mito ec 12 coa mito + K m ec 12 coa mito ) [00054] V max ehyd - ec 12 = V max ehyd - ec 4 .Math. 160 1670 [ 22 ] K eq ehyd - ec 12 = 2 [ 21 ] [00055] K m ec 12 coa mito = K 0 ec 12 coa mito .Math. ( 1 + kc 4 coa mito K i kc 4 coa mito ) K 0 ec 12 coa mito = 0.03 [ 22 ] K i kc 4 coa mito = 0.025 [ 23 ] Enoyl-coa hydratase (Crontonase) (ec14) [00056] v ehyd - ec 14 = V max ehyd - ec 14 .Math. ( ec 14 coa mito - 1 / K eq ehyd - ec 14 .Math. lc 14 coa mito ec 14 coa mito + K m ec 14 coa mito ) [00057] V max ehyd - ec 14 = V max ehyd - ec 16 .Math. 5 2.3 [ 24 ] K eq ehyd - ec 14 = 2 [ 21 ] [00058] K m ec 14 coa mito = K 0 ec 14 coa mito .Math. ( 1 + kc 4 coa mito K i kc 4 coa mito ) K.sub.0.sup.ec14coa.sup.mito = 0.025 [23] K.sub.i.sup.kc4coa.sup.mito = 0.025 [23] Enoyl-coa hydratase (Crontonase) (ec16) [00059] v ehyd - ec 16 = V max ehyd - ec 16 .Math. ( ec 16 coa mito 1 / K eq ehyd - ec 16 .Math. lc 16 coa mito ec 16 coa mito + K m ec 16 coa mito ) [00060] V max ehyd - ec 16 = V max ehyd - ec 4 .Math. 40 1670 [ 22 ] K eq ehyd - ec 16 = 2 [ 21 ] [00061] K m ec 16 coa mito = K 0 ec 16 coa mito .Math. ( 1 + kc 4 coa mito K i kc 4 coa mito ) K.sub.0.sup.ec16coa.sup.mito = 0.030 [22] K.sub.i.sup.kc4coa.sup.mito = 0.025 [23] 3-hydroxyacyl-coa dehydrogenase (Ic4) (identic with liver enzyme [25]) [00062] v 3 hdh - lc 4 = V max 3 hdh - lc 4 .Math. ( lc 4 coa mito .Math. nad mito - 1 / K eq 3 hdh - lc 4 .Math. kc 4 coa mito .Math. nadh mito ( 1 + lc 4 coa mito K m lc 4 coa mito ) .Math. ( 1 + nad mito K m nad mito ) + ( 1 + kc 4 coa mito K m kc 4 coa mito ) .Math. ( 1 + nadh mito K m nadh mito ) - 1 ) V.sub.max.sup.3hdh-ic4 for numerical value see Table 10 [00063] K eq 3 hdh - lc 4 = 1 0.012 [ 26 ] K m lc 4 coa mito = 0.0072 [ 27 ] K.sub.m.sup.nad.sup.mito = 0.0154 [27] K.sub.m.sup.kc4coa.sup.mito = 0.0169 [28] = K.sub.m.sup.nadh.sup.mito = 0.0118 [27] 3-hydroxyacyl-coa dehydrogenase (Ic6) (identic with liver enzyme [25]) [00064] v 3 hdh - lc 6 = V max 3 hdh - lc 6 .Math. ( lc 6 coa mito .Math. nad mito - 1 / K eq 3 hdh - lc 6 .Math. kc 6 coa mito .Math. nadh mito ( 1 + lc 6 coa mito K m lc 6 coa mito ) .Math. ( 1 + nad mito K m nad mito ) + ( 1 + kc 6 coa mito K m kc 6 coa mito ) .Math. ( 1 + nadh mito K m nadh mito ) - 1 ) V.sub.max.sup.3hdh-lc6 for numerical value see Table 10 [00065] K eq 3 hdh - lc 6 = 1 8 .Math. 10 - 4 [ 29 ] K m lc 6 coa mito = 0.0286 [ 30 ] K m nad mito = 0.015 [ 27 ] K.sub.m.sup.kc6coa.sup.mito 0.0057 [31] K.sub.m.sup.nadh.sup.mito = 0.011 [27] 3-hydroxyacyl-coa dehydrogenase (Ic8) (identic with liver enzyme [25]) [00066] v 3 hdh - lc 8 = V max 3 hdh - lc 8 .Math. ( lc 8 coa mito .Math. nad mito - 1 / K eq 3 hdh - lc 8 .Math. kc 8 coa mito .Math. nadh mito ( 1 + lc 8 coa mito K m lc 8 coa mito ) .Math. ( 1 + nad mito K m nad mito ) + ( 1 + kc 8 coa mito K m kc 8 coa mito ) .Math. ( 1 + nadh mito K m nadh mito ) - 1 ) V.sub.max.sup.3hdh-lc8 for numerical value see Table 10 [00067] K eq 3 hdh - lc 8 = 1 10 - 3 K m lc 8 coa mito = 0.0163 [ 28 ] K m nad mito = 0.015 [ 27 ] K.sub.m.sup.kc8coa.sup.mito = 0.0031 [31] K.sub.m.sup.nadh.sup.mito = 0.011 [27] 3-hydroxyacyl-coa dehydrogenase (Ic10) (identic with liver enzyme [25]) [00068] v 3 hdh - lc 10 = V max 3 hdh - lc 10 .Math. ( lc 10 coa mito .Math. nad mito - 1 / K eq 3 hdh - lc 10 .Math. kc 10 coa mito .Math. nadh mito ( 1 + lc 10 coa mito K m lc 10 coa mito ) .Math. ( 1 + nad mito K m nad mito ) + ( 1 + kc 10 coa mito K m kc 10 coa mito ) .Math. ( 1 + nadh mito K m nadh mito ) - 1 ) V.sub.max.sup.3hdh-lc10 for numerical value see Table 10 [00069] K eq 3 hdh - lc 10 = 1 10 - 3 K m lc 10 coa mito = 0.0029 [ 27 ] K m nad mito = 0.0104 [ 27 ] [00070] K m kc 10 coa mito = 0 . 0 0 1 8 [ 31 ] K m nadh mito = 0 . 0 0 1 1 [ 2 7 ] 3-hydroxyacyl-coa dehydrogenase (Ic12) (identic with liver enzyme [25]) [00071] v 3 hdh - lc 12 = V max 3 hdh - lc 12 .Math. ( lc 12 coa mito .Math. nad mito - 1 / K eq 3 hdh - lc 12 .Math. kc 12 coa mito .Math. nadh mito ( 1 + lc 12 coa mito K m lc 12 coa mito ) .Math. ( 1 + nad mito K m nad mito ) + ( 1 + kc 12 coa mito K m kc 12 coa mito ) .Math. ( 1 + nadh mito K m nadh mito ) - 1 ) V.sub.max.sup.3hdh-lc12 for numerical value see Table 10 [00072] K eq 3 hdh - lc 12 = 1 10 - 3 K m lc 12 coa mito = 0.0018 [ 31 ] K m nad mito = 0.015 [ 27 ] K.sub.m.sup.kc12coa.sup.mito = 0.0018 [31] K.sub.m.sup.nadh.sup.mito = 0.011[27] 3-hydroxyacyl-coa dehydrogenase (Ic14) (identic with liver enzyme [25]) [00073] v 3 hdh - lc 14 = V max 3 hdh - lc 14 .Math. ( lc 14 coa mito .Math. nad mito - 1 / K eq 3 hdh - lc 14 .Math. kc 14 coa mito .Math. nadh mito ( 1 + lc 14 coa mito K m lc 14 coa mito ) .Math. ( 1 + nad mito K m nad mito ) + ( 1 + kc 14 coa mito K m kc 14 coa mito ) .Math. ( 1 + nadh mito K m nadh mito ) - 1 ) V.sub.max.sup.3hdh-lc14 for numerical value see Table 10 [00074] K eq 3 hdh - lc 14 = 1 10 - 3 K m lc 14 coa mito = 0.0015 [ 31 ] K m nad mito = 0.015 [ 27 ] K.sub.m.sup.kc14coa.sup.mito = 0.0013[31] K.sub.m.sup.nadh.sup.mito = 0.011[27] 3-hydroxyacyl-coa dehydrogenase (Ic16) (identic with liver enzyme [25]) [00075] v 3 hdh - lc 16 = V max 3 hdh - lc 16 .Math. ( lc 16 coa mito .Math. nad mito - 1 / K eq 3 hdh - lc 16 .Math. kc 16 coa mito .Math. nadh mito ( 1 + lc 16 coa mito K m lc 16 coa mito ) .Math. ( 1 + nad mito K m nad mito ) + ( 1 + kc 16 coa mito K m kc 16 coa mito ) .Math. ( 1 + nadh mito K m nadh mito ) - 1 ) V.sub.max.sup.3hdh-lc16 for numerical value see Table 10 [00076] K eq 3 hdh - lc 16 = 1 10 - 3 K m lc 16 coa mito = 0.003 [ 27 ] [00077] K m nad mito = 0 . 0 1 4 5 [ 27 ] K m kc 16 coa mito = 0 . 0 0 1 3 [ 31 ] K m nadh mito = 0 . 0 11 [ 27 ] 3-ketoacyl-coa thiolase I (kc4) [00078] v 3 kt kc 4 coa = V max 3 kt - kc 4 coa .Math. ( coa mito .Math. kc 4 coa mito - 1 / K eq 3 kt .Math. acoa mito 2 ( 1 + coa mito K m coa mito ) .Math. ( 1 + kc 4 coa mito K m kc 4 coa mito ) + ( 1 + acoa mito K m acoa mito ) - 1 ) V.sub.max.sup.3kt-kc4 for numerical value see Table 10 K.sub.eq.sup.3kt = 2500 [32] K.sub.m.sup.coa.sup.mito = 0.0087 [33] [00079] K m kc 4 coa mito = K 0 kc 4 coa mito .Math. ( 1 + acoa mito K i acoa mito ) K i acoa mito = 0.125 [ 34 ] K 0 kc 4 coa mito = 0.017 [ 33 ] [00080] K m acoa mito = K 0 acoa mito .Math. ( 1 + kc 4 coa mito K i kc 4 coa mito ) K 0 acoa mito = 0.3 [ 35 ] K i kc 4 coa mito = 0.0022 [ 36 ] 3-ketoacyl-coa thiolase II (kc4) [00081] v 3 ktII kc 4 coa = V max 3 ktII - kc 4 coa .Math. ( coa mito .Math. kc 4 coa mito - 1 / K eq 3 kt .Math. acoa mito 2 ( 1 + coa mito K m coa mito ) .Math. ( 1 + kc 4 coa mito K m kc 4 coa mito ) + ( 1 + acoa mito K m acoa mito ) - 1 ) V.sub.max.sup.3ktll-kc4c for numerical value see Table 10 K.sub.eq.sup.3kt = 2500 [32] K.sub.m.sup.coa.sup.mito = 0.0513 [33] [00082] K m kc 4 coa mito = K 0 kc 4 coa mito .Math. ( 1 + acoa mito K i acoa mito ) K i acoa mito = 0.125 [ 34 ] K 0 kc 4 coa mito = 0.0135 [ 33 ] [00083] K m acoa mito = K 0 acoa mito .Math. ( 1 + kc 4 coa mito K i kc 4 coa mito ) K 0 acoa mito = 0.3 [ 35 ] K i kc 4 coa mito = 0.0022 [ 36 ] 3-ketoacyl-coa thiolase I (kc6) [00084] v 3 kt kc 6 coa = V max 3 kt - c 6 coa .Math. ( kc 6 coa mito .Math. coa mito - 1 / K eq 3 kt .Math. acoa mito .Math. c 4 coa mito ( coa mito + K m coa mito ) .Math. ( kc 6 coa mito + K m kc 6 coa mito ) ) V.sub.max.sup.3kt-kc6 = 2.4 .Math. V.sub.max.sup.3kt-kc4 [33] K.sub.eq.sup.3kt = 2500 [32] K.sub.m.sup.coa.sup.mito 0.0087 [33] K.sub.m.sup.kc6coa.sup.mito = 0.0083[33] 3-ketoacyl-coa thiolase I (kc8) [00085] v 3 kt kc 8 coa = V max 3 kt - kc 8 .Math. ( kc 8 coa mito .Math. coa mito - 1 / K eq 3 kt .Math. acoa mito .Math. c 6 coa mito ( coa mito + K m coa mito ) .Math. ( kc 8 coa mito + K m kc 8 coa mito ) ) V.sub.max.sup.3kt-kc8 = 2.2 .Math. V.sub.max.sup.3kt-kc4 [33] K.sub.eq.sup.3kt = 2500 [32] K.sub.m.sup.coa.sup.mito = 0.0024[33] K.sub.m.sup.kc8coa.sup.mito = 0.025 [37] 3-ketoacyl-coa thiolase I (kc10) [00086] v 3 kt kc 10 coa = V max 3 kt - kc 10 .Math. ( kc 10 coa mito .Math. coa mito - 1 / K eq 3 kt .Math. acoa mito .Math. c 8 coa mito ( coa mito + K m coa mito ) .Math. ( kc 10 coa mito + K m kc 10 coa mito ) ) V.sub.max.sup.3kt-kc10 = 2 3 .Math. V.sub.max.sup.3kt-kc4 [33] K.sub.eq.sup.3kt = 2500 [32] K.sub.m.sup.coa.sup.mito = 0.0087 [33] K.sub.m.sup.kc10coa.sup.mito = 0.0018[33] 3-ketoacyl-coa thiolase I (kc12) [00087] v 3 k t k c 1 2 c o a = V ma x 3 k t - k c 1 2 .Math. ( k c 1 2 c o a mito .Math. coa mito - 1 K e q 3 k t .Math. acoa mito .Math. c 10 coa mito ( c o a m i t o + K m c o a mito ) .Math. ( kc 12 coa m i t o + K m kc 12 coa mito ) ) V.sub.max.sup.3kt-kc12 = 2.1 .Math. V.sub.max.sup.3kt-kc4 [37] K.sub.eq.sup.3kt = 2500 [32] K.sub.m.sup.coa.sup.mito = 0.0087 [33] K.sub.m.sup.kc12coa.sup.mito = 0.006 [37] 3-ketoacyl-coa thiolase I (kc14) [00088] v 3 k t k c 1 4 c o a = V ma x 3 k t - k c 1 4 .Math. ( k c 1 4 c o a mito .Math. coa mito - 1 K e q 3 k t .Math. acoa mito .Math. c 12 coa mito ( c o a mito + K m c o a m i t o ) .Math. ( kc 14 coa mito + K m k c 1 4 c o a m i t o ) ) V.sub.max.sup.3kt-kc14 = 1.7 .Math. V.sub.max.sup.3kt-kc4 [37] K.sub.eq.sup.3kt = 2500 [32] K.sub.m.sup.coa.sup.mito = 0.0087 [33] K.sub.m.sup.kc14coa.sup.mito = 0.0065 [37] 3-ketoacyl-coa thiolase I (kc16) [00089] v 3 k t k c 1 6 c o a = V ma x 3 k t - k c 1 6 .Math. ( k c 1 6 c o a m i t o .Math. coa m i t o - 1 K e q 3 k t .Math. acoa mito .Math. c 14 coa mito ( c o a mito + K m c o a mito ) .Math. ( kc 16 coa mito + K m k c 1 6 c o a mito ) ) V.sub.max.sup.3kt-kc16 for numerical value see Table 10 K.sub.eq.sup.3kt = 2500 [32] K.sub.m.sup.coa.sup.mito = 0.0087 [33] K.sub.m.sup.kc16coa.sup.mito = 0.0011 [38] ETF-FAD V.sub.ETF-FAD = V.sub.max.sup.ETF-FAD .Math. (etffadh2.sub.mito .Math. etfq.sub.mito ? 1/K.sub.eq.sup.ETF-FAD .Math. etfqh2.sub.mito .Math. etffad.sub.mito) V.sub.max.sup.ETF-FAD for numerical value see Table 10 [00090] K e q ETF - FAD = exp ( ( - n .Math. E 0 etffad mito / etffadh 2 mito - n .Math. E 0 etfqh 2 mito / etfq mito ) .Math. F R .Math. T ) E.sub.0.sup.etfqh2.sup.mito.sup./etfq.sup.mito = ?25 mV [39] E.sub.0.sup.etffad.sup.mito.sup./etffadh2.sup.mito = ?23 mV [40] n = 2 ETF-QO [00091] v ETF - QO = V ma x ETF - QO .Math. ( etfqh 2 mito .Math. q m m - 1 K e q ETF - Q O .Math. etfq mito .Math. qh 2 m m ) V.sub.max.sup.ETF-QO for numerical value see Table 10 [00092] K e q ETF - QO = exp ( ( n .Math. E 0 q m m / q h 2 m m + n .Math. E 0 etfqh 2 m i t o / etfq mito ) .Math. F R .Math. T ) E.sub.0.sup.q.sup.mm.sup./qh2.sup.mm = 87 mV [41] E.sub.0.sup.etfqh2.sup.mito.sup./etfq.sup.mito = ?25 mV [39] n = 2 Citric acid cycle Pyruvate dehydrogenase complex v.sub.pdhc = Y.sub.pdhc .Math. V.sub.pdhc-np [00093] v pdhc - np = V ma x pdhc - np .Math. ( pyr mito pyr mito + K m - pyr pdhc - np ) .Math. ( nad mito nad mito + K m - nad pdhc - np ) .Math. ( coa mito coa mito + K m - coa pdhc - np ) .Math. ( 1 + k ca ca mito ca mito + K a ca ) V.sub.max.sup.pdhc-up for numerical value see Table 10 [00094] K m - p y r pdhc - np = 0 . 0 77 [ 42 ] K m - nad pdhc - np = K 0 nad .Math. ( 1 + nadh mito K i nadh mito ) K 0 nad = 0.07 [ 42 ] [00095] K i nadh mito = 0.3 [ 43 ] K m - coa pdhc - np = K 0 coa .Math. ( 1 + acoa mito K i acoa mito ) K 0 coa = 0.0122 [ 42 ] K.sub.i.sup.acoa.sup.mito = 0.029 [44] k.sub.ca = 1.7 [45] K.sub.a.sup.ca = 0.001 [46] ?.sub.pdhc = ?.sub.pdhc.sup.acoa .Math. ?.sub.pdhc.sup.nadh [00096] ? pdhc acoa = 1 - f 1 .Math. acoa mito coa mito acoa mito coa mito + K i ( acoa mito coa mito ) [ 47 ] K i ( acoa mito coa mito ) = 0.4 [ 47 ] f 1 = 0.71 [ 47 ] [00097] ? pdhc nadh = 1 - f 2 .Math. nadh mito nad mito nadh mito nad mito + K i ( nadh mito nad mito ) f 2 = 0.75 [ 47 ] K i ( nadh mito nad mito ) = 0.5 [ 47 ] Citrate synthase [00098] v c s = V ma x c s .Math. ( o a a mito o a a mito + K m o a a mito ) .Math. ( a c o a mito a c o a mito + K m acoa mito ) [00099] V ma x c s = V 0 c s ( 1 + c 16 coa mito K i c 16 coa mito ) .Math. ( 1 + atp mito K i atp mito ) V.sub.0.sup.cs for numerical value see Table 10 K.sub.i.sup.c16coa.sup.mito = 0.0042 [48] K.sub.i.sup.atp.sup.mito = 0.7 [49] [00100] K m o a a mito = K 0 o a a m i t o .Math. ( 1 + c i t mito K i cit mito ) K i cit mito = 1.6 [ 50 ] K 0 o a a mito = 0.0036 [ 49 ] [00101] K m a c o a mito = K 0 a c o a mito .Math. ( 1 + succoa mito K i succoa mito ) K i c o a mito = 0 . 0 67 [ 51 ] K.sub.i.sup.atp.sup.mito = 0.95 [51] K.sub.i.sup.succoa.sup.mito = 0.13 [51] K.sub.0.sup.acoa.sup.mito = 0.006 [52] Aconitase [00102] v a c = V ma x a c .Math. ( cit mito - 1 K e q a c .Math. isocit mito 1 + c i t m i t o K m c i t mito + i s o c i t mito K m isocit mito ) V.sub.max.sup.ac for numerical value see Table 10 K.sub.eq.sup.ac = 0.1 [53] K.sub.m.sup.cit.sup.mito = 0.62 [54] K.sub.m.sup.isocit.sup.mito = 0.2 [54] NAD-dependent isocitrate dehydrogenase [00103] v idh nad = V ma x idh nad .Math. ( isocit mito n isocit mito n + ( K m isocit mito ) n ) .Math. ( nad mito nad mito + K m nad mito ) V.sub.max.sup.idh.sup.nad for numerical value see Table 10 [00104] K m isocit mito = K 0 isocit mito .Math. ( 1 - n adp mito adp mito adp mito + K a adp mito ) .Math. ( 1 - n cit mito cit mito cit mito + K a cit mito ) K.sub.0.sup.isocit.sup.mito = 0.21 [55] n = 3 [55] n.sub.adp.sub.mito = 0.67 [56] K.sub.a.sup.adp.sup.mito = 0.1 [56] n.sub.cit.sub.mito = 0.85 [57] K.sub.a.sup.cit.sup.mito = 0.033 [57] [00105] K m nad mito = K 0 nad mito .Math. ( 1 + nadh mito K i nadh mito ) K 0 nad mito = 0.06 [ 56 ] K i nadh mito = 0 . 0 043 [ 58 ] NADP-dependen isocitrate dehydrogenase [00106] v idh nadph = V ma x idh nadp .Math. ( isocit mito isocit mito + K m isocit mito ) .Math. ( nadp mito nadp mito + K m nad mito ) V.sub.max.sup.idh.sup.nadp for numerical value see Table 10 [00107] K m isocit mito = K 0 isocit mito .Math. ( 1 + cit mito K i cit mito ) .Math. ( 1 + akg mito K i akg mito ) [00108] K 0 isocit mito = 0.045 [ 59 ] K m nadp mito = K 0 nadp mito .Math. ( 1 + nadph mito K i nadph mito ) K 0 nadp mito = 0 . 0 46 [ 59 ] K.sub.i.sup.nadph.sup.mito = 0.125 [58] K.sub.i.sup.cit.sup.mito = 0.159 [59] K.sub.i.sup.akg.sup.mito = 0.08 [59] ?-ketogluterate dehydrogenase [00109] v kgdhc = V m x kgdhc .Math. ( akg mito akg mito + K m akg mito .Math. ( 1 + nadh mito K i 2 nadh mito ) ) .Math. ( nad mito nad mito + K m nad .Math. ( 1 + nadh mito K i nadh mito ) ) .Math. ( coa mito coa mito + K m coa mito .Math. ( 1 + succoa mito K i succoa mito ) ) V.sub.mx.sup.kgdhc for numerical value see Table 10 K.sub.i2.sup.nadh.sup.mito = 0.0127 [60] K.sub.m.sup.akg.sup.mito = 0.6 [61] K.sub.m.sup.nad.sup.mito = 0.021[60] K.sub.i.sup.nadh.sup.mito = 0.0045 [60] K.sub.m.sup.coa.sup.mito = 0.0027 [60] K.sub.i.sup.succoa.sup.mito = 0.0069[60] Succinyl-Coa synthetase [62] [00110] v s c s - atp = V ma x scs - atp .Math. ( succoa mito .Math. adp mito .Math. p mito - 1 K eq suc - atp .Math. suc mito .Math. coa mito .Math. atp mito ( 1 + succoa mito K m succoa mito ) .Math. ( 1 + adp mito K m adp mito ) .Math. ( 1 + p mito K m p mito ) + ( 1 + s u c mito K m suc mito ) .Math. ( 1 + coa mito K m coa mito ) .Math. ( 1 + atp mito K m atp mito ) - 1 ) [00111] V ma x scs - atp = V 0 scs - atp .Math. ( p mito n p mito n + K a p n ) V.sub.0.sup.scs-atp for numerical value see Table 10 K.sub.a.sup.p.sup.n = 2.3 [63] n = 2.4 [63] K.sub.eq.sup.scs-atp = 1/0.27 [64] K.sub.m.sup.succoa.sup.mito = 0.041 [65] K.sub.m.sup.adp.sup.mito = 0.25 [65] K.sub.m.sup.p.sup.mito = 0.72 [65] K.sub.m.sup.suc.sup.mito = 5.1[65] K.sub.m.sup.coa.sup.mito = 0.032 [65] K.sub.m.sup.atp.sup.mito = 0.055 [65] [00112] v scs - gtp = V ma x scs - gtp .Math. ( succoa mito .Math. gdp mito .Math. p mito - 1 K e q scs - atp .Math. suc mito .Math. coa mito .Math. gtp mito ( 1 + succoa mito K m succoa mito ) .Math. ( 1 + gdp mito K m gdp mito ) .Math. ( 1 + p mito K m p mito ) + ( 1 + suc mito K m suc mito ) .Math. ( 1 + coa mito K m coa mito ) .Math. ( 1 + gtp mito K m gtp mito ) - 1 ) [00113] V ma x scs - gtp = V 0 scs - gtp .Math. ( p mito n p mito n + K a p n ) V.sub.0.sup.scs-gtp = 0.11 .Math. V.sub.0.sup.scs-atp [65] K.sub.a.sup.p.sup.mito = 2.3 [63] n = 2.4 [63] K.sub.eq.sup.scs-gtp = 1/0.27 [66] K.sub.m.sup.succoa.sup.mito = 0.086 [65] K.sub.m.sup.gdp.sup.mito = 0.007 [65] K.sub.m.sup.p.sup.mito = 2.26[65] K.sub.m.sup.suc.sup.mito = 0.49 [65] K.sub.m.sup.coa.sup.mito = 0.036 [65] K.sub.m.sup.gtp.sup.mito = 0.036 [65] Succinate dehydrogenase [00114] v succdh = V ma x s u c c a h .Math. ( suc mito .Math. q mm - 1 K e q succdh .Math. fum mito .Math. qh 2 m m ( suc mito + K m suc mito ) .Math. ( q m m + K m q m m ) ) V.sub.max.sup.succdh for numerical value see Table 10 [00115] K eq succdh = exp ( E 0 fum mito / suc mito - E 0 q m m / qh 2 mm R .Math. T .Math. F ) E 0 fum mito / suc mito - E 0 q m m / q h 2 m m = 25 mV [00116] K 0 suc mito = 1.3 [ 67 ] K m suc mito = K 0 suc mito .Math. ( 1 + mal mito K i mal mito ) K i mal mito = 2.2 [ 68 ] K m q m m = 0 . 0 005 [ 69 ] Fumarase [00117] v fum = V ma x fum .Math. ( fum mito - 1 K eq fum .Math. mal mito 1 + fum mito K m fum mito + mal mito K m mal mito ) V.sub.max.sup.fum for numerical value see Table 10 K.sub.eq.sup.fum = 4.2 [70] K.sub.m.sup.fum.sup.mito = 0.333 [71] K.sub.m.sup.mal.sup.mito = 0.59 [71] Malate dehydrogenase (mitochondrial) [00118] v mdh mito = V ma x mdh mito .Math. ( mal mito .Math. nad mito - 1 K eq mdh mito .Math. oaa mito .Math. nadh mito ( 1 + mal mito K m mal mito ) .Math. ( 1 + nad mito K m nad mito ) + ( 1 + oaa mito K m oaa mito ) .Math. ( 1 + nadh mito K m nadh mito ) - 1 ) v.sub.max.sup.mdh.sup.mito for numerical value see Table 10 [00119] K eq mdh mito = 1 .Math. 10 - 5 .Math. ( h cyt h mito ) [ 72 ] K.sub.m.sup.mal.sup.mito = 0.4 [73] K.sub.m.sup.nad.sup.mito = 0.06 [74] K.sub.m.sup.oaa.sup.mito = 0.017 [74] K.sub.m.sup.nadh.sup.mito = 0.044 [74] Transdehydrogenase [75] [00120] v tdh = V ma x tdh .Math. ( nadh mito .Math. nadp mito - 1 K e q tdh .Math. nad mito .Math. nadph mito ) V.sub.max.sup.tdh.sup.mito for numerical value see Table 10 [00121] K eq tdh mito = K 0 tdh .Math. exp ( - v m m .Math. F R .Math. T ) .Math. ( h cyt h mito ) K 0 tdh = 1.5 [ 76 ] Mitochondrial electrophysiology and ATP synthesis Chloride [00122] I c l e d = P c l .Math. A m .Math. U .Math. F .Math. ( cl cy𝔱 - cl mito .Math. exp ( - U ) 1 - exp ( - U ) ) U = v m m .Math. F R .Math. T P c l = 5 .Math. 10 - 1 0 m / s Sodium [00123] I n a pump = V ma x N a - pump .Math. ( na cyt .Math. h mito - na mito .Math. h cyt 1 + na cyt K m na + na mito K m na ) V.sub.max.sup.Na-pump for numerical value see Table 10 [00124] K m n a = 32.4 [ 77 ] I n a e d = P n a .Math. A m .Math. U .Math. F .Math. ( n a cyt - n a mito .Math. exp ( U ) exp ( U ) - 1 ) [00125] U = v m m .Math. F R .Math. T P n a = 1 .Math. 10 - 1 0 m / s I n a = I n a pump + I n a e d Potassium I.sub.K.sup.pump = V.sub.max.sup.K-pump .Math. (k.sub.cyt .Math. h.sub.mito ? k.sub.mito .Math. h.sub.cyt) V.sub.max.sup.K-pump for numerical value see Table 10 [00126] I k ed = P k .Math. A m .Math. U .Math. F .Math. ( k cyt - k mito .Math. exp ( U ) exp ( U ) - 1 ) [00127] U = v m m .Math. F R .Math. T P K = 5 .Math. 10 - 1 0 m / s I k = I k pump + I k e d F0F1 synthetase [00128] v F 0 F 1 = V ma x F 0 F 1 .Math. ( adp mito .Math. p mito - 1 K eq F 0 F 1 .Math. atp mito ( K m adp mito + adp mito ) .Math. ( K m p mito + p mito ) ) [00129] V ma x F 0 F 1 = V F 0 F 1 .Math. ( 0.114 + 0.886 ( .Math. "\[LeftBracketingBar]" V m m .Math. "\[RightBracketingBar]" ) n ( .Math. "\[RightBracketingBar]" V m m .Math. "\[RightBracketingBar]" ) n + ( K m V m m ) n ) [ 78 ] V.sub.F0F1 for numerical value see Table 10 n = 10 [78] K.sub.m.sup.V.sup.mm = 140 mV [78] [00130] K e q F 0 F 1 = exp ( ( - E 0 ATP R .Math. T ) - n H .Math. ( V m m .Math. F R .Math. T ) ) .Math. ( H cyt H mito ) n H mM - 1 n.sub.H = 3 E.sub.0.sup.ATP = 30500 J/mol K.sub.m.sup.adp.sup.mito = 0.025 [79] K.sub.m.sup.p.sup.mito = 6.1 [79] ATP-ADP nucleotide exchanger [80] [00131] v nex = V ma x nex .Math. ( 1 - atp cyt .Math. adp mito adp cyt .Math. atp mito .Math. exp ( v m m .Math. F R .Math. T ) 1 + atp cyt adp cyt .Math. exp ( f .Math. v m m .Math. F R .Math. T ) .Math. ( 1 + adp mito atp mito ) ) V.sub.max.sup.nex for numerical value see Table 10 f = 0.2 Phosphate exchanger [00132] v P - ex = V ma x P - ex .Math. ( p cyt .Math. h cyt - p mito .Math. h mito ( p cyt + K m p cy𝔱 ) ) V.sub.max.sup.P-ex for numerical value see Table 10 K.sub.m.sup.p.sup.cyt = 1.89 [81] Complex I [00133] v c x l = V ma x c x l .Math. ( nadh mito .Math. q m m - 1 K e q c x l .Math. nad m i t o .Math. qh 2 m m ( nadh mito + K m nadh mito ) .Math. ( q m m + K m q m m ) ) V.sub.max.sup.cxI for numerical value see Table 10 [00134] K e q cxl = exp ( ( n .Math. E 0 nadh / nad + n .Math. E 0 Q / Q H 2 + n H .Math. V m m ) .Math. F R .Math. T ) .Math. ( h mito h cyt ) n H n = 2 E.sub.0.sup.nadh/nad = 320 mV [82] E.sub.0.sup.Q/QH.sup.2 = 87 mV [41] N.sub.H = 4 K.sub.m.sup.nadh.sup.mito = 0.0017 [83] K.sub.m.sup.q.sup.mm = 0.013 [83] Complex II see succinate dehydrogenase Complex III [00135] v cxIII = V ma x cxIII .Math. ( qh 2 m m .Math. cyc o x m m - 1 K eq cxIII .Math. q m m .Math. cytc red m m ( q h 2 m m + K m q h 2 m m ) .Math. ( cytc o x m m + K m cytc o x ) 2 ) V.sub.max.sup.cxIII for numerical value see Table 10 [00136] K eq cxIII = exp ( ( - n .Math. E 0 Q / Q H 2 + n .Math. E 0 cytC o x / c y t C red + n .Math. v m m ) .Math. F R .Math. T ) .Math. ( h mito h ? ) n h mito .Math. ( h ? h cyt ) n h cyt n = 2 E.sub.0.sup.cytC.sup.ox.sup./cytC.sup.red = 255 mV [84] E.sub.0.sup.Q/QH.sup.2 = 87 mV [41] n.sub.h.sub.mito = 2 n.sub.h.sub.cyt = 4 h.sub.? = 10.sup.?4 mM custom-character pH 7 K.sub.m.sup.qh.sub.2.sub.mm = 0.013 [85] K.sub.m.sup.cytc.sup.ox = 0.014 [85] Complex IV [00137] v cxIV = V ma x cxIV .Math. ( cytc red cytc red + K m cytc red ) .Math. ( O 2 O 2 + K m O 2 ) [00138] V ma x cxIV = V 0 cxIV .Math. exp ( - dGp .Math. F R .Math. T ) dGp = - v m m + R .Math. T F .Math. log ( h cyt h mito ) V.sub.0.sup.cxIV for numerical value see Table 10 K.sub.m.sup.cytc.sup.red = 0.007 [86] K.sub.m.sup.0.sup.2 = 2 mmHg Adenylate kinase [00139] v ak cyc = V ma x ak cyt .Math. ( atp cyt .Math. amp cyt - 1 K eq ak .Math. adp cyt .Math. adp cyt ( 1 + atp cyt K m atp cyt ) .Math. ( 1 + amp cyt K m amp cyt ) + ( 1 + adp cyt K m adp cyt ) 2 - 1 ) V.sub.max.sup.ak.sup.cyt for numerical value see Table 10 K.sub.eq.sup.ak = 1 [87] K.sub.m.sup.atp.sup.cyt = 0.039 [88] K.sub.m.sup.adp.sup.cyt = 0.112 [88] K.sub.m.sup.amp.sup.cyt = 0.026 [88] Pyrophosphatase [00140] v ppase = V ma x ppase .Math. ( pp cyt pp cyt + K m pp cyt ) V.sub.max.sup.ppase for numerical value see Table 10 K.sub.m.sup.pp.sup.cyt = 0.016 [89] ATP usage [00141] v atp - usage = V ma x atp - usage .Math. ( atp cyt atp cyt + K m atp cyt ) .Math. ( 1 + k load ) V.sub.max.sup.atp-usage for numerical value see Table 10 K.sub.m.sup.atp.sup.cyt = 2 O.sub.2 diffusion [00142] v O 2 diff = V max O 2 - diff .Math. ( o 2 ext - o 2 cyt ) V.sub.max.sup.O.sup.2.sup.-diff for numerical value see Table 10 Proton fluxes I.sub.H.sup.pump = 4 .Math. v.sub.cxl + 2 .Math. V.sub.cxIII + 4 .Math. v.sub.cxIV [00143] I H e d = P H .Math. A m .Math. U .Math. F .Math. ( H cyt - H mito .Math. exp ( U ) exp ( U ) - 1 ) P.sub.H = 3 .Math. 10.sup.?4 m/s Mitochondrial membrane potential [00144] v V m m = 1 0 - 1 c m .Math. A m .Math. ( - I C e d + I K e d + I H e d + I Na ed + I H pump + v n e x + 3 .Math. v syn + F .Math. 10 .Math. v pepT .Math. Vol cyt ) Glycolysis Glut1 glucose transporter (Glut1) [00145] v gluT 1 = V ma x gluT 1 .Math. glc ext - glc cyt 1 + glc ext n m glc ext + glc cyt K m glc cyt V ma x gluT 1 = V 0 gluT 1 .Math. ( 1 - c 1 6 ext n c 1 6 ext n + K i c 16 ext ) V.sub.0.sup.gluT1 for numerical value see Table 10 n = 2 [90] K.sub.i.sup.c16.sup.ext = 0.2 [90] K.sub.m.sup.glc.sup.cyt = 5 [91] K.sub.m.sup.glc.sup.ext = 5 [91, 92] Glut4 glucose transporter (Glut4) [00146] v gluT 4 = V ma x gluT 4 .Math. glc ext - glc cyt 1 + glc ext K m glc ext + glc cyt K m glc cyt [00147] V ma x gluT 4 = V 0 gluT 4 .Math. ( 1 - c 1 6 ext n c 1 6 ext n + K i c 16 ext ) .Math. ( 1 - ? .Math. ( 1 - epi ext epi ext + K a epi ext ) .Math. ( 1 - amp cyt amp cyt + K a amp cyt ) ) [ 93 ] V.sub.0.sup.gluT4 [94] for numerical value see Table 10n = 2 [90] K.sub.i.sup.c16.sup.ext = 0.2 [90] K.sub.a.sup.epi.sup.ext = 200 pM K.sub.a.sup.amp.sup.cyt = 0.2 K.sub.m.sup.glc.sup.cyt = 5 [91] K.sub.m.sup.glc.sup.ext = 5 [91] Hexokinase A [00148] v hkA = V ma x hkA .Math. ( glc cyt glc cyt + K m glc cyt ) .Math. ( atp cyt atp cyt + K m atp cyt ) [00149] V ma x hkA = V 0 hkA 1 + glc 6 p cyt K i hk V 0 hkA for numerical value see Table 10 K.sub.i.sup.glc.sup.cyt = 0.05 [95] K.sub.m.sup.glc.sup.cyt = 0.25 [96] [00150] K m atp cyt = K 0 atp cyt .Math. ( 1 + glc6p cyt K i glc 6 p cyt ) .Math. ( 1 + adp cyt K i adp cyt ) K.sub.0.sup.atp.sup.cyt = 0.75 [96] K.sub.i.sup.adp.sup.cyt = 0.22 [96] K.sub.ig.sup.lc6p.sup.cyt = 0.021 [96] Hexokinase 1 [00151] v hkB = V ma x hkB .Math. ( glc cyt glc cyt + K m glc cyt ) .Math. ( atp cyt atp cyt + K m atp cyt ) [00152] V ma x hkB = V 0 hkB 1 + glc 6 p cyt K i hk V 0 hkB = 10 .Math. V 0 hkA [ 97 ] K i hk = 0.05 [ 95 ] K m glc cyt = 0.02 [ 95 ] [00153] K m atp cyt = K 0 atp cyt .Math. ( 1 + glc 6 p cyt K i glc 6 p cyt ) .Math. ( 1 + adp cyc K i adp cyt ) K.sub.0.sup.atp.sup.cyt = 0.44 [95] K.sub.i.sup.adp.sup.cyt = 0.62 [96] K.sub.i.sup.glc6p.sup.cyt = 0.02 [95] D-Glucose-6-phosphate isomerase (Gpi) [00154] v gpi = V ma x gpi .Math. glc 6 p cyt - fru 6 p cyt K eq gpi 1 + glc 6 p cyt K m glp cyt + fru 6 p cyt K m fru 6 p cyt V.sub.max.sup.gpi for numerical value see Table 10 K.sub.eq.sup.Gpi = 0.3 [98] K.sub.m.sup.glc6p.sup.cyt = 0.55 [99] K.sub.m.sup.fru6p.sup.cyt = 0.12 [99] Phosphofructokinase 2 (Pfk2) v.sub.pfk2 = V.sub.max.sup.pfk2.sup.native .Math. (1 ? ?.sup.Pfk2) .Math. v.sub.pfk2.sup.native + V.sub.max.sup.pfk2.sup.p (?.sup.pfk2 .Math. v.sub.pfk2.sup.p) ?.sup.pfk2 = ? .Math. (1 ? ?.sup.amp) V.sub.max.sup.pfk2.sup.native for numerical value see Table 10 V.sub.max.sup.pfk2.sup.p = 2.3 .Math. V.sub.max.sup.pfk2.sup.native [100] [00155] v pfk 2 native = fru 6 p cyt fru 6 p cyt + K m fru 6 p cyt .Math. atp cyt atp cyt + K m atp cyt .Math. ( 1 - cit cyt cit cyt + K i cit cyt ) K.sub.m.sup.fru6p.sup.cyt = 0.121 [100] K.sub.m.sup.atp.sup.cyt = 0.63 [100] K.sub.i.sup.cit.sup.cyt = 0.029 [100] [00156] v pfk 2 p = fru 6 p cyt fru 6 p cyt + K m fru 6 p cyt .Math. atp cyt atp cyt + K m atp cyt .Math. ( 1 - cit cyt cit cyt + K i cit cyt ) K.sub.m.sup.fru6p.sup.cyt = 0.061 [100] K.sub.m.sup.atp.sup.cyt = 0.63 [100] K.sub.i.sup.cit.sup.cyt = 0.061 [100] Fructose-2,6-bisphosphatase (FBP2) v.sub.fbp2 = V.sub.max.sup.fbp2.sup.phospho .Math. ?.sup.fbp2 .Math. v.sub.fbp2.sup.p ?.sup.fbp2 = ? .Math. (1 ? ?.sup.amp) [00157] V ma x fbp 2 phospho = V ma x fbp 2 native [ 101 ] v fbp 2 p = fru 26 bp cyt fru 26 bp cyt + K m fru 26 bp cyt K.sub.m.sup.fru26p.sup.cyt = 0.026 [102] Phosphofructokinase 1 (Pfk1): v.sub.pfk1 = V.sub.max.sup.pfk1 .Math. ((1 ? ?.sup.Pfk1) .Math. v.sub.pfk1.sup.native + ?.sup.pfk1 .Math. v.sub.pfk1.sup.p) ?.sup.pfk1 = ? .Math. (1 ? ?.sup.amp) V.sub.max.sup.pfk1 for numerical value see Table 10 [00158] v pfk 1 native = fru 26 cyr n fru 26 cyt n + ( K a fru 26 cyt ) n .Math. atp cyt atp cyt + K m atp cyt .Math. ( 1 - f atp atp cyt n atp atp cyt n atp + ( K i atp cyt ) n atp ) .Math. ( 1 - f cit cit cyt n cit cit cyt n cit + ( K i cit cyt ) n cit ) .Math. ( fru 6 p cyt ) n fru 6 p cyt ( fru 6 p cyt ) n fru 6 p cyt + ( K m fru 6 p cyt ) n fru 6 p cyt n = 2 [103] [00159] K a fru 26 cyt = K 0 fru 26 cyt .Math. ( atp cyt n fru 26 atp cyt n fru 26 + ( K i fru 26 atp cyt .Math. ( 1 + cit cyt cit cyt + K i atp cit cyt ) ) n fru 26 ) [00160] K 0 fru 26 cyt = 0 . 0 10 [ 104 ] n fru 26 = n 0 - cit cyt cit cyt + K cit n fru 26 n 0 = 5 [ 104 ] K.sub.cit.sup.n.sup.fru26 = 0.05 [104] K.sub.i.sub.fru26.sup.atp.sup.cyt = 3.4 [104] K.sub.i.sub.atp.sup.cit.sup.cyt = 0.065 [104] K.sub.m.sup.atp.sup.cyt = 0.2 [105] f.sub.atp = 0.95 [103] n.sub.atp = 6 [103] K.sub.i.sup.atp.sup.cyt = 1.3 [103] n.sub.cit = 4 [103] f.sub.cit = 0.485 [103] K.sub.i.sup.cit.sup.cyt = 0.192 [103] [00161] K m fru 6 p cyt = K 0 .Math. ( 1 - fru 26 cyt fru 26 cyt + K a fru 6 p fru 26 cyt ) .Math. ( 1 - p cyt p cyt + K a fru 6 p p cyt ) .Math. ( 1 + f atp atp cyt n atp atp cyt n atp + ( K i atp fru 26 ) n atp ) .Math. ( 1 + k cit cit cyt n cit cit cyt n cit + ( K i cit cyt ) n cit ) K.sub.0 = 7 [104] K.sub.a.sub.fru6p.sup.fru26.sup.cyt = 0.00015 [104] K.sub.afru6p.sup.p.sup.cyt = 0.15 [106] n.sub.atp = 2 [106] K.sub.i.sub.atp.sup.fru26 = 0.2 [106] f.sub.atp = 2 [106] k.sub.cit = 8 [106] n.sub.cit = 4 [106] K.sub.i.sup.cit.sup.cyt = 0.13 [106] [00162] n fru 6 p cyt = n 0 .Math. ( 1 - f fru 26 cyt fru 26 cyt + K n fru 6 p fru 26 cyt ) .Math. ( 1 + ( f atp atp cyt atp cyt + K n fru 6 p fatp ) .Math. ( 1 - fru 6 p cyt fru 6 p cyt + K n fru 6 p fru 6 ) .Math. ( 1 - p cyt p cyt + K n fru 6 p p ) ) n.sub.0 = 1 [104] f = 0.66 [104] f.sub.atp = 2.75 [104] K.sub.n.sub.fru6p.sup.fru26.sup.cyt = 0.0001 [104] K.sub.n.sub.fru6p.sup.atp = 0.1 [104] K.sub.n.sub.fru6p.sup.fru6 = 0.4 [106] K.sub.n.sub.fru6p.sup.p = 0.5 [106] [00163] v p f k 1 p = f r u 2 6 c y t n f r u 2 6 c y t n + ( K a fru 26 c y 𝔱 ) n .Math. a t p c y t a t p c y t + K m a t p cy t .Math. ( 1 - f a t p a t p c y t n atp a t p c y t n atp + ( K i a t p c y t ) n atp ) .Math. ( 1 - f c i t c i t c y t n c i t c i t c y t n c i t + ( K i c i t c y t ) n c i 𝔱 ) .Math. ( f r u 6 p c y t ) n fru 6 p c y t ( f r u 6 p c y t ) n fru 6 p c y t + ( K m fru 6 p c y 𝔱 ) n fru 6 p c y t n = 2 [103] [00164] K a fru 26 c y 𝔱 = K 0 fru 26 c y 𝔱 .Math. ( a t p c ? t n f r u 2 6 a t p c y t n fru 26 + ( K i fru 26 a t p c y t .Math. ( 1 + c i t c y t c i t c y t + K i atp c i t c y t ) ) n fru 26 ) [00165] K 0 f r u 2 6 c y 𝔱 = 0 . 0 1 [ 1 0 4 ] [ 103 ] n fr?.Math. 26 = n 0 - c i t c y t c i t c y t + K c i t n f r u 2 6 n 0 = 5 [ 104 ] K.sub.cit.sup.n.sup.fru26 = 0.05 [104] K.sub.i.sub.fru26.sup.atp.sup.cyt = 3.4 [104] K.sub.i.sub.atp.sup.cit.sup.cyt = 0.065 [104] K.sub.m.sup.atp.sup.cyt = 0.2 [105] f.sub.atp = 0.95 [103] n.sub.atp = 5 [103] K.sub.i.sup.atp.sup.cyt = 0.9 [103] n.sub.cit = 2 [103] f.sub.cit = 0.55 [103] K.sub.i.sup.cit.sup.cyt = 0.18 [103] [00166] K m f r u 6 p c y t = K 0 .Math. ( 1 - f r u 2 6 c y t f r u 2 6 c y t + K a f r u 6 p f r u 2 6 c y t ) .Math. ( 1 - p c y t p c y t + K a fru 6 p p c y t ) .Math. ( 1 + f a t p a t p c y t n a t p a t p c y t n atp + ( K i atp f r u 2 6 ) n atp ) .Math. ( 1 + k c i t c i t c y t n c i t c i t c y t n c i t + ( K i c i t c y t ) n c i t ) K.sub.0 = 5 [104] [103] K.sub.a.sub.fru6p.sup.fru26.sup.cyt = 0.00015 [104] K.sub.a.sub.fru6p.sup.p.sup.cyt = 0.15 [106] n.sub.atp = 2 [106] K.sub.i.sub.atp.sup.fru26 = 0.2 [106] f.sub.atp = 2 [106] k.sub.cit = 8 [106] n.sub.cit = 4 [106] K.sub.i.sup.cit.sup.cyt = 0.13 [106] [00167] n fru 6 p c y t = n 0 .Math. ( 1 - f f r u 2 6 c y t f r u 2 6 c y t + K n fru 6 p f r u 2 6 c y t ) .Math. ( 1 + ( f a t p a t p c y t a t p c y t + K n fru 6 p f a t p ) .Math. ( 1 - f r u 6 p c y t f r u 6 p c y t + K n f r u 6 p f r u 6 ) .Math. ( 1 - p c y t p c y t + K n fru 6 p p ) ) n.sub.0 = 1 [104] f = 0.66 [104] f.sub.atp = 2.75 [104] K.sub.nfru6p.sup.fru26.sup.cyt = 0.0001 [104] K.sub.n.sub.fru6p.sup.atp = 0.1 [104] K.sub.n.sub.fru6p.sup.fru6 = 0.4 [106] K.sub.n.sub.fru6p.sup.p = 0.5 [106] Fructose-1,6-bisphosphatase (Fbp1) v.sub.fbp1 = V.sub.max.sup.vfbp1 .Math. ((1 ? ?.sup.fbp1) .Math. v.sub.fbp1.sup.native + ?.sup.fbp1 .Math. v.sub.fbp1.sup.p) ?.sup.fbp1 = ? .Math. (1 ? ?.sup.amp) V.sub.max.sup.fbp1 for numerical value see Table 10 [00168] v f b ? 1 n a t i v e = f r u 1 6 b p c y t f r u 1 6 b p c y t + K m f r u 1 6 b ? cyt / ( 1 + f r u 2 6 b p c y t n ( K i fru 26 bp c y t ) n ) K.sub.m.sup.fru16bp.sup.cyt = 0.0029 [107] K.sub.i.sup.fru26p.sup.cyt = 0.00113 [107] n = 1.26 [107] [00169] v f b ? 1 p = f r u 1 6 b p c y t f r u 1 6 b p c y t + K m f r u 1 6 b p c y t / ( 1 + f r u 2 6 b p c y t n ( K i f r u 2 6 b p c y t ) n ) K.sub.m.sup.fru16bp.sup.cyt = 0.0019 [107] K.sub.i.sup.fru26bp.sup.cyt = 0.00113 [107] n = 1.26 [107] Aldolase (Ald) [00170] v ald = v ma x ald .Math. f r u 1 6 b p c y t - 1 K e q a l d g r a p c y t .Math. dhap c y t ( 1 + f r u 1 6 b p c y t K m f r u 1 6 b p cy t ) + ( 1 + g r a p c y t K m g r a p c y t ) .Math. ( 1 + d h a p c y t K m dhap c y t ) - 1 v.sub.max.sup.ald for numerical value see Table 10 K.sub.eq.sup.ald = 0.099 [108] K.sub.m.sup.fru16bp.sup.cyt = 0.004 [109] K.sub.m.sup.grap.sub.cyt = 0.48 [110] K.sub.m.sup.dhap.sup.cyt = 0.38 [110] Triosephosphate isomerase (Tpi) [00171] v t ? i = ? m ax t ? i .Math. d h a p c y t - grap cyt K eq tpi 1 + d h a p c y t K m d ? a p c y 𝔱 + gra p c y t K m g r a p c y t v.sub.max.sup.tpi for numerical value see Table 10 K.sub.eq.sup.tpi = 0.04545 [108] K.sub.m.sup.dhap.sup.cyt = 0.58 [111] K.sub.m.sup.grap.sup.cyt = 0.4 [11] D-Glyceraldehyde-3-phosphate:NAD.sup.+ oxidoreductase (Gapdh) [00172] v gap dh = v m ax Gap dh * nad cyt .Math. grap cyt .Math. p cyt - 1 K eq gapdh .Math. bpg 13 cyt .Math. nadh cyt ( 1 + nad cyt K m nad cyt ) .Math. ( 1 + grap cyt K m grap cyt ) .Math. ( 1 + p cyt K m p cyt ) + ( 1 + nadh cyt K m nadh cyt ) .Math. ( 1 + bpg 13 cyt K m bpg 13 cyt ) - 1 v.sub.max.sup.Gapdh for numerical value see Table 10 K.sub.eq.sup.gapdh = 10.sup.?4 mM.sup.?1 [112] K.sub.m.sup.nad.sup.cyt = 0.09 [113] K.sub.m.sup.grap.sup.cyt = 0.044 [114] K.sub.m.sup.p.sup.cyt = 3.8 [115] K.sub.m.sup.nadh.sup.cyt = 0.006 [115] K.sub.m.sup.bpg13.sup.cyt = 0.01 [113] Phosphoglycerate kinase (Pgk) [00173] v pgk = v m ax pgk .Math. adp cyt .Math. bpg 13 cyt - 1 K eq pgk .Math. atp cyt .Math. pg 3 cyt ( 1 + adp cyt K m adp cyt ) .Math. ( 1 + bgp 13 cyt K m bpg 13 cyt ) + ( 1 + atp cyt K m atp cyt ) .Math. ( 1 + pg 3 cyt K m pg 3 cyt ) - 1 v.sub.max.sup.pgk for numerical value see Table 10 K.sub.eq.sup.pgk = 1830 [116] K.sub.m.sup.adp.sup.cyt = 0.35 [117] K.sub.m.sup.bpg13.sup.cyt 0.0022 [117] K.sub.m.sup.atp.sup.cyt = 0.151 [118] K.sub.m.sup.pg3.sup.cyt = 1.397 [118] 2-Phospho-D-glycerate 2,3 phosphomutase (Pgm) [00174] v p g m = v m ax pgm .Math. p g 3 c y t - 1 K e q p g m p g 2 c y t p g 3 c y t + K m pg 3 c ? t .Math. ( 1 + p g 2 cy t K m pg 2 ) v.sub.max.sup.pgm for numerical value see Table 10 K.sub.eq.sup.pgm = 0.1725 [119] K.sub.m.sup.pg3.sup.cyt = 0.52 [120] K.sub.m.sup.pg2 = 0.24 [120] 2-Phospho-D-glycerate hydrolase (Eno) [00175] v e n o = ? m ax e n o .Math. p g 2 c y t - 1 K e q en o .Math. pep c y t 1 + p g 2 c y t K m p g 2 c y t + p e p c y t K m p e p cyt v.sub.max.sup.eno for numerical value see Table 10 K.sub.eq.sup.eno = 1.7 [121] K.sub.m.sup.pg2.sup.cyt = 0.12 [122] K.sub.m.sup.pep.sup.cyt = 0.37 [122] Pyruvate kinase (Pk) [00176] v p k = v ma x P k p e p c y t p e p c y t + K m p e p cyt .Math. .Math. a d p c y t a d p c y t + K m a d p c y t v.sub.max.sup.pk for numerical value see Table 10 K.sub.m.sup.pep.sup.cyt = 0.08 [123] K.sub.m.sup.adp.sup.cyt = 0.3 [123] Pyruvate carboxylase [00177] v p c = ? m ax P c .Math. a t p m i t o .Math. pyr m i t o ( a t p m i t o + k m a t p m i t o ) .Math. ( pyr m i t o + k m p y r mito ) v.sub.max.sup.Pc for numerical value see Table 10 K.sub.m.sup.atp.sup.mito = 0.14 [124] K.sub.m.sup.pyr.sup.mito = 0.33 [124] Lactate dehydrogenase (Ldh): [00178] v l d h = ? m ax l d ? * p y r c y t .Math. nadh c y t - 1 K e q l d h .Math. lac c y t .Math. nad c y t ( 1 + n a d h c y t K m nadh cyt ) .Math. ( 1 + p y r c y t K m p y r c y t ) + ( 1 + l a c c y t K m l a c c y t ) .Math. ( 1 + n a d c y t K m n a d cyt ) - 1 v.sub.max.sup.ldh for numerical value see Table 10 K.sub.eq.sup.ldh = 9000 [125] K.sub.m.sup.nadh.sup.cyt = 0.0121 [126] K.sub.m.sup.pyr.sup.cyt = 0.1 [127] K.sub.m.sup.lac.sup.cyt = 4.4 [126] K.sub.m.sup.nad.sup.cyt = 0.1 [126] Lactate transport (LacT): [00179] v lacT = v m ax lacT .Math. l a c e x t - lac cyt 1 + l a c c y t K m l a c c y t + lac e x t K m lac e x t v.sub.max.sup.lacT for numerical value see Table 10 K.sub.m.sup.lac.sup.cyt = 2.5 [128] K.sub.m.sup.lac.sup.ext = 2.5 [128] Pyruvate transport (PyrT): [00180] v lacT = v m ax p y r T .Math. p y r e x t - pyr cyt 1 + p y r c y t K m p y r c y 𝔱 + pyr e x t K m p y r e x t v.sub.max.sup.pyrT for numerical value see Table 10 K.sub.m.sup.pyr.sup.ext = 0.1 [128] K.sub.m.sup.pyr.sup.cyt = 0.1 [128] Mitochondrial pyruvate transport: [00181] v pyrT mito = v m ax p y r T mito .Math. p y r c y t .Math. h c y t - p y r m i t o .Math. h m i t o 1 + p y r c y t K m p y r c y t + p y r m i t o K m p y r m i t o v.sub.max.sup.PyrT.sup.mito for numerical value see Table 10 K.sub.m.sup.pyr.sup.cyt = 0.15 [129] K.sub.m.sup.pyr.sup.mito = 0.15 [129] Mitochondrial malate-phosphate transport [00182] v m a l p T = v m ax m a l p T .Math. ( mal m i t o .Math. p cyt - mal cyt .Math. p mito ( 1 + mal m i t o K m mal mito ) .Math. ( 1 + p c y t K m p c y t ) + ( 1 + m a l c y t K m mal c y t ) .Math. ( 1 + p m i t o K m p mito ) - 1 ) v.sub.max.sup.malpT for numerical value see Table 10 K.sub.m.sup.p.sup.cyt = 1.41 [130] K.sub.m.sup.mal.sup.mito = 0.4 [131] K.sub.m.sup.p.sup.mito = 1.41 [130] K.sub.m.sup.mal.sup.cyt = 0.4 [131] Malate-pyruvate antiport (MalPyrT) [00183] v m a l - p y r T = v ma x mal - pyrT * ( mal m i t o .Math. pyr c y t - m a l c y t .Math. p?r mito ( 1 + mal m i t o K m m a l mito ) .Math. ( 1 + p y r c y t K m pyr c y t ) + ( 1 + m a l c y t K m m a l c y t ) .Math. ( 1 + p y r m i t o K m p y r m i t o ) - 1 ) v.sub.max.sup.MalPyrT for numerical value see Table 10 K.sub.m.sup.pyr.sup.cyt = 0.84 [132] K.sub.m.sup.mal.sup.cyt = 0.7 [133] K.sub.m.sup.pyr.sup.mito = 0.84 [132] K.sub.m.sup.mal.sup.cyt = 0.7 [133] Cytosolic malate dehydrogenase (Mdh) [00184] v m d ? = ? m ax M d h .Math. mal cyt .Math. nad cyt - 1 K eq mdh cyt .Math. oaa cyt .Math. nadh cyt ( 1 + m a l c y t K m m a l c y 𝔱 ) .Math. ( 1 + n a d c y t K m n a d c y t ) + ( 1 + o a a cyt K m oaa cyt ) .Math. ( 1 + n a d h cyt K m n a d h c y t ) - 1 v.sub.max.sup.Mdh for numerical value see Table 10 K.sub.eq.sup.mdh.sup.cyt = 10.sup.?5 [72] K.sub.m.sup.mal.sup.cyt = 0.47 [134] K.sub.m.sup.nad.sup.cyt = 0.099 [134] K.sub.m.sup.oaa.sup.cyt = 0.042 [134] K.sub.m.sup.nadh.sup.cyt = 0.027 [134] NADP-dependent malic enzyme (cytosol) [00185] v m e = V m ax m e .Math. ( m a l c y t .Math. nadp cyt - 1 / K eq me .Math. pyr cyt .Math. nadph cyt .Math. hco 3 cyt ( 1 + m a l c y t K m m a l c y t ) .Math. ( 1 + n a d p c y t K m n a d p c y t ) + ( 1 + p y r c y t K m p y r c y t ) .Math. ( 1 + n a d p h c y t K m nadph c y t ) .Math. ( 1 + h c o 3 c y t K m h c o 3 c y t ) ) V.sub.max.sup.me for numerical value see Table 10 K.sub.eq.sup.me = 34.4 [135] K.sub.m.sup.mal.sup.cyt = 0.12 [136] K.sub.m.sup.nadp.sup.cyt = 0.0092 [136] K.sub.m.sup.pyr.sup.cyt = 8 [137] K.sub.m.sup.nadph.sup.cyt = 0.0053 [136] K.sub.m.sup.hco3.sup.cyt = 13 [137] Nucleoside diphosphokinase (cytosolic) [00186] v n d k cyt = V ma x ndk c y t .Math. ( atp cyt .Math. gdp cyt - 1 / K e q n d k .Math. adp c y t .Math. gtp c y t ( 1 + a t p c y t K m atp c y t ) .Math. ( 1 + g d p c y t K m gdp c y t ) + ( 1 + a d p c y t K m a d p c y t ) .Math. ( 1 + g t p c y t K m g t p c y t ) - 1 ) V.sub.max.sup.ndk.sup.cyt for numerical value see Table 10 K.sub.eq.sup.ndk = 1 [66] K.sub.m.sup.atp.sup.cyt = 1.8 [138] K.sub.m.sup.gdp.sup.cyt = 0.049 [138] K.sub.m.sup.adp.sup.cyt = 0.066 [138] K.sub.m.sup.gtp.sup.cyt = 0.15 [138] Nucleoside diphosphokinase (mito) [00187] v n d k m i t o = V ma x ndk mito .Math. ( atp mito .Math. gdp mito - 1 / K e q ndk .Math. adp m i t o .Math. gtp mito ( 1 + atp m i t o K m a t p m i t o ) .Math. ( 1 + g d p m i t o K m g t p m i t o ) + ( 1 + a d p m i t o K m adp m i t o ) .Math. ( 1 + g t p m i t o K m gtp mito ) - 1 ) v.sub.max.sup.ndk.sup.mito for numerical value see Table 10 K.sub.eq.sup.ndk = 1 [66] K.sub.m.sup.atp.sup.mito = 1.66 [139] K.sub.m.sup.gdp.sup.mito = 0.036 [139] K.sub.m.sup.adp.sup.mito = 0.073 [139] K.sub.m.sup.gtp.sup.mito = 0.15 [138] Glycogen metabolism Alpha-D-Glucose 1-phosphate 1,6-phosphomutase: [00188] v gpm = v m ax gpm .Math. g l c 1 p c y t - 1 K e q g p m .Math. glc 6 p c y t 1 + g l c 1 p c y t K m glc 1 p cyt + g l c 6 p c y t K m glc 6 p c y t v.sub.max.sup.gpm for numerical value see Table 10 K.sub.eq.sup.gpm = 16.2 [140] K.sub.mg.sup.lc1p.sup.cyt = 0.045 [141] Km.sup.glc6p.sup.cyt = 0.67 [141] UTP:Glucose-1-phosphate uridylyltransferase (UPGase): [00189] v u p g a s e = v m ax upgase .Math. utp cyt .Math. glc 1 p cyt - 1 K eq upgase .Math. udpglc cyt .Math. pp cyt ( 1 + u t p c y t K m u t p cyt ) .Math. ( 1 + g l c 1 p c y t K m glc 1 p c y t ) + ( 1 + u d p g l c c y t K m udphlc cyt ) .Math. ( 1 + p p c y t K m pp c y t ) - 1 v.sub.max.sup.UPGase for numerical value see Table 10 K.sub.eq.sup.upgase = 0.3122 [142] K.sub.m.sup.utp.sup.cyt = 0.2 [142] K.sub.m.sup.glc1p.sup.cyt = 0.055 [142] K.sub.m.sup.udpglc.sup.cyt = 0.06 [142] K.sub.m.sup.pp.sup.cyt = 0.084 [142] Glycogen synthase (GS): v.sub.gs = V.sub.max.sup.gs .Math. ((1 ? ?.sup.gs) .Math. v.sub.gs.sup.native + ?.sup.gs .Math. v.sub.gs.sup.p) [00190] ? gs = 1 - ? .Math. ( 1 - epi e x t e p i e x t + K i epi ) K i e p i = 200 pM V m ax gs = V 0 gs ( store - glyglc ) ( store - glyglc ) + 10 mM V.sub.0.sup.gs for numerical value see Table 10 Geben Sie hier eine Formel ein. store = 5 mM [00191] v g s n a t i v e = ( u d p g l c c y t u d p g l c c y t + K m - n a t i v e udpglc cyt ) .Math. ( glc 6 p c y t g l c 6 p c y t + K a g l c 6 p c y t ) [00192] K m - n a t i ? e udpglc c y t = K 0 - n a t i ? e u d p g l c c y t .Math. ( 1 - g l c 6 p c y t glc 6 p c y t + K a 2 glc 6 p c y t ) + K b - n a t i v e udpglc cyt K.sub.0-native.sup.udpglc.sup.cyt = 0.9 [143] K.sub.a.sup.glc6p.sup.cyt = 0.004 [143] K.sub.a2.sup.glc6p.sup.cyt = 0.004 [143] K.sub.b-native.sup.udpglc.sup.cyt = 0.2 [143] [00193] v gs p = ( u d p g l c c y t u d p g l c c y t + K m - p udpglc cyt ) .Math. ( g l c 6 p c y t g l c 6 p c y t + K a g l c 6 p c y t ) K.sub.m-p.sup.udpglc.sup.cyt = K.sub.0-p.sup.udpglc.sup.cyt K.sub.0-p.sup.udpglc.sup.cyt = 0.9 [143] K.sub.a.sup.glc6p.sub.cyt =2 [143] Glycogen phosphorylase (GP): v.sub.gp = ((1 ? ?.sup.gp) .Math. v.sub.gp.sup.native + ?.sup.gp .Math. v.sub.gp.sup.p) Y.sup.gp = y.sup.gs [00194] v gp n a t i v e = V m ax gp - native .Math. glyglc .Math. p cyt - 1 K eq gp .Math. glc 1 p cyt ( 1 + glyglc K m - n a t i ? e glycogen ) .Math. ( 1 + p c y t K m - n a t i ? e p c y t ) + ( 1 + g l c 1 p c y t K m - n a t i v e glc 1 p c y t ) - 1 [00195] V m ax - n a t i v e gp = V 0 g p K m - n a t i ? e p c y t .Math. K m - native glyplc .Math. ( a m p c y t a m p c y t + K a - n a t i v e amp cyt ) .Math. ( g l y g l c g l y g l c + 0.1 .Math. store ) V.sub.0.sup.gp for numerical value see Table 10 store = 5 mM K.sub.a-native.sup.amp = 0.0022 [144] K.sub.eq.sup.gp = 0.21(mM).sup.?1 [145] K.sub.m-native.sup.glyglc = 2.5 [146] K.sub.m-native.sup.p.sup.cyt = 500 [146] [00196] K m - n a t i ? e g l c 1 p c y t = K 0 g l c 1 p .Math. ( 1 - a m p c y t a m p c y t + K a - glc 1 p a m p c y t ) K 0 glc 1 p = 2 5 0 [ 1 4 6 ] K a - glc1p a m p c y t = 0.5 [ 146 ] [00197] v gp p = V ma x - p gp .Math. glyglc .Math. p c y t - 1 K e q g p .Math. glc 1 p c y t ( 1 + glyglc K m - p glycogen ) .Math. ( 1 + p c y t K m - p p c y t ) + ( 1 + g l c 1 p c y t K m - p glc 1 p cyt ) - 1 [00198] V ma x - p gp = V 0 g p K m - p p .Math. K m - p glyglc .Math. ( k 1 + a m p c y t a m p c y t + K a - p a m p c y t ) .Math. ( g l y g l c g l y g l c + 0.1 .Math. store ) k.sub.1 = 0.5 [144] K.sub.a-native.sup.amp = 0.22 [144] K.sub.m-p.sup.glyglc = 0.27 [144] K.sub.m-p.sup.p.sup.cyt = 3.8 [144] K.sub.m-p.sup.glc1p.sup.cyt = 0.7 [146] Nucleoside diphosphokinase (cytosolic) (udp) [00199] v ndk cyt = V m ax ndk cyt .Math. ( a t p c y t .Math. udp cyt - 1 / K eq ndk .Math. adp cyt .Math. utp cyt ( 1 + a t p c y t K m a t p c y t ) .Math. ( 1 + u d p c y t K m udp c y t ) + ( 1 + a d p c y t K m adp c y t ) .Math. ( 1 + u t p c y t K m u t p c y t ) - 1 ) V.sub.max.sup.ndk.sup.cyt for numerical value see Table 10 K.sub.eq.sup.ndk = 1 [66] K.sub.m.sup.atp.sup.cyt = 0.5 [147] Kmudpcyt = 0.05 [147] K.sub.m.sup.adp.sup.cyt = 0.07 [147] K.sub.m.sup.utp.sup.cyt = 0.15 [147] Malate-Aspartate shuttle Aspartate-amino transferase (mitochondrial) [00200] v asat mito = V m ax a s a t .Math. ( a s p m i t o .Math. akg m i t o - 1 / K eq asat .Math. oaa m i t o .Math. glu m i t o ( 1 + a s p m i t o K m a s p m i t o ) .Math. ( 1 + a k g m i t o K m a k g m i t o ) + ( 1 + o a a m i t o K m o a a mito ) .Math. ( 1 + g l u m i t o K m glu m i t o ) - 1 ) V.sub.max.sup.asatfor numerical value see Table 10 K.sub.eq.sup.asat = 0.147 [148] K.sub.m.sup.asp.sup.mito = 0.35 [149] K.sub.m.sup.akg.sup.mito = 1.1 [149] K.sub.m.sup.oaa.sup.mito = 1.84 [150] K.sub.m.sup.glu.sup.mito = 0.48 [150] Aspartate-amino transferase (cytosolic) [00201] v a s a t = V ma x a s a t .Math. ( a s p c y t .Math. akg cyt - 1 / K eq asat .Math. oaa cyt .Math. glu cyt ( 1 + a s p c y t K m a s p c y t ) .Math. ( 1 + a k g c y t K m akg cyt ) + ( 1 + o a a c y t K m o a a c y t ) .Math. ( 1 + g l u cyt K m g l u c y t ) - 1 ) V.sub.max.sup.asat for numerical value see Table 10 K.sub.eq.sup.asat = 0.147 [148] K.sub.m.sup.asp.sup.cyt = 3.9 [149] K.sub.m.sup.akg.sup.cyt = 0.57 [149] K.sub.m.sup.oaa.sup.cyt = 2.05 [150] K.sub.m.sup.glu.sup.cyt = 0.38 [150] Aspartate-glutamate carrier [00202] v agc = V ma x agc .Math. ( a s p m i t o .Math. glu cyt - 1 / K eq agc .Math. asp cyt .Math. glu mito ( 1 + a s p m i t o K m asp mi𝔱o ) .Math. ( 1 + g l u c y t K m glu c y t ) + ( 1 + a s p c y t K m asp c y t ) .Math. ( 1 + g l u m i t o K m g l u mito ) - 1 ) V.sub.max.sup.asatfor numerical value see Table 10 [00203] K e q a s a t = exp ( - V m m .Math. F R .Math. T ) .Math. ( H cyt H mito ) K m asp mito = K 0 asp mito .Math. ( 1 + glu mito K i glu mito ) [00204] K 0 asp mito = 0.05 [ 151 ] K i glu mito = 0.5 [ 152 ] K m asp cyt = K 0 asp cyt .Math. ( 1 + glu cyt K i glu cyt ) K.sub.0.sup.asp.sup.cyt = 0.043 [152] K.sub.i.sup.glu.sup.cyt = 0.5 [152] K.sub.m.sup.glu.sup.mito = 3 [153] K.sub.m.sup.glu.sup.cyt = 3.2 [153] Malate - ?-ketogluterate carrier [00205] v m a c = V m ax m a c .Math. ( m a l c y t .Math. akg mito - 1 / K eq mac .Math. mal mito .Math. akg cyt ( 1 + m a l c y t K m m a l c y t ) .Math. ( 1 + a k g m i t o K m akg mito ) + ( 1 + m a l m i t o K m mal mito ) .Math. ( 1 + a k g c y t K m a k g c y t ) - 1 ) V.sub.max.sup.mac for numerical value see Table 10 K.sub.eq.sup.mac = 1 K.sub.m.sup.mal.sup.cyt = 0.7 [154] K.sub.m.sup.akg.sup.mito = 0.17 [154] K.sub.m.sup.mal.sup.mito = 1.4 [154] K.sub.m.sup.akg.sup.cyt = 0.3 [154] Glycerol-3-phosphate dehydrogenase (cytosolic) [00206] v g3pdh = V m ax g 3 pdh cyt .Math. ( dhap cyt .Math. nad cyt - 1 / K eq g 3 pdh .Math. g 3 p cyt .Math. nad cyt ( 1 + d h a p c y t K m dhap c y t ) .Math. ( 1 + n a d h c y t K m nadh cyt ) + ( 1 + g 3 p c y t K m g 3 p c y 𝔱 ) .Math. ( 1 + n a d c y t K m n a d c y t ) - 1 ) V.sub.max.sup.g3pdh.sup.cyt for numerical value see Table 10 [00207] K e q g 3 pdh cyt = 1 3 .Math. 10 - 4 [ 155 ] K.sub.m.sup.dhap.sup.cyt = 0.2 [156] K.sub.m.sup.nadh.sup.cyt = 0.1 [156] K.sub.m.sup.g3p.sup.cyt = 0.17 [156] K.sup.mnad.sup.cyt = 0.063 [156] Glycerol-3-phosphate dehydrogenase (mitochondrial) [00208] v g 3 pdh mito = y m ax g3pdh mito .Math. ( d h a p c y t .Math. qh 2 m m - 1 / K eq g 3 pdh .Math. g 3 p cyt .Math. q m m ( 1 + d h a p c y t K m d h a p c y t ) + ( 1 + g 3 p c y t K m g 3 p c y t ) - 1 ) V.sub.max.sup.g3pdh.sup.mito for numerical value see Table 10 [00209] K eq g 3 pdh mito = K eq g 3 p dh cyt .Math. exp ( ( n .Math. E 0 nad / nadh + n .Math. E 0 QH 2 / Q ) .Math. F R .Math. T ) K.sub.m.sup.dhap.sup.cyt = 0.23 [157] K.sub.m.sup.g3p.sup.cyt = 1.8 [158] E.sub.0.sup.nad/nadh = ?320 mV [82] E.sub.0.sup.QH2/Q = ?87 mV [41] n = 2 Pentose phosphate shunt Glucose-6-phosphate dehydrogenase [00210] v g 6 pdh = V m ax g 6 pdh .Math. ( ( glc 6 p cyt glc 6 p cyt + K m glc 6 cyt .Math. ( 1 + c 16 coa cyt K i c 16 coa cyt ) ) .Math. ( n a d p c y t n a d p c y t + K m nadp cyt .Math. ( 1 + n a d p h c y t K i nadph c y t ) ) ) V.sub.max.sup.g6pdh for numerical value see Table 10 K.sub.mglc6p.sup.cyt = 0.013 [159] K.sub.ic16coa.sup.cyt = 0.029 [160] K.sub.m.sup.nadp.sup.cyt = 0.013 [159] K.sub.i.sup.nadph.sup.cyt = 0.01 [161] 6-Phosphogluconolactase [00211] v pgls = V ma x ? gls .Math. ( pgl 6 cyt pgl 6 c y t + K m p g l 6 c y t ) V.sub.max.sup.pglsfor numerical value see Table 10 K.sub.m.sup.pg16.sup.cyt = 0.7 [162] 6-Phosphogluconate dehydrogenase [00212] v p g d h = V ma x pgdh .Math. ( nadp cyt .Math. pg 6 cyt - 1 / K eq pgdh .Math. ru 5 p cyt .Math. nadph cyt ( 1 + n a d p c y t K m n a d p c y 𝔱 .Math. ( 1 + n a d p h c y t K i n a d p h c y t ) ) .Math. ( 1 + p g 6 c y t K m pg 6 cyt ) + ( 1 + r u 5 p c y t K m r u 5 p c y t ) .Math. ( 1 + c o 2 c y t K m c o 2 c y 𝔱 ) .Math. ( 1 + n a d p h c y t K m nadph c y t ) - 1 ) V.sub.max.sup.pgdh for numerical value see Table 10 K.sub.eq.sup.pgdh = 74 [163] K.sub.m.sup.nadp.sup.cyt = 0.028 [159] K.sub.i.sup.nadph = 0.02 [164] K.sub.m.sup.pg6.sup.cyt = 0.071 [164] K.sub.m.sup.co2.sup.cyt = 5 [165] K.sub.m.sup.nadph.sup.cyt = 0.001 [165] K.sub.m.sup.ru5p.sup.cyt = 0.123 [165] Ribulose-phosphate-3-epimerase [00213] ? r p e = V m ax r p e .Math. ( ru 5 p cyt - 1 / K eq rpe .Math. x 5 p cyt 1 + r u 5 p c y t K m r u 5 p c ? t + x 5 p c y t K m x 5 p c y t ) V.sub.max.sup.rpe for numerical value see Table 10 K.sub.eq.sup.rpe = 1.5 [166] K.sub.m.sup.ru5p.sup.cyt = 0.2 [167] K.sub.m.sup.x5p.sup.cyt = 0.5 Ribose-phosphate-isomerase [00214] v r p i = V m ax r p i .Math. ( r 5 p cyt - 1 / K eq rpi .Math. ru 5 p cyt 1 + r 5 p c y t K m r 5 p c y t + r u 5 p c y t K m r u 5 p c y t ) V.sub.max.sup.rpi for numerical value see Table 10 K.sub.eq.sup.rpi = 0.32 [168] K.sub.m.sup.r5p.sup.cyt = 9.1 [169] K.sub.m.sup.ru5p.sup.cyt = 0.78 [169] Transladolase [00215] v taldo = V ma x taldo .Math. ( s 7 p c y t .Math. grap cyt - 1 / K eq taldo .Math. e 4 p cyt .Math. fru 6 p cyt ( 1 + s 7 p c y t K m s 7 p c y 𝔱 ) .Math. ( 1 + g r a p c y t K m g r a p c y t ) + ( 1 + e 4 p c y t K m e 4 ? cyt ) .Math. ( 1 + f r u 6 p c y t K m f r u 6 p c y t ) - 1 ) V.sub.max.sup.tado for numerical value see Table 10 K.sub.eq.sup.taldo = 0.95 [170] K.sub.m.sup.s7p.sup.cyt = 0.17 [170] K.sub.m.sup.grap.sup.cyt = 0.038 [171] K.sub.m.sup.e4p.sup.cyt = 0.13 [172] K.sub.m.sup.fru6p.sup.cyt = 0.3 [172] Transketolase 1 [00216] v t k e t o 1 = V m ax tketo 1 .Math. ( s 7 p c y t .Math. grap c y t - 1 / K e q t k e t o 1 .Math. r 5 p c y t .Math. x 5 p c y t ( 1 + s 7 p c y t K m s 7 p c y t ) .Math. ( 1 + g r a p c y t K m grap cyt ) + ( 1 + r 5 p c y t K m r 5 p cyt ) .Math. ( 1 + x 5 p c y t K m x 5 p c y t ) .Math. - 1 ) V.sub.max.sup.tketo1 for numerical value see Table 10 K.sub.eq.sup.tketo1 = 0.845 [173] K.sub.m.sup.s7p.sup.cyt = 0.285 [171] K.sub.m.sup.grap.sup.cyt = 0.38 [171] K.sub.m.sup.r5p.sup.cyt = 0.066 [174] K.sub.m.sup.x5p.sup.cyt = 0.15 [175] Transketolase 2 [00217] v t k e t o 2 = V m ax t k e t o 1 .Math. ( f r u 6 p c y t .Math. grap cyt - 1 / K e q t k e t o 2 .Math. e 4 p c y t .Math. x5p c y t ( 1 + f r u 6 p c y t K m f r u 6 p c y t ) .Math. ( 1 + g r a p c y t K m grap c y t ) + ( 1 + e 4 p c y t K m e 4 p c y t ) .Math. ( 1 + x 5 p c y t K m x 5 p c y t ) .Math. - 1 ) V.sub.max.sup.tketo2 for numerical value see Table 10 K.sub.eq.sup.tketo2 = 0.084 [173] K.sub.m.sup.fru6p.sup.cyt = 0.34 [176] K.sub.m.sup.grap.sup.cyt = 0.38 [171] K.sub.m.sup.e4p.sup.cyt = 0.044 [177] K.sub.m.sup.x5p.sup.cyt = 0.16 [177] Fatty acid synthesis Citrate-malate exchanger [00218] ? c i t - m a l = V ma x c i t - m a l K m c i t m i t o .Math. K m m a l cyt .Math. ( c i t m i t o .Math. mal cyt - 1 / K eq cit - mal .Math. cit cyt .Math. mal mito ( 1 + c i t m i t o K m c i t m i t o ) .Math. ( 1 + m a l c y t K m mal cyt ) + ( 1 + c i t c y t K m c i t c y t ) .Math. ( 1 + m a l m i t o K m mal mito ) .Math. - 1 ) [00219] V ma x cit - mal = V 0 c i t - mal .Math. ( 1 - ( c 1 6 c o a c y t ) n ( c 1 6 c o a c y t ) n + ( K i c 1 6 c o a c y t ) n ) V.sub.0.sup.cit-mal for numerical value see Table 10 K.sub.i.sup.c16coa.sup.cyt = 0.033 [178] n = 3 [178] K.sub.eq.sup.cit-mal = 1 [00220] K m c i t m i t o = K 0 c i t mito .Math. ( 1 + s u c m i t o K i s u c mito ) .Math. ( 1 + i s o c i t m i t o K i i s o c i t mito ) .Math. ( 1 + p e p m i t o K i p e p mito ) K.sub.0.sup.cit.sup.mito = 0.14 [179] K.sub.i.sup.suc.sup.mito = 2.5 [179] K.sub.i.sup.isocit.sup.mito = 0.08 [179] K.sub.i.sup.pep.sup.mito = 0.18 [179] [00221] K m m a l c y t = 0 . 7 6 [ 179 ] K m c i t c y t = K 0 c i t c y t .Math. ( 1 + p e p c y t K i p e p c y t ) K.sub.0.sup.cit.sup.cyt = 0.039 [180] K.sub.i.sup.pep.sup.cyt = 0.18 [179] K.sub.m.sup.mal.sup.mito = 0.76 [179] ATP dependent citrate lyase v.sub.cit-lys = V.sub.max.sup.cit-lys .Math. ((1 ? ?.sup.cit-lys) .Math. v.sup.cit-lysnative + ?.sup.cit-lys .Math. v.sub.cit-lys.sup.phospho) ?.sup.cit-lys = ? V.sub.max.sup.cit-lys for numerical value see Table 10 [00222] v c i t - l y s n a t i v e = c i t c y t n c i t c y t n + ( K m c i t c y t ) n .Math. c o a c y t c o a c y t + K m c o a c y t .Math. a t p c y t a t p c y t + K m atp cyt K.sub.m.sup.cit.sup.cyt = 0.154 [181] n = 0.65 [181] K.sub.m.sup.coa.sup.cyt = 0.0026 [181] K.sub.m.sup.atp.sup.cyt = 0.041 [181] [00223] v c i t - l y s phospho = c i t c y t n c i t c y t n + ( K m c i t c y t ) n .Math. c o a c y t c o a c y t + K m c o a c y t .Math. a t p c y t a t p c y t + K m a t p cyt K.sub.m.sup.cit.sup.cyt = 0.103 [181] n = 0.91 [181] K.sub.m.sup.coa.sup.cyt = 0.002 [181] K.sub.m.sup.atp.sup.cyt = 0.041 [181] Acetyl-CoA carboxylase 1 v.sub.acc1 = ? .Math. v.sub.acc1-p + (1 ? ?) .Math. v.sub.acc1-up [00224] ? a c c 1 - p = V m ax a c c 1 - p .Math. ( a t p c y t a t p c y t + K m atp cyt ) .Math. ( a c o a c y t a c o a c y t + K m a c o a c y t ) .Math. ( h c o 3 c y t h c o 3 c y t + K m h c o 3 c y t ) [00225] V m ax a c c 1 - p = V a c c 1 - p .Math. ( c i t c y t c i t c y t + K a c i t c y t ) .Math. ( 1 - malcoa c y t m a l c o a c y t + K i malcoa c y t ) .Math. ( 1 - c 1 6 c o a c y t c 1 6 c o a c y t + K i c 1 6 c o a c y t ) V.sub.acc1-p for numerical value see Table 10 K.sub.i.sup.c16coa.sup.cyt = 0.0022 [182] K.sub.a.sup.cit.sup.cyt = 2.3 [183] K.sub.i.sup.malcoa.sup.cyt = 0.0106 [182] K.sub.m.sup.atp.sup.cyt = 0.057 [182] K.sub.m.sup.acoa.sup.cyt 0.18 [183 K.sub.m.sup.hco3.sup.cyt = 2.25 [1.82] [00226] v a c c 1 - u p = V ma x acc 1 - up .Math. ( a t p c y t a t p c y t + K m a t p c y t ) .Math. ( a c o a c y t a c o a c y t + K m acoa c y t ) .Math. ( h c o 3 c y t h c o 3 c y t + K m h c o 3 c y t ) [00227] V m ax a cc1 - up = V a c c 1 - u p .Math. ( 1 + n u p c i t c y t c i t c y t + K a c i t c y t ) .Math. ( 1 - m a l c o a c y t malcoa c y t + K i m a l c o a c y t ) V.sub.acc1-up = 2.5 .Math. V.sub.acc1-p [184] n.sub.up = 1.4 [184] K.sub.a.sup.cit.sup.cyt = 0.8 [184] K.sub.m.sup.atp.sup.cyt = 0.057 [182] K.sub.m.sup.acoa.sup.cyt = 0.18 [183] K.sub.i.sup.malcoa.sup.cyt = 0.0106 [182] K.sub.m.sup.hco3.sub.cyt = 2.25 [182] Malonyl-CoA decarboxylase [00228] v m c d c = V ma x mcdc .Math. ( m a l c o a c y t m a l c o a c y t + K m m a l c o a cyt ) K m malcoa c y t = 0.04 [ 185 ] Acetyl-CoA hydrolase [00229] v a c o a h = V ma x a c o a h .Math. ( a c o a c y t a c o a c y t + K m a c o a c y t ) K m a c o a c y t = 0.153 [ 186 ] TAG synthesis Glycerol-uptake [00230] v glycT = V m a x glycT .Math. ( glyc ext - glyc cyt 1 + glyc ext K m glyc ext + glyc cyt K m glyc cyt ) V.sub.max.sup.glycT for numerical value see Table 10 K.sub.m.sup.glyc.sup.ext = 0.012 [187] K.sub.m.sup.glyc.sup.cyt = 0.012 [187] Glycerol kinase [00231] v glycK = V m a x glycK .Math. ( glyc cyt glyc cyt + K m glyc cyt .Math. ( 1 + g 3 p cyt K i g 3 p cyt ) ) .Math. ( atp cyt atp cyt + K m atp cyt ) V.sub.max.sup.glycK or numerical value see Table 10 K.sub.m.sup.glyc.sup.cyt = 0.003 [188] K.sub.i.sup.g3p.sup.cyt = 0.58 [188] K.sub.m.sup.ATP.sup.cyt = 0.058 [188] Glycerophosphate acyltransferase [00232] v gpat = V m a x gpat .Math. ( g 3 p cyt g 3 p cyt + K m g 3 p cyt ) .Math. ( c 16 coa cyt c 16 coa cyt + K m c 16 coa cyt ) V.sub.max.sup.gpat for numerical value see Table 10 K.sub.m.sup.g3p.sup.cyt = 0.67 [189] K.sub.m.sup.c16coa.sup.cyt = 0.02 [189] Acetyl glycerol-3-phosphate acyltransferase [00233] v agpat = V m a x agpat .Math. ( lpa er lpa er + K m lpa er ) .Math. ( c 16 coa cyt c 16 coa cyt + K m c 16 coa cyt ) V.sub.max.sup.agpat for numerical value see Table 10 K.sub.m.sup.lpa.sup.er = 0.0065 [190] K.sub.m.sup.c16coa.sup.cyt = 0.004 [190] Phosphatidic acid phosphatase [00234] v pap = V m a x pap .Math. ( pa er n pa er n + K m pa er ) n ) V.sub.max.sup.pap for numerical value see Table 10 K.sub.m.sup.pa.sup.er = 0.35 [191] n = 2.2 [191] Diacylglycerol acyltransferase [00235] v dgat = V m a x dgat .Math. ( d a g er d a g er + K m d a g er ) .Math. ( c 16 coa cyt c 16 coa cyt + K m c 16 coa cyt ) V.sub.max.sup.dgat for numerical value see Table 10 K.sub.m.sup.dag.sup.cyt = 0.03 [192] K.sub.m.sup.c16coa.sup.cyt = 0.1 [193] ATGL [194] [00236] v ATGL tag = V m a x - tag ATGL .Math. Sur ld .Math. ? .Math. ( tag ld tag ld + K m tag ld ) V.sub.max-tag.sup.ATGL for numerical value see Table 10 [00237] K m tag ld = 10 Sur ld = ( tag ld + 2 3 .Math. dag ld + 1 3 .Math. mag ld + 2 3 ce ld ) 2 3 Hormone sensitive lipase (HSL) (dag) [195] [00238] v HSL tag = V m a x - tag HSL .Math. Sur ld .Math. ? .Math. ( d a g ld d a g ld + K m d a g ld ) V.sub.max-tag.sup.HSL for numerical value see Table 10 [00239] K m d a g ld = 10 Sur ld = ( tag ld + 2 3 .Math. d a g ld + 1 3 .Math. mag ld + 2 3 ce ld ) 2 3 Monoaclyglycerol lipase [00240] v magl = V m a x magl .Math. Sur ld .Math. ( mag ld mag ld + K m mag ld ) V.sub.max.sup.magl for numerical value see Table 10 [00241] K m mag ld = 0.51 [ 196 ] Sur ld = ( tag ld + 2 3 .Math. d a g ld + 1 3 .Math. mag ld + 2 3 ce ld ) 2 3 Cholesterol ester esterase [00242] v cee = V m a x cee .Math. Sur ld .Math. ? .Math. ( ce ld ce ld + K m ce ld ) V.sub.max.sup.cee for numerical value see Table 10 [00243] K m ce ld = 5 Sur ld = ( tag ld + 2 3 .Math. d a g ld + 1 3 .Math. mag ld + 2 3 ce ld ) 2 3 Ketone body utilization B-Hydroxy butyrate dehydrogenase [00244] v ? hdh = V m a x ? hdh .Math. ? ( acac mito .Math. nadh mito - 1 K eq ? hdh .Math. bhbut mito .Math. nad mito ( 1 + acac mito K m mito acac ) .Math. ( 1 + nadh mito K m nadh mito ) + ( 1 + bhbut mito K m bhbut mito ) .Math. ( 1 + nad mito K m nad mito ) - 1 ) V.sub.max.sup.?hdh for numerical value see Table 10 [00245] K eq ? hdh = 20.3 .Math. h mito h cyt [ 125 ] K m acac mito = 0.204 [ 197 ] K m nadh mito = K 0 nadh mito .Math. ( 1 + nad mito K i nad mito ) K.sub.0.sup.nadh.sup.mito = 0.017 [197] K.sup.i.sub.nad.sup.mito 0.121 [197] K.sub.m.sup.hbut.sup.mito = 1.604 [197] [00246] K m nad mito = K 0 nad mito .Math. ( 1 + nadh mito K i nadh mito ) K 0 nad mito = 0.067 [ 197 ] K i nadh mito = 0.066 [ 197 ] Succinyl-CoA-oxaloacid CoA transferase [00247] v scot = V m a x scot .Math. ( acac mito .Math. succoa mito - 1 K eq scot .Math. kc 4 coa mito .Math. succ mito ( 1 + acac mito K m mito acac ) .Math. ( 1 + succoa mito K m succoa mito ) + ( 1 + kc 4 coa mito K m kc 4 coa mito ) .Math. ( 1 + succ mito K m succ mito ) - 1 ) V.sub.max.sup.scot for numerical value see Table 10 [00248] K m mito acac = 0.44 [ 198 ] K m succoa mito = K 0 succoa mito .Math. ( 1 + succ mito K i succ mito ) [00249] K 0 succoa mito = 0.28 [ 198 ] K i succ mito = 0.72 [ 198 ] K m kc 4 coa mito = K 0 kc 4 coa mito .Math. ( 1 + acac mito K i acac mito ) K.sub.0.sup.kc4coa.sup.mito = 0.44 [198] K.sub.i.sup.acac.sup.mito = 3.7 [198] K.sub.m.sup.succ.sup.mito = 34 [198] Acetoacetate transport (mitochondrial) [00250] v acacT = V m a x acacT .Math. ( acac mito acac mito + K m acac mito ) V.sub.max.sup.acacT for numerical value see Table 10 K.sub.m.sup.acac.sup.mito = 0.56 [199] B-Hydroxy butyrate transport (mitochondrial) [00251] v ? hbT = V m a x ? hbT .Math. ( bhbut mito bhbut mito + K m bhbut mito ) V.sub.max.sup.?hbt for numerical value see Table 10 K.sub.m.sup.bhbut.sup.mito = 0.8 [200] Acetoacetate export (MCT1/MCT2) [00252] v acac - ex = V m a x acac - ex .Math. ( acac ext - acac cyt 1 + acac cyt K m acac cyt + acac ext K m acac ext ) V.sub.max.sup.acac-ex for numerical value see Table 10 K.sub.m.sup.acac.sup.cyt = 1.2 [200] K.sub.m.sup.acac.sup.ext = 1.2 [200] B-Hydroxy butyrate export (MCT1/MCT2) [00253] v ? hb - ex = V m a x ? hb - ex .Math. ( bhbut ext - bhbut cyt 1 + bhbut cyt K m bhbut cyt + bhbut ext K m bhbut ext ) V.sub.max.sup.?hb-ex for numerical value see Table 10 K.sub.m.sup.bhbut.sup.cyt = 0.8 [200] K.sub.m.sup.bhbut.sup.ext 0.8 [200] Branched chain amino acid metabolism Valine transport [00254] v valT = V m a x valT .Math. ( val ext - val cyt 1 + val ext K m val ext + val cyt K m val cyt ) V.sub.max.sup.valT for numerical value see Table 10 K.sub.m.sup.val.sup.ext = 0.124 [201] K.sub.m.sup.val.sup.cyt = 0.124 [201] Leucine transport [00255] v leuT = V m a x leuT .Math. ( leu ext - leu cyt 1 + leu ext K m leu ext + leu cyt K m leu cyt ) V.sub.max.sup.leuT for numerical value see Table 10 K.sub.m.sup.leu.sup.ext = 0.119 [201] K.sub.m.sup.leu.sup.cyt = 0.119 [201] Isoleucine transport [00256] v isoleuT = V m a x isoleuT .Math. ( isoleu ext - isoleu cyt 1 + isoleu ext K m isoleu ext + isoleu cyt K m isoleu cyt ) V.sub.max.sup.isoleuT for numerical value see Table 10 K.sub.m.sup.isoleu.sup.ext = 0.0967 [201] K.sub.m.sup.isoleu.sup.cyt = 0.0967 [201] Branched chain amino acid aminotransferase valine [00257] v BCAAT - val = V m a x BCAAT - val .Math. ( val cyt .Math. akg cyt - 1 K eq BCAAT - val .Math. aKIVA cyt .Math. glu cyt ( 1 + val cyt K m val cyt ) .Math. ( 1 + akg cyt K m akg cyt ) + ( 1 + aKIVA cyt K m aKIVA cyt ) .Math. ( 1 + glu cyt K m glu cyt ) - 1 ) V.sub.max.sup.BCAAT-val for numerical value see Table 10 K.sub.eq.sup.BCAAT-val = 1 K.sub.m.sup.val.sup.cyt = 0.62 [202] [00258] K m akg cyt = 0.63 [ 203 ] K m aKIVA cyt = K 0 aKIVA cyt .Math. ( 1 + aKICA cyt K i aKICA cyt ) .Math. ( 1 + KMeVA cyt K i KMeVA cyt ) K.sub.0.sup.aKIVA.sup.cyt = 0.11 [204] K.sub.i.sup.aKICA.sup.cyt = 2.1 [204] K.sub.i.sup.KMeVA.sup.cyt = 1.57 [204] K.sub.m.sup.glu.sup.cyt = 3.6 [203] Branched chain amino acid aminotransferase leucine [00259] v BCAAT - leu = V m a x BCAAT - leu .Math. ( leu cyt .Math. akg cyt - 1 K eq BCAAT - leu .Math. aKICA cyt .Math. glu cyt ( 1 + leu cyt K m leu cyt ) .Math. ( 1 + akg cyt K m akg cyt ) + ( 1 + aKICA cyt K m aKICA cyt ) .Math. ( 1 + glu cyt K m glu cyt ) - 1 ) V.sub.max.sup.BCAAT-leu for numerical value see Table 10 K.sub.eq.sup.BCAAT-leu = 1.75 [205] K.sub.m.sup.leu.sup.cyt = 3.8 [203] K.sub.m.sup.akg.sup.cyt = 0.63 [203] [00260] K m aKIVA cyt = K 0 aKIVA cyt .Math. ( 1 + aKICA cyt K i aKICA cyt ) .Math. ( 1 + KMeVA cyt K i KMeVA cyt ) K.sub.0.sup.aKICA.sup.cyt = 0.14 [204] K.sub.i.sup.aKICA.sup.cyt = 4.19 [204] K.sub.i.sup.KMeVA.sup.cyt = 1.57 [204] K.sub.m.sup.glu.sup.cyt = 6.65 [203] Branched chain amino acid aminotransferase isoleucine [00261] v BCAAT - isoleu = V m a x BCAAT - isoleu .Math. ( isoleu cyt .Math. akg cyt - 1 K eq BCAAT - leu .Math. KMeVA cyt .Math. glu cyt ( 1 + isoleu cyt K m isoleu cyt ) .Math. ( 1 + akg cyt K m akg cyt ) + ( 1 + KMeVA cyt K m KMeVA cyt ) .Math. ( 1 + glu cyt K m glu cyt ) - 1 ) V.sub.max.sup.BCAAT-isoleu for numerical value see Table 10 K.sub.eq.sup.BCAAT-isoleu = K.sub.m.sup.isoleu.sup.cyt = 3.8 [203] [00262] K m akg cyt = 0.63 [ 203 ] K m KMeVA cyt = K 0 KMeVA cyt .Math. ( 1 + aKICA cyt K i aKICA cyt ) .Math. ( 1 + aKIVA cyt K i aKICV cyt ) K.sub.0.sup.KMeVA.sup.cyt = 0.07 [204] K.sub.i.sup.aKIVA.sup.cyt 4.19 [204] K.sub.i.sup.aKICA.sup.cyt 2.1 [204] K.sub.m.sup.glu.sup.cyt = 2.45 [203] A-ketoisovalerate transport (mitochondrial) [00263] v aKIVAT mito = V m a x aKIVAT mito .Math. ( aKIVA cyt - aKIVA mito aKIVA cyt + K m aKIVA cyt ) V.sub.max.sup.aKIVAT.sup.mito for numerical value see Table 10 K.sub.m.sup.aKIVA.sup.cyt = 0.025 [206] A-ketoisocaproate transport (mitochondrial) [00264] v aKICAT mito = V m a x aKICAT mito .Math. ( aKICA cyt - aKICA mito aKICA cyt + K m aKICA cyt ) V.sub.max.sup.aKICAT mito for numerical value see Table 10 K.sub.m.sup.aKICA.sup.cyt = 0.01 [206] A-ketomethylvalerate transport (mitochondrial) [00265] v KMeVAT mito = V m a x KMeVAT mito .Math. ( KMeVA cyt - KMeVA mito KMeVA cyt + K m KMeVA cyt ) V.sub.max.sup.KMeVAT.sup.mito for numerical value see Table 10 K.sub.m.sup.KMeVA.sup.cyt = 0.01 Branched chain keto-amino acid dehydrogenase (aKIVA) [00266] v bckadh - aKIVA = V m a x bckadh - aKIVA .Math. ( aKIVA mito aKIVA mito + K m aKIVA mito ) .Math. ( nad mito nad mito + K m nad mito ) .Math. ( coa mito coa mito + K m coa mito ) V.sub.max.sup.bckadh-aKIVA for numerical value see Table 10 K.sub.m.sup.aKIVA.sup.mito = 0.05 [207] K.sub.m.sup.nad.sup.mito = 0.04 [208] K.sub.m.sup.coa.sup.mito = 0.01 [208] Branched chain keto-amino acid dehydrogenase (aKIVA) [00267] v bckadh - aKICA = V m a x bckadh - aKICA .Math. ( aKICA mito aKICA mito + K m aKICA mito ) .Math. ( nad mito nad mito + K m nad mito ) .Math. ( coa mito coa mito + K m coa mito ) V.sub.max.sup.bckadh-aKICA for numerical value see Table 10 K.sub.m.sup.aKICA.sup.mito = 0.038 [209] K.sub.m.sup.nad.sup.mito = 0.04 [208] K.sub.m.sup.coa.sup.mito = 0.01 [208] Branched chain keto-amino acid dehydrogenase (aKIVA) [00268] v bckadh - KMeVA = V m a x bckadh - KMeVA .Math. ( KMeVA mito aKICA mito + K m aKICA mito ) .Math. ( nad mito nad mito + K m nad mito ) .Math. ( coa mito coa mito + K m coa mito ) V.sub.max.sup.bckadh-KMeVA for numerical value see Table 10 K.sub.m.sup.KMeVAmito = 0.035 [210] K.sub.m.sup.nad.sup.mito = 0.04 [208] K.sub.m.sup.coa.sup.mito = 0.01 [208] 2-methylacyl-CoA dehydrogenase (isobutyryl-CoA) [00269] v MBCoADH - IsoButCoA = V m a x MBCoADH .Math. ( IsoButCoA mito IsoButCoA mito + K m IsoButCoA mito ) .Math. ( etffad mito etffad mito + K m etffad mito ) V.sub.max.sup.MBCoADH for numerical value see Table 10 K.sub.m.sup.IsoButCoA.sup.mito = 0.013 [211] K.sup.etffad.sup.mito = 0.0083 [19] 2-methylacyl-CoA dehydrogenase (methylbutyryl-CoA) [00270] v MBCoADH - MeButCoA = V m a x MBCoADH .Math. ( MeButCoA mito MeButCoA mito + K m MeButCoA mito ) .Math. ( etffad mito etffad mito + K m etffad mito ) V.sub.max.sup.MBCoADH for numerical value see Table 10 K.sub.m.sup.MeButCoA.sup.mito = 0.027 [211] K.sub.m.sup.etffad.sup.mito = 0.0083 [19] Enoyl-CoA hydratase (methyl acrylyl CoA) [00271] v ECoAH - MeAcrCoA = V m a x ECoAH - MeACrCoA .Math. ( MeAcrCoA mito MeAcrCoA mito + K m MeAcrCoA mito ) V.sub.max.sup.ECoAH-MeACrCoA for numerical value see Table 10 K.sub.m.sup.MeAcrCoA.sup.mito = 0.001 [211] Enoyl-CoA hydratase (Tiglyl CoA) [00272] v ECoAH - TigCoA = V m a x ECoAH - TigCoA .Math. ( TigCoA mito TigCoA mito + K m TigCoA mito ) V.sub.max.sup.ECoAH-TigCoA for numerical value see Table 10 K.sub.m.sup.TigCoA.sup.mito = 0.0047 [211] 3-hydroxyisobutyryl-CoA hydrolase [00273] v HibCoAhyd = V m a x HibCoAhyd .Math. ( HibCoA mito HibCoA mito + K m HibCoA mito ) V.sub.max.sup.HibCoAhyd for numerical value see Table 10 K.sub.m.sup.HibCoA.sup.mito = 0.006 [212] 3-hydroxyisobutyrate dehydrogenase [00274] v HibDh = V m a x HibDh .Math. ( Hib mito Hib mito + K m Hib mito ) .Math. ( nad mito nad mito + K m nad mito ) V.sub.max.sup.HibDh for numerical value see Table 10 [00275] K m Hib mito = 0.061 [ 213 ] K m nad mito = K 0 nad mito .Math. ( 1 + nadh mito K i nadh mito ) K.sub.0.sup.nadh.sup.mito = 0.023 [213] K.sub.i.sup.nadh.sup.mito = 0.0057 [213] Methylmalonate-semialdehyde dehydrogenase [00276] v mmsdh = V m a x mmsd .Math. ( mmsald mito mmsald mito + K m mmsald mito ) .Math. ( nad mito nad mito + K m nad mito ) .Math. ( coa mito coa mito + K m coa mito ) V.sub.max.sup.mmsd for numerical value see Table 10 K.sub.m.sup.mmsald.sup.mito = 0.0053 [214] K.sub.m.sup.nad.sup.mito = 0.15 [214] K.sub.m.sup.coa.sup.mito = 0.03 [214] 3-hydroxy-2-methylbutyryl-CoA dehydrogenase [00277] v HMBCDH = V m a x HMBCDH .Math. ( MeHButCoA mito MeHButCoA mito + K m MeHButCoA mito ) .Math. ( nad mito nad mito + K m nad mito ) V.sub.max.sup.HMBCDH for numerical value see Table 10 K.sub.m.sup.MeHButCoA.sup.mito = 0.005 [215] K.sub.m.sup.nad.sup.mito = 0.01 [215] acetyl-CoA C-acyltransferase [00278] v MAACT = V m a x MAACT .Math. ( MeAACoA mito MeAACoA mito + K m MeAACoA mito ) .Math. ( coa mito coa mito + K m coa mito ) V.sub.max.sup.MAACT for numerical value see Table 10 K.sub.m.sup.MeAACoA.sup.mito = 0.008 [216] K.sub.m.sup.coa.sup.mito = 0.02 [216] isovaleryl-CoA dehydrogenase [00279] v IVCoADh = V m a x IVCoADh .Math. ( IsoValCoA mito IsoValCoA mito + K m IsoValCoA mito ) .Math. ( etffad mito etffad mito + K m etffad mito ) V.sub.max.sup.IVCoADh for numerical value see Table 10 K.sub.m.sup.IsoValCoA.sup.mito = 0.014 [217] K.sub.m.sup.etffad.sup.mito = 0.0083 [19] Methylcrotonoyl-CoA carboxylase [00280] v MECCC = V m a x MECCC .Math. ( MeCroCoA mito MeCroCoA mito + K m MeCroCoA mito ) .Math. ( atp mito atp mito + K m atp mito ) V.sub.max.sup.MECCC for numerical value see Table 10 K.sub.m.sup.MeCroCoA.sup.mito = 0.0747 [218] K.sub.m.sup.atp.sup.mito = 0.045 [218] Methylglutaconyl-CoA hydratase [00281] v MEGCCH = V m a x MEGCCH .Math. ( MeGCCoA mito MeGCCoA mito + K m MeGCCoA mito ) V.sub.max.sup.MEGCCH for numerical value see Table 10 K.sub.m.sup.MeGCCoA.sup.mito = 0.0083 [219] Hydroxymethylglutaryl-CoA lyase [00282] v HMGCL = V m a x HMGCL .Math. ( HMeGCoA mito HMeGCoA mito + K m HMeGCoA mito ) V.sub.max.sup.HMGCL for numerical value see Table 10 K.sub.m.sup.HMeGCoA.sup.mito = 0.0448 [220] Propionyl-CoA carboxylase [00283] v PCC = V m a x PCC .Math. ( ProCoA mito ProCoA mito + K m ProCoA mito ) .Math. ( atp mito atp mito + K m atp mito ) V.sub.max.sup.PCC for numerical value see Table 10 K.sub.m.sup.ProCoA.sup.mito = 0.2 [221] K.sub.m.sup.atp.sup.mito = 0.08 [222] Methylmalonyl-CoA mutase [00284] v MMCM = V m a x MMCM .Math. ( MeMalCoA mito MeMalCoA mito + K m MeMalCoA mito ) V.sub.max.sup.MMCM for numerical value see Table 10 K.sub.m.sup.MeMalCoA.sup.mito = 0.133 [223] Glutamate transport [00285] v gluT mito = V m a x gluT mito .Math. ( glu cyt .Math. h cyt - glu mito .Math. h mito 1 + glu cyt K m glu cyt + glu mito K m glu mito ) V.sub.max.sup.gluT.sup.mito for numerical value see Table 10 K.sub.m.sup.glu.sup.cyt = 5 [224] K.sub.m.sup.glu.sup.mito = 0.25 [225] Glutamate dehydrogenase (nad-dependent) [00286] v gdh = V m a x gdh .Math. ( glu mito .Math. nad mito - 1 K eq gdh .Math. akg mito .Math. nadh mito .Math. nh 3 mito ( 1 + glu mito K m glu mito ) .Math. ( 1 + nad mito K m nad mito ) + ( 1 + akg mito K m akg mito ) ( 1 + nadh mito K m nadh mito ) .Math. ( 1 + nh 3 mito K m nh 3 mito ) ) [00287] V m a x gdh = V 0 gdh .Math. ( 1 - c 16 coa mito c 16 coa mito + K i c 16 coa mito ) .Math. ( A 0 + ( 1 - A 0 ) ( 1 - mal mito mal mito + K i mal mito ) ) .Math. V.sub.0.sup.gdh for numerical value see Table 10 K.sub.i.sup.c16coa.sup.mito = 0.0001 [226] A.sub.0 = 0.7 [226] K.sub.i.sup.mal.sup.mito = 2 [226] K.sub.eq.sup.gdh = 0.00387 mM [125] [00288] K m glu mito = K 0 glu mito .Math. ( 1 + akg mito K i akg mito ) .Math. ( 1 + nh 3 mito K i nh 3 mito ) K.sub.0.sup.glu.sup.mito = 4.61 [227] K.sub.i.sup.akg.sup.mito = 1.49 [228] K.sub.i.sup.nh3.sup.mito = 3.1 [228] [00289] K m nad mito = K 0 nad mito .Math. ( 1 + nadh mito K i nadh mito ) K 0 nad mito = 0.364 [ 227 ] K.sub.i.sup.nadh.sup.mito = 0.0086 [228] K.sub.m.sup.akg.sup.mito = 0.18 [229] K.sub.m.sup.nadh.sup.mito = 0.03 [229] K.sub.m.sup.nh3.sup.mito = 20 [229] Stoichiometric matrix: [00290] d dt acac cyt = + Vol mito Vol cyt .Math. v acacT + v acac - ex d dt acac ext = 0 [00291] d dt acac mito = - v scot - v ? hdh - v acacT + v HMGCL d dt acetate cyt = + v acoah + v aceT [00292] d dt acoa cyt = + v cit - lys - v acc 1 + v mcdc + v acoah + v HMGCL + v MAACT [00293] d dt acoa mito = + 2 .Math. v 3 kt kc 4 coa + 2 .Math. v 3 ktII kc 4 coa + v 3 kt kc 6 coa + v 3 kt kc 8 coa + v 3 kt kc 10 coa + v 3 kt kc 12 coa + v 3 kt kc 14 coa + v 3 kt kc 16 coa + v pdhc - v cs [00294] d dt adp cyt = - v nex 10 .Math. F .Math. Vol cyt + v ndk cyt + 2 .Math. v ak cyt + v atp - usage + v hka + v hkb + v ndk cyt udp + v pfk 2 - v pfk1 - v pgk - v p k + v cit - lys + v acc 1 + v glycK [00295] d dt adp mito = - v scs - atp - v F 0 F 1 10 .Math. F .Math. Vol mito + v nex 10 .Math. F .Math. Vol mito + v ndk mito + v pc + v PCC + v MECCC [00296] d dt akg cyt = - v asat + v mac - v BCAAT - val - v BCAAT - leu - v BCAAT - isoleu [00297] d dt akg mito = + v idh nad + v idh nadp - v kgdhc - v asat mito - Vol cyt Vol mito .Math. v mac + v gdh [00298] d dt aKICA cyt = + v BCAAT - val - v aKICAT [00299] d d t aKICA m i t o = + v aKICAT .Math. V o l m i t o V o l c y t - v b c k a d h - aKICA [00300] d dt aKIVA cyt = + v BCAAT - leu - v aKIVAT [00301] d dt aKIVA m i t o = + v aKIVAT .Math. V o l mito V o l c y 𝔱 - v bckadh - aKIVA [00302] d dt amp cyt = + v ACS 1 + v FAB 1 + v FAB 4 - v ak cyt [00303] d d t a s p cyt = - v a s a t + v agc [00304] d dt asp mito = - v asat mito - Vol cyt Vol er .Math. v agc [00305] d dt atp cyt = - v ACS 1 - v FAB 1 - v FAB 4 + v nex 10 .Math. F .Math. Vol cyt - v ndk cyt - v atp - usage - v hka - v hkb - v pfk 2 - v pfk 1 + v pgk + v p k - v ndk cyt udp - v cit - lys - v acc 1 - v glycK - v ak cyt [00306] d d t a t p m i t o = + v s c s - a t p + v F 0 F 1 10 .Math. F .Math. Vol m i t o - ? n e x 10 .Math. F .Math. Vol m i t o - v ndk mito - v p c - v P C C - v M E C C C [00307] d d t b h b u t c y t = + V o l m i t o Vol c y t .Math. v ? h b T + v ? h b - e x [00308] d d t b h b u t e x t = 0 [00309] d d t b h b u t m i t o = + v ? h a h - v ? h b T [00310] d d t b p g 1 3 cyt = + v gapdh - v p g k [00311] d d t c 1 0 c o a mito = - v C 1 0 c o a - mcdh - v c 1 0 coa - lcdh + v 3 k t k c 1 2 c o a [00312] d d t c 1 2 c o a m i t o = - v c 12 coa - mcdh - v c 1 2 coa - lcdh + v 3 k t k c 1 4 c o a [00313] d d t c 1 4 c o a m i t o = - v c 1 4 c o a - l c d h + v 3 k t k c 1 6 c o a [00314] d d t c 1 6 c a r c y t = + v C P T 1 - v C A C T [00315] d d t c 1 6 c a r m i t o = + V o l c y t V o l mito .Math. v CACT - v C P T 2 [00316] d d t c 1 6 c o a c y 𝔱 = + v A C S 1 + v FATP 1 + v FATP 4 - v CPT 1 - v gpat - v a g p a t - v d g a t [00317] d d t c 1 6 c o a m i t o = + v C P T 2 - v c 16 coa - lcdh [00318] d d t c 1 6 e x t = 0 [00319] d d t c 1 6 c y t = + v C D 3 6 - v A C S 1 - v F A T P 1 - v F A T P 4 + V o l l d V o l c y t .Math. v H S L dag + V o l ld V o l c y t .Math. v A T G L t a g + Vol ld Vol cyt .Math. v magl [00320] d d t c 4 c o a mito = - v c 4 c o a - scdh + v 3 k t k c 6 c o a [00321] d d t c 6 c o a m i t o = - v c 6 c o a - m c d h + v 3 k t k c 8 c o a [00322] d d t c 8 c o a m i t o = - v c 8 coa - mcdh + v 3 k t k c 1 0 c o a [00323] d d t c a r c ? t = - v C P T 1 + v CACT [00324] d d t c a r m i t o = - V o l c y t Vol mito .Math. v C A C T + v C P T 2 [00325] d d t c i t c y t = + V o l mito Vol cyt .Math. v cit - mal - v cit - lys [00326] d d t c i t m i t o = + v c s - v a c - v cit - mal [00327] d d t cl c y t = 0 [00328] d d t c l m i t o = + I cI ed 10 .Math. F .Math. Vol mito [00329] a d t c o a c y t = - v F A B P 1 - v F A B P 4 - v A C S 1 + v C P T 1 - v cit - lys + v acoah + v gpat + v agpat + v dgat [00330] d dt coa mito = - v CPT 2 - v 3 kt kc 4 coa - v 3 ktII kc 4 coa - v 3 kt kc 6 coa - v 3 kt kc 8 coa - v 3 kt kc 10 coa - v 3 kt kc 12 coa - v 3 kt kc 14 coa - v 3 kt kc 16 coa - v pdhc + v cs - v kgdhc + v scs - atp + v scs - gtp - v bckadh - aKICA - v bckadh - aKIVA - v bckadh - KNeVA - v HibDh - v mmsdg - v MMACT [00331] d dt c o 2 c y t = 0 [00332] d d t c o 2 m i t o = 0 [00333] d d t c y t c o x m m = - 2 .Math. v cxIII 10 .Math. F .Math. Vol membrane + ? cxIV 10 .Math. F .Math. Vol m e m b r a n e [00334] d d t c y t c red m m = + 2 .Math. v cxIII 10 .Math. F .Math. Vol m e m b r a n e - v cxIV 10 .Math. F .Math. Vol m e m b r a n e [00335] d d t dag e r = + V o l c y t Vol e r .Math. v p a p - V o l c y t Vol e r .Math. v d g a t [00336] d d t d a g ld = + v A T G L t a g - v HSL dag [00337] d d t d h a p c y t = + v ald - v t p i - v g 3 pdh - v g 3 pd h m i t o [00338] d d t e c 1 0 c o a m i t o = + v c 1 0 c o a - m c d h + v c 10 coa - lcdh - v ehyd - ec 10 [00339] d d t ec 12 coa m i t o = + v c 12 coa - m c d h + v c 12 coa - lcdh - v ehyd - ec 12 [00340] d d t e c 1 4 c o a m i t o = + v c 14 coa - lcdh - v e hyd - ec 14 [00341] d d t e c 1 6 c o a m i t o = + v c 1 6 coa - lcdh - v e h y d - e c 1 6 [00342] d d t e c 4 c o a m i t o = + v c 4 coa - scdh - v ehyd - ec 4 [00343] d d t e c 6 c o a mito = + v c 6 coa - v ehyd - ec 6 [00344] d dt e c 8 c o a m i t o = + v c 8 coa - mcdh - v ehyd - ec 8 [00345] d d t e 4 p c y t = + v taldo + v t k e t o 2 [00346] d dt etffad mito = - v c 4 coa - scdh - v c 6 coa - mcdh - v c 8 coa - mcdh - v c 10 coa - mcdh - v c 12 coa - mcdh - v c 10 coa - lcdh - v c 12 coa - lcdh - v c 14 coa - lcdh - v c 16 coa - lcdh + v ETF - FAD - v MBCoADH - IsoButCoA - v M B C o A D H - MeButCoA - v IVCoADh [00347] d dt etffadh 2 mito = + v c 4 coa - scdh + v c 6 coa - mcdh + v c 8 coa - mcdh + v c 10 coa - mcdh + v c 12 coa - mcdh + v c 10 coa - lcdh + v c 12 coa - lcdh + v c 14 coa - lcdh + v c 16 coa - lcdh - v ETF - FAD + v MBCoADH - IsoButCoA + v M B C o A D H - MeButCoA + v IVCoADh [00348] d d t e t f q m i t o = - v ETF - FAD + v E T F - QO [00349] d d t e t f q h 2 m i t o = + v E T F - F F D - v E T F - Q O [00350] d d t fru 16 bp c y t = + v p f k 1 - v f b p 1 - v ald [00351] d d t f r u 2 6 b p c y t = + v pfk 2 - v f b p 2 [00352] d d t f r u 6 p c y t = + v gpi - v p f k 2 + v f b p 2 - v p f k 1 + v f b p 1 + v t a l d o - v t k e t o 2 [00353] d d t f u m m i t o = + v s u c c d h - v f u m [00354] d d t g 3 p c y t = + v g 3 pdh + v g 3 pd h m i t o + v glycK - v gpat [00355] d d t g d p c y t = - v ndk c y 𝔱 + v pepck [00356] d d t g d p mito = - v scs - gtp - v ndk mito [00357] d d t g l c c y t = + v gluT 1 + v gluT 4 - v h k A - v h k B [00358] d d t glc e x t = 0 [00359] d d t g l c 1 p c y t = - v gpm - v u p g a s e + v gp [00360] d d t g l c 6 p c y t = + v h k A + v hkB - v g p i + v g p m - v g 6 pdh [00361] d dt glu cyt = + v asat - v agc - v gluT mito + v BCAAT - val + v BCAAT - leu + v BCAAT - isoleu [00362] d d t g l u e x t = 0 [00363] d d t g l u m i t o = + v a s a t mito + V o l c y t V o l m i t o .Math. v a g c - v g d h + V o l c y t V o l m i t o .Math. v gluT mito [00364] d dt glyc cyt = + v glycT - v glycK + Vol ld Vol cyt .Math. v magl [00365] d d t glyc e x t = 0 [00366] d dt glyglc = + v gs - v gp [00367] d d t g r a e x t = 0 [00368] d d t g r a p c y t = + v ald + v t p i - v gapdh - v taldo - v tketo 1 - v t k e t o 2 [00369] d dt gtp cyt = + v ndk cyt - v pepck [00370] d d t g t p mito = + v scs - gtp + v n d k m i t o [00371] d d t h c y 𝔱 = 0 [00372] d d t h m i t o = + - I H pump + I H ed + v P - ex - I k p u m p - I n a p u m ? + 3 .Math. v F 0 F 1 10 .Math. F .Math. Vol mito [00373] d d t h c o 3 c y t = 0 d dt h c o 3 m i t o = 0 d dt h i b m i t o = + v H i b C o A h y d - v H i b D h [00374] d d t H i b C o A m i t o = + v ECoAH - MeAcrCoA - v H i b C o A h y d 1 d t H M e G C o A m i t o = + v M E G C C H - v H M G C L [00375] d dt IsoButCoA m i t o = + v bckadhh - aKIVA - v M B C oADH - IsoButCoA [00376] d d t i s o l e u c y t = + v i s o l e u T - v B CAAT - isoleu [00377] d dt isoleu ext = 0 [00378] d dt isocit mito = + v ac - v idh nad - v idh nadp [00379] d dt IsoValCoA mito = + v bckadh - aKICA - v IVCoADh [00380] d dt kc 10 coa mito = + v 3 hdh - lc 10 - v 3 kt kc 10 coa [00381] d dt kc 12 coa mito = + v 3 hdh - lc 12 - v 3 kt kc 12 coa [00382] d dt kc 14 coa mito = + v 3 hdh - lc 14 - v 3 kt kc 14 coa [00383] d dt kc 16 coa mito = + v 3 hdh - lc 16 - v 3 kt kc 16 coa [00384] d dt kc 4 coa mito = + v 3 hdh - lc 4 - v 3 kt kc 4 coa - v 3 ktII kc 4 coa + v scot [00385] d dt kc 6 coa mito = + v 3 hdh - lc 6 - v 3 kt kc 6 coa [00386] d dt kc 8 coa mito = + v 3 hdh - lc 8 - v 3 kt kc 8 coa [00387] d dt k cyt = 0 [00388] d dt k mito = + I K pump + I k ed 10 .Math. F .Math. Vol mito [00389] d dt KMeVA cyt = + v BCAAT - isoleu - v KMeVAT [00390] d dt KMeVA mito = + v KMeVAT .Math. Vol mito Vol cyt - v bckadh - KMeVA [00391] d dt lc 10 coa mito = + v ehyd - ec 10 - v 3 hdh - lc 10 [00392] d dt lc 12 coa mito = + v ehyd - ec 12 - v 3 hdh - lc 12 [00393] d dt lc 14 coa mito = + v ehyd - ec 14 - v 3 hdh - lc 14 [00394] d dt lc 16 coa mito = + v ehyd - ec 16 - v 3 hdh - lc 16 [00395] d dt lc 4 coa mito = + v ehyd - ec 4 - v 3 hdh - lc 4 [00396] d dt lc 6 coa mito = + v ehyd - ec 6 - v 3 hdh - lc 6 [00397] d dt lc 8 coa mito = + v ehyd - ec 8 - v 3 hdh - lc 8 [00398] d dt lac cyt = + v ldh + v lacT [00399] d dt lac ext = 0 d dt leu cyt = + v leuT - v BCAAT - leu [00400] d dt leu ext = 0 [00401] d dt lpa er = + Vol cyt Vol er .Math. v gpat - Vol cyt Vol er .Math. v agpat [00402] d dt mag ld = - v magl + v HSL dag [00403] d dt mal cyt = + v malpT + v mal - pyrT - v mdh - v mac - Vol mito Vol cyt .Math. v cit - mal - v me [00404] d dt mal mito = + v fum - v mdh mito - Vol cyt Vol mito .Math. v malpT - Vol cyt Vol mito .Math. v mal - pyrT + Vol cyt Vol mito .Math. v mac + v cit - mal [00405] d dt malcoa cyt = + v acc 1 - v mcdc d dt MeAACoA mito = + v HMBCDH - v MAACT [00406] d dt MeAcrCoA mito = + v MBCoADH - IsoButCoA - v ECoAH - MeAcrCoA [00407] d dt MeButCoA mito = + v bckadh - KMeVA - v MBCoADH - MeButCoA [00408] d dt MeCroCoA mito = + v IVCoADh - v MECCC [00409] d dt MeGCCoA mito = + v MECCC - v MEGCCH [00410] d dt MeHButCoA mito = + v ECoAH - TigCoA - v HMBCDH [00411] d dt MeMalCoA mito = + v PCC - v MMCM [00412] d dt mmsald mito = + v HibDh - v mmsdh [00413] d dt na cyt = 0 [00414] d dt na mito = + I na pump + I na ed 10 .Math. F .Math. Vol mito [00415] d dt nad cyt = - v gapdh + v ldh - v mdh + v g 3 pdh [00416] d dt nad mito = - v 3 hdh - lc 4 - v 3 hdh - lc 6 - v 3 hdh - lc 8 - v 3 hdh - lc 10 - v 3 hdh - lc 12 - v 3 hdh - lc 14 - v 3 hdh - lc 16 - v pdhc - v idh nad - v kgdhc - v mdh mito + v tdh + v cxI 10 .Math. F .Math. Vol mito + v ? hdh - v bckadh - aKICA - v bckadh - aKIVA - v bckadh - KMeVa - v HibDh - v mmsdh - v HMBCDH - v gdh [00417] d dt nadh cyt = + v gapdh - v ldh + v mdh [00418] d dt nad mito = + v 3 hdh - lc 4 + v 3 hdh - lc 6 + v 3 hdh - lc 8 + v 3 hdh - lc 10 + v 3 hdh - lc 12 + v 3 hdh - lc 14 + v 3 hdh - lc 16 + v pdhc + v idh nad + v kgdhc + v mdh mito - v tdh - v cxI 10 .Math. F .Math. Vol mito - v ? hdh + v bckadh - aKICA + v bckadh - aKIVA + v bckadh - KMeVa + v HibDh - v mmsdh + v HMBCDH + v gdh [00419] d dt nadp cyt = - v g 6 pdh - v pgdh - v me + v nadph - use [00420] d dt nadp mito = - v tdh - v idh nadp [00421] d dt nadph cyt = + v g 6 pdh + v pgdh + v me - v nadph - use [00422] d dt nadph mito = + v tdh + v idh nadp [00423] d dt o 2 cyt = - 1 4 .Math. v cxIV 10 .Math. F .Math. Vol cyt + v O 2 diff d dt o 2 ext = 0 [00424] d dt oaa cyt = v mdh + v asat + v cit - lys [00425] d dt oaa mito = + v mdh mito + v pc + v asat mito - v cs [00426] d dt p cyt = - v P - ex 10 .Math. F .Math. Vol cyt + 2 .Math. v ppase + v atp - usage + v fbp 2 + v fbp 1 - v gapdh - v malpT - v gp + v cit - lys + v acc 1 + v pap [00427] d dt p mito = - v scs - atp - v scs - gtp - v F 0 F 1 10 .Math. F .Math. Vol mito + v P - ex 10 .Math. F .Math. Vol mito + v pc + Vol cell Vol mito .Math. v malpT + v PCC + v MECCC [00428] d dt pa er = + Vol cyt Vol er .Math. v agpat - Vol cyt Vol er .Math. v pap d dt pep cyt = + v eno - v pk d dt pg 2 cyt = + v pgm - v eno [00429] d dt pg 3 cyt = + v pgk - v pgm d dt pg 6 cyt = + v pgls - v pgdh d dt pgl 6 cyt = + v g 6 pdh - v pgls [00430] d dt pp cyt = + v ACS 1 + v FAB 1 + v FAB 4 - v ppase + v upgase [00431] d dt propcoa mito = + v mmsdh + v MAACT - v PCC [00432] d dt pyr cyt = + v pk - v ldh - v mal - pyrT + v pyrT - v pyrT mito + v me [00433] d dt pyr ext = 0 [00434] d dt pyr mito = - v pdhc - v pc + Vol cell Vol mito .Math. v pyrT + Vol cell Vol mito .Math. v mal - pyrT [00435] d dt q mm = - Vol mito Vol membrane .Math. v ETF - QO - Vol mito Vol membrane .Math. v succdh - v cxI 10 .Math. F .Math. Vol membrane + v cxIII 10 .Math. F .Math. Vol membrane + Vol cyt Vol membrane v g 3 pdh mito [00436] d dt qh 2 mm = + Vol mito Vol membrane .Math. v ETF - QO + Vol mito Vol membrane .Math. v succdh + v cxI 10 .Math. F .Math. Vol membrane - v cxIII 10 .Math. F .Math. Vol membrane - Vol cyt Vol membrane v g 3 pdh mito [00437] d dt r 5 p cyt = - v rpi + v tketo 1 [00438] d dt ru 5 p cyt = + v pgdh - v rpe + v rpi [00439] d dt s 7 p cyt = - v taldo - v tketo 1 [00440] d dt suc mito = + v scs - atp + v scs - gtp - v succdh + v scot [00441] d dt succoa mito = + v kgdhc - v scs - atp - v scs - gtp - v scot + v MMCM [00442] d dt tag er = + Vol cyt Vol er .Math. v dgat - v LD - syn - tag [00443] d dt tag ld = + Vol er Vol ld .Math. v LD - syn - tag - v ATGL tag [00444] d dt TigCoA mito = + v MBCoADH - MeButCoA - v ECoAH - TigCoA [00445] d dt udp cyt = - v ndk cyt udp + v gs [00446] d dt udpglc cyt = + v upgase - v gs [00447] d dt utp cyt = + v ndk cyt udp - v upgase [00448] d dt val cyt = + v valT - v BCAAT - val [00449] d dt val ext = 0 [00450] d dt v mm = 10 - 1 c m .Math. A m .Math. ( - I C ed + I K ed + I H ed + I Na ed + I H pump + v ex + 3 .Math. v syn ) [00451] d dt x 5 p cyt = + v rpe + v tketo 1 + v tketo 2

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TABLE-US-00010 TABLE 9 Metabolite concentrations (Table 9 uses separate reference numbering) Mammalian Modeled Metabolite Location min [mM] max [mM] min [mM] max [mM] References ACoA Acetyl coenzyme A cell <0.01 0.11 0.0061 0.0673 [1-7] Acyl-CoA Acyl coenzyme A cell <0.01 0.11 0.02 0.05 [2, 4, 7] CoA.sub.mito Coenzyme A mito 0.05 2.26 0.0213 1.1477 [8, 9] NAD+ Nicotinamide adenine dinucleotide cell 0.59 1.45 1.13 1.14 [1, 10] NAD+.sub.cyt Nicotinamide adenine dinucleotide cyt 0.51 1.39 1.13 1.13 [11] NAD+.sub.mito Nicotinamide adenine dinucleotide mito 0.19 0.87 0.026 0.05 [9, 11] NADH Reduced nicotinamide adenine dinucleotide cell 0.02 0.36 <0.01 0.0042 [1, 12] NADH.sub.cyt Reduced nicotinamide adenine dinucleotide cyt <0.01 0.01 <0.01 <0.01 [11] NADH.sub.mito Reduced nicotinamide adenine dinucleotide mito 0.05 0.20 <0.01 0.024 [11] P Phosphate cell 2.25 20.50 11.37 21.7 [2, 13-15] P.sub.cyt Phosphate cyt 2.18 7.81 5.45 15.25 [15, 16] AMP Adenosine monophosphate cell 0.07 2.62 0.02 3.89 [2, 10, 17, 18] ADP Adenosine diphosphate cell 0.69 4.49 0.34 2.67 [1, 2, 10, 17-19] ADP.sub.cyt Adenosine diphosphate cyt 0.32 0.93 0.34 2.66 [15] ATP Adenosine triphosphate cell 4.05 28.29 3.28 9.32 [1, 2, 6, 12, 13, 17, 19-25] GDP Guanosine diphosphate cell 0.11 0.21 0.04 0.61 [10] GTP Guanosine triphosphate cell 0.31 0.59 0.47 1.04 [10] Glc6P Glucose 6-phosphate cell 0.10 0.93 0.05 0.34 [2, 27] Fru6P Fructose-6-phosphate cell 0.03 0.23 <0.01 0.08 [2, 17, 27] Fru26P2 Fructose-2,6-bisphosphate cell <0.01 0.01 <0.01 0.01 [17] Fru16P2 Fructose-1,6-bisphosphate cell 0.01 0.13 <0.01 <0.01 [2, 17, 26, 27] DHAP Dihydroxyacetone phosphate cell 0.01 0.14 0.01 0.037 [2, 17] GAP Glyceraldehyde 3-phosphate cell 0.02 0.09 <0.01 0.02 [2, 27] 13BPG 1,3-Bisphosphoglycerate cell <0.01 <0.01 <0.01 <0.01 [26] 3PG 3-Phosphoglycerate cell 0.03 0.57 0.06 0.21 [2, 26, 27] 2PG 2-Phosphoglycerate cell <0.01 0.03 <0.01 0.036 [2, 27] PEP Phosphoenolpyruvate cell 0.01 0.04 0.01 0.01 [2, 26, 27] Pyr Pyruvate cell 0.01 6.00 0.02 1.5 [1, 2, 6, 26, 27] Gly3P Glycerol 3-phosphate cell <0.01 0.25 <0.01 0.09 [2, 26, 27] Glc1P Glucose 1-phosphate cell 0.01 0.16 <0.01 0.02 [2, 26] UDP-Glc Uridine diphosphate glucose cell 0.26 0.72 <0.01 2.1 [2, 16] Cit Citrate cell 0.19 1.42 0.04 0.1 [1, 2, 28] IsoCit Isocitrate cell 0.02 0.07 <0.01 <0.01 [2, 28] aKG Alpha-ketoglutarate cell 0.05 0.29 <0.01 0.05 [1, 2, 28] aKG.sub.mito Alpha-ketoglutarate mito 0.13 0.21 0.02 0.15 [9] Suc Succinate cell 0.26 4.42 <0.01 0.06 [1, 2, 6] Fum Fumarate cell 0.11 0.72 0.5 0.66 [1, 2] Mal Malate cell 0.13 0.49 0.11 0.99 [1, 2, 28] OA Oxaloacetate cell 0.02 0.05 <0.01 0.04 [2] Asp Aspartate cell 3.01 10.78 <0.01 4.74 [2, 28, 29] Gln Glutamine cell 10.38 26.24 10.33 10.33 [30, 31] Glu Glutamate cell 4.63 18.72 <0.01 1.09 [2, 28, 29, 31] IsoLeu Isoleucine cell <0.01 0.23 0.18 0.2 [29-31] Leu Leucine cell 0.07 0.37 0.33 0.39 [29, 30] Val Valine cell 0.23 0.36 0.35 0.4 [29] Acyl-Carn Acylcarnitine cell 0.01 0.94 0.03 0.14 [9, 32] Acyl-Carn.sub.cyt Acylcarnitine cyt 0.03 0.38 0.01 0.08 [8] Acyl-Carn.sub.mito Acylcarnitine mito 0.00 0.22 0.08 0.44 [8] Carn Carnitine cell 0.74 4.24 0.78 0.89 [2, 14, 33] Carn.sub.cyt Carnitine cyt 2.56 2.65 0.32 0.39 [8] Carn.sub.mito Carnitine mito 1.84 2.03 2.66 3.02 [8] TAG Triacylglycerol cell 3.34 9.78 1.4 2.77 [2, 34] DAG Diacyl-glycerol cell 0.03 0.43 0.51 0.51 [2, 34] MalCoA Malonyl coenzyme A cell <0.01 0.02 <0.01 0.01 [3, 5, 7, 35-37] C4CoA Butyryl coenzyme A cell <0.01 0.01 <0.01 <0.01 [38] C6CoA Hexanoyl coenzyme A cell <0.01 0.01 <0.01 <0.01 [39] C8CoA Octanoyl coenzyme A cell <0.01 0.01 <0.01 <0.01 [39] C10CoA Decanoyl coenzyme A cell 0.01 0.02 <0.01 <0.01 [39] C14CoA Myristoyl coenzyme A cell <0.01 <0.01 <0.01 <0.01 [4] C16CoA Palmitoyl coenzyme A cell <0.01 0.01 <0.01 <0.01 [4] References [1.] Sharma, N., et al., Regulation of pyruvate dehydrogenase activity and citric acid cycle intermediates during high cardiac power generation. 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Reinauer, [Influence of heart work and substrate uptake on the regulation of pyruvate dehydrogenase activity in isolated guinea pig hearts (author's transl)]. Pflugers Arch, 1975. 355(1): p. 27-37. [20.] El-Sharkawy, A. M., et al., Quantification of human high-energy phosphate metabolite concentrations at 3 T with partial volume and sensitivity corrections. Nmr in Biomedicine, 2013. 26(11): p. 1363-1371. [21.] Weiss, R. G., G. Gerstenblith, and P. A. Bottomley, ATP flux through creatine kinase in the normal, stressed, and failing human heart. Proceedings of the National Academy of Sciences of the United States of America, 2005. 102(3): p. 808-813. [22.] Smith, C. S., et al., Altered creatine kinase adenosine triphosphate kinetics in failing hypertrophied human myocardium. Circulation, 2006. 114(11): p. 1151-1158. [23.] Bottomley, P. A., et al., Reduced Myocardial Creatine Kinase Flux in Human Myocardial Infarction An In Vivo Phosphorus Magnetic Resonance Spectroscopy Study. 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Wool, Effect of diabetes on the concentration of amino acids in plasma and heart muscle of rats. Biochem J, 1966. 99(1): p. 173-8. [30.] Morgan, H. E., et al., Regulation of protein synthesis in heart muscle. I. Effect of amino acid levels on protein synthesis. J Biol Chem, 1971. 246(7): p. 2152-62. [31.] Morgan, H. E., et al., Regulation of protein synthesis and degradation during in vitro cardiac work. Am J Physiol, 1980. 238(5): p. E431-42. [32.] Whitmer, J. T., et al., Control of fatty acid metabolism in ischemic and hypoxic hearts. J Biol Chem, 1978. 253(12): p. 4305-9. [33.] Cederbla. G, Lindsted. S, and K. Lundholm, Concentration of Carnitine in Human Muscle-Tissue. Clinica Chimica Acta, 1974. 53(3): p. 311-321. [34.] Denton, R. M. and P. J. Randle, Hormonal control of lipid concentration in rat heart and gastrocnemius. Nature, 1965. 208(5009): p. 488. [35.] McGarry, J. D., et al., Observations on the affinity for carnitine, and malonyl-CoA sensitivity, of carnitine palmitoyltransferase I in animal and human tissues. Demonstration of the presence of malonyl-CoA in non-hepatic tissues of the rat. Biochem J, 1983. 214(1): p. 21-8. [36.] Minkler, P. E., et al., Quantification of malonyl-coenzyme A in tissue specimens by high-performance liquid chromatography/mass spectrometry. Anal Biochem, 2006. 352(1): p. 24-32. [37.] Reszko, A. E., et al., Assay of the concentration and 13C-isotopic enrichment of malonyl-coenzyme A by gas chromatography-mass spectrometry. Anal Biochem, 2001. 298(1): p. 69-75. [38.] Li, Q., et al., 4-Hydroxy-2(E)-nonenal (HNE) catabolismand formation of HNE adducts are modulated by beta oxidation of fatty acids in the isolated rat heart. Free Radic Biol Med, 2013. 58: p. 35-44. [39.] Kasuya, F., et al., Analysis of medium-chain acyl-coenzyme A esters in mouse tissues by liquid chromatography-electrospray ionization mass spectrometry. 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TABLE-US-00011 TABLE 10 Estimated V.sub.max values Estimated v.sub.max Short Name Long Name EC/TCDB Number value [?mol/g/h] v_CD36 fatty acid translocase TCDB 4.C.1.1 4.20E+01 v_acs1 (Long-chain) acyl-coa synthetase 1 EC 6.2.1.3 2.80E+00 v_fatp1 fatty acid transport protein 1 TCDB 4.C.1.1 1.04E?01 v_fatp4 fatty acid transport protein 4 TCDB 4.C.1.1 1.35E?01 v_CPT1 Carnitine O-palmitoyltransferase 1, liver isoform EC 2.3.1.21 7.50E-02 v_CACT Carnitin-Acylcarnitin translocase TCDB 2.A.29.8 5.00E+00 v_CPT2 Carnitine O-palmitoyltransferase 2, mitochondrial EC 2.3.1.21 5.00E+01 v_c4coa_scdh Short chain acyl-coa dehydrogenase (c4) EC 1.3.8.1 5.00E+00 v_c6coa_mcdh medium chain acyl-coa dehydrogenase (c6) EC 1.3.8.7 5.25E+01 v_c8coa_mcdh medium chain acyl-coa dehydrogenase (c8) EC 1.3.8.7 6.25E+01 v_c10coa_mcdh medium chain acyl-coa dehydrogenase (c10) EC 1.3.8.7 1.20E+01 v_c12coa_mcdh medium chain acyl-coa dehydrogenase (c12) EC 1.3.8.7 9.75E+00 v_c10coa_lcdh long chain acyl-coa dehydrogenase (c10) EC 1.3.8.8 1.20E+00 v_c12coa_lcdh long chain acyl-coa dehydrogenase (c12) EC 1.3.8.8 9.75E?01 v_c14coa_lcdh long chain acyl-coa dehydrogenase (c14) EC 1.3.8.8 5.25E?01 v_c16coa_lcdh long chain acyl-coa dehydrogenase (c16) EC 1.3.8.8 1.20E?01 v_etf ETF-FAD 2.50E+02 v_etfq ETF-QO 1.25E+03 v_E_hyd_C4_CoA_MC Enoyl-coa hydratase (Crontonase) (ec4) EC 4.2.1.17 2.50E+03 v_E_hyd_C6_CoA_MC Enoyl-coa hydratase (Crontonase) (ec6) EC 4.2.1.17 3.20E+04 v_E_hyd_C8_CoA_MC Enoyl-coa hydratase (Crontonase) (ec8) EC 4.2.1.17 2.28E+04 v_E_hyd_C10_CoA_MC Enoyl-coa hydratase (Crontonase) (ec10) EC 4.2.1.17 1.35E+04 v_E_hyd_C12_CoA_MC Enoyl-coa hydratase (Crontonase) (ec12) EC 4.2.1.17 4.00E+03 v_E_hyd_C14_CoA_MC Enoyl-coa hydratase (Crontonase) (ec14) EC 4.2.1.17 2.17E+03 v_E_hyd_C16_CoA_MC Enoyl-coa hydratase (Crontonase) (ec16) EC 4.2.1.17 1.00E+03 v_3HdH_C4_CoA 3-hydroxyacyl-coa dehydrogenase (Ic4) EC 1.1.1.35 5.75E+10 v_3HdH_C6_CoA 3-hydroxyacyl-coa dehydrogenase (Ic6) EC 1.1.1.35 5.75E+10 v_3HdH_C8_CoA 3-hydroxyacyl-coa dehydrogenase (Ic8) EC 1.1.1.35 5.75E+10 v_3HdH_C10_CoA 3-hydroxyacyl-coa dehydrogenase (Ic10) EC 1.1.1.35 5.75E+10 v_3HdH_C12_CoA 3-hydroxyacyl-coa dehydrogenase (Ic12) EC 1.1.1.35 5.75E+10 v_3HdH_C14_CoA 3-hydroxyacyl-coa dehydrogenase (Ic14) EC 1.1.1.35 5.75E+10 v_3HdH_C16_CoA 3-hydroxyacyl-coa dehydrogenase (Ic16) EC 1.1.1.35 5.75E+10 v_3KT_C4_I 3-ketoacyl-coa thiolase (kc4) EC 2.3.1.16 2.50E+00 v_3KT_C4_II 3-ketoacyl-coa thiolase (kc4) EC 2.3.1.16 2.50E+01 v_3KT_C6 3-ketoacyl-coa thiolase (kc4) EC 2.3.1.16 6.00E+00 v_3KT_C8 3-ketoacyl-coa thiolase (kc4) EC 2.3.1.16 5.50E+00 v_3KT_C10 3-ketoacyl-coa thiolase (kc4) EC 2.3.1.16 5.75E+00 v_3KT_C12 3-ketoacyl-coa thiolase (kc4) EC 2.3.1.16 5.25E+00 v_3KT_C14 3-ketoacyl-coa thiolase (kc4) EC 2.3.1.16 4.25E+00 v_3KT_C16 3-ketoacyl-coa thiolase (kc4) EC 2.3.1.16 2.50E+00 v_pdhc Pyruvate dehydrogenase complex EC 1.2.4.1; EC 1.8.1.4; EC 2.3.1.12 1.00E?01 v_cs Citrate synthase, mitochondrial EC 2.3.3.1 8.00E+01 v_ac Aconitase EC 4.2.1.3 9.00E+04 v_icdh_nad NAD-dependent isocitrate dehydrogenase EC 1.1.1.41 2.70E+01 v_icdh_nadp NADP-dependent isocitrate dehydrogenase EC 1.1.1.42 4.50E+00 v_akdhc ?-ketogluterate dehydrogenase EC 1.2.4.2; EC 1.8.1.4; EC 2.3.1.61 4.50E+02 v_succoas_atp Succinyl-Coa Synthetase (ATP) EC 6.2.1.4; EC 6.2.1.5; EC 6.2.1.5 2.25E+04 v_succoas_gtp Succinyl-Coa Synthetase (GTP) EC 6.2.1.4; EC 6.2.1.4; EC 6.2.1.5 2.48E+03 v_succdh Succinate dehydrogenase EC 1.3.5.1 9.00E+03 v_fum Fumerase EC 4.2.1.2 1.80E+05 v_mdh Malate dehydrogenase, mitochondrial EC 1.1.1.37 9.00E+04 v_tdh NAD(P) transhydrogenase, mitochondrial EC 1.6.1.2 3.60E+03 v_ATP_use ATP usage 1.20E?01 v_Phos Phosphate carrier protein, mitochondrial TCDB 2.A.29.4.2 7.72E+10 v_syn F0F1 synthetase EC 3.6.3.14 6.40E-06 v_ex ATP-ADP nucleotide exchanger TCDB 2.A.29 7.20E-07 v1 Complex I EC 1.6.5.3 6.72E-07 v3 Complex III EC 1.10.2.2 2.40E-06 v4 Complex IV EC 1.9.3.1 9.60E-04 v_ak_cyt Adenylate kinase EC 2.7.4.3 8.00E+03 v_02_diff O2 diffusion 8.00E+01 v_ppase Pyrophosphatase EC 3.6.1.1 8.00E?02 I_C_ED Chloride electro diffusion 8.00E?01 IK_P Sodium pump 2.40E?05 I_K_ED Sodium electro diffusion 8.00E?01 I_Na_P Potassium pump 1.60E-04 I_Na_ED Sodium electro diffusion 8.00E?01 I_H ED Mitochondrial uncoupling protein TC 2.A.29.24.1; TC 2.A.29.24.3; 8.00E?01 TC 2.A.29.3.2; TC 2.A.29.3.4; TC 2.A.29.3.5 v_gpi Glucose-6-phosphate isomerase EC 5.3.1.9 3.51E+03 v_ald Fructose-bisphosphate aldolase B EC 4.1.2.13 1.17E+03 v_tpi Triosephosphate isomerase 1 EC 5.3.1.1 1.17E+03 v_gapdh Glyceraldehydephosphate dehydrogenase EC 1.2.1.12 1.76E+05 v_pgk Phosphyglyceratekinase (Pgk) EC 2.7.2.3 5.85E+02 v_pgm 2-Phospho-D-glycerate 2,3 phosphomutase (Pgm) EC 5.4.2.1 5.85E+05 v_eno 2-Phospho-D-glycerate hydrolase (Eno) EC 4.2.1.11 1.17E+03 v_glcT1 Glucose transporter type 1 TC 2.A.1.1 4.15E-04 v_glcT4 Glucose transporter type 4 TC 2.A.1.1 6.31E?03 v_hk1 Hexokinase EC 2.7.1.1 4.68E?02 v_hk2 Hexokinase EC 2.7.1.1 4.68E?03 v_fbp2 Phosphofructokinase 2 (FBP2) EC 2.7.1.105; EC 3.1.3.46; EC 3.1.3.46 4.68E?03 v_pfk2 Phosphofructokinase 2 (Pfk2) EC 2.7.1.105; EC 3.1.3.46; EC 3.1.3.46 1.17E?02 v_fbp1 Fructose-1,6-bisphosphatase (Fbp1) EC 3.1.3.11 1.17E+00 v_pfk1 Phosphofructokinase 1 (Pfk1) EC 2.7.1.11 5.85E?01 v_pk Pyruvate kinase (Pk) EC 2.7.1.40 5.85E?02 v_pc Pyruvate carboxylase; mitochondrial EC 6.4.1.1 1.17E?02 v_mal_pyrT Malate-pyruvate antiport (MalPyrT) 4.68E?01 v_me_nadp Identifier nicht gefunden 1.17E+01 v_ldh Lactate dehydrogenase EC 1.1.1.27 1.17E+05 v_mdh_cyt Malate dehydrogenase, cytoplasmic EC 1.1.1.37 1.17E+03 v_lacT Lactate transport (LacT) TCDB 2.A.1.13.1; TCDB 2.A.1.13.5; 1.17E?02 TCDB 2.A.1.13.6; TCDB 2.A.1.13.7; TCDB 2.A.1.13.9 v_pyrT pyruvate transport (pyrT) TCDB 2.A.1.13.1 1.17E?02 v_pyrT_mito Mitochondrial pyruvate transport TCDB 2.A.1.13.1 1.17E+05 v_ndk_cyt Nudiki (cytosolic) EC 2.7.4.6 1.17E+04 v_ndk_mito Nudiki (mitochondrial) EC 2.7.4.6 1.17E+06 v_ASAT_mito Aspartate aminotransferase, mitochondrial EC 2.6.1.1 1.50E+02 v_ASAT_in Aspartate aminotransferase, cytoplasmic EC 2.6.1.1 1.50E+02 v_asp_glu_T aspartate -glutamate carrier TCDB 2.A.29.14.1 2.25E?01 v_mal_akg_T Malate - ?-ketogluterate carrier TCDB 2.A.29.2.13 1.50E+06 v_g3pdh_cyt Glycerol-3-phosphate dehydrogenase (cytosolic) EC 1.1.1.8 1.50E+06 v_g3pdh_mito Glycerol-3-phosphate dehydrogenase (mitochondrial) EC 1.1.5.3 3.00E-10 v_g6pd Glucose-6-phosphate 1-dehydrogenase EC 1.1.1.49 5.00E-06 v_pglase 6-phosphogluconolactonase EC 3.1.1.31 3.00E?05 v_pgdh 6-phosphogluconate dehydrogenase; decarboxylating EC 1.1.1.44 1.00E?01 v_rpe Ribulose-phosphate 3-epimerase EC 5.1.3.1 5.00E?03 v_rpi Ribose-5-phosphate isomerase EC 5.3.1.6 1.00E?02 v_taldo Transaldolase EC 2.2.1.2 1.00E?02 v_tkl1 Transketolase 1 EC 2.2.1.1 1.00E+02 v_tkl2 Transketolase 2 EC 2.2.1.1 1.00E+00 v_Cit_Mal Citrate-malate exchanger TCDB 2.A.29.7.2 3.00E?03 v_Cit_Lys ATP dependent citrate lyase EC 2.3.3.8 1.00E?05 v_ACC1 Acetyl-CoA carboxylase 1 EC 6.4.1.2 1.40E?05 v_Mal_CoA_dc Malonyl-CoA decarboxylase EC 4.1.1.9 1.00E-06 v_glycerol_uptake Glycerol-uptake 7.50E?03 v_glycerol_kinase Glycerol kinase EC 2.7.1.30 3.60E?03 v_gpat Glycerol-3-phosphate acyltransferase EC 2.3.1.15 3.00E?03 v_agpat Acetyl glycerol-3-phosphate acyltransferase EC 2.3.1.51 4.50E?03 v_PAP Phosphatidic acid phosphatase EC 3.1.3.4 9.00E?03 v_dgat Diacylglycerol acyltransferase EC 2.3.1.20 1.05E?02 v_ld_syn LD synthesis (tag) 3.00E?03 v_atgl ATGL EC 3.1.1.3 3.00E?04 v_hsl Hormone-sensitive lipase EC 3.1.1.79 3.00E?04 v_magl Monoacylglycerol lipase EC 3.1.1.23 3.00E?04 v_g16pi alpha-D-Glucose 1-phosphate 1,6-phosphomutase EC 5.4.2.2 1.20E+04 v_upgase UTP:Glucose-1-phosphate uridylyltransferase (UPGase) EC 2.7.7.9 9.00E+00 v_ndkutp Nudiki (cytosolic) (udp) EC 2.7.4.6 6.00E+01 v_gs Glycogen synthase (GS) EC 2.4.1.11 3.00E?04 v_gp Glycogen-phosphorylase (GP) EC 2.4.1.1 1.80E?02 v_acac_cytT Acetoacetate export (MCT1/MCT2) TCDB 2.A.1.13.1; TCDB 2.A.1.13.5; 2.85E?02 TCDB 2.A.1.13.6; TCDB 2.A.1.13.7; TCDB 2.A.1.13.9 v_bhbut_cytT B-Hydroxy butyrate export (MCT1/MCT2) TCDB 2.A.13.1 2.85E?02 v_acac_mito_ex Acetoacetate transport (mitochondrial) TCDB 2.A. 13.1 8.55E?02 v_bhbut_mito_ex B-Hydroxy butyrate transport (mitochondrial) TCDB 2.A.13.1 8.55E?02 v_bHBDH D-beta-hydroxybutyrate dehydrogenase, mitochondrial EC 1.1.1.30 5.70E+03 v_scot Succinyl-CoA:3-ketoacid coenzyme A transferase 1, EC 2.8.3.5 5.70E+01 mitochondrial v_valT valine transporter 1.00E?01 v_leuT leucine transporter 1.00E?01 v_isoleuT isoleucine transporter 1.00E?01 v_BCAAT_val Branched-chain-amino-acid aminotransferase EC 2.6.1.42 1.00E?01 v_BCAAT_leu Branched-chain-amino-acid aminotransferase EC 2.6.1.42 1.00E?01 v_BCAAT_isoleu Branched-chain-amino-acid aminotransferase EC 2.6.1.42 1.00E?01 v_BCKADH_aKIVA Branched-chain alpha-keto acid dehydrogenase EC 1.2.4.4 1.00E?01 v_BCKADH_aKICA Branched-chain alpha-keto acid dehydrogenase EC 1.2.4.4 1.00E?01 v_BCKADH_KMeVA Branched-chain alpha-keto acid dehydrogenase EC 1.2.4.4 1.00E?01 v_MBCoADH_IsoButCoA 2-methylacyl-CoA dehydrogenase EC 1.3.99.12 1.00E+01 v_MBCoADH_MeButCoA 2-methylacyl-CoA dehydrogenase EC 1.3.99.12 1.00E+01 v_ECoAH_MeAcrCoA Enoyl-CoA hydratase, mitochondrial EC 4.2.1.17 1.00E+03 v_ECoAH_TigCoA Enoyl-CoA hydratase, mitochondrial EC 4.2.1.17 1.00E+01 v_HibCDA_HibCoA 3-hydroxyisobutyryl-CoA hydrolase, mitochondrial EC 3.1.2.4 1.00E+01 v_HibCDH_HBA 3-hydroxyisobutyryl-CoA hydrolase, mitochondrial EC 3.1.2.4 1.00E+01 v_MMSDH_MMSALD Methylmalonate-semialdehyde dehydrogenase, mitochondrial EC 1.2.1.27 1.00E+01 v_HMBCDH_MeHButCoA Methylmalonate-semialdehyde dehydrogenase, mitochondria EC 1.2.1.27 1.00E+01 v_MAACT_MeAACoA 3-ketoacyl-CoA thiolase, mitochondrial EC 2.3.1.16 1.00E+01 v_IVCoADH_isoValCoA Isovaleryl-CoA dehydrogenase, mitochondrial EC 1.3.8.4 1.00E+01 v_MECCC_MeCroCoA Methylcrotonoyl-CoA carboxylase, mitochondrial EC 6.4.1.4 1.00E+01 v_MEGCCH_MeGCCoA Methylglutaconyl-CoA hydratase, mitochondrial EC 4.2.1.18 1.00E+01 v_HMGCL_HMeGCoA Hydroxymethylglutaryl-CoA lyase, mitochondrial EC 4.1.3.4 1.00E+01 v_PCC_PropCoa Propionyl-CoA carboxylase, mitochondrial EC 6.1.4.3 1.00E+01 v_MMCM_MeMalCoa Methylmalonyl-CoA mutase, mitochondrial EC 5.4.99.2 1.00E+01