COMPOSITION FOR PRODUCTION OF GINSENOSIDE COMPOUND K COMPRISING HIGH TEMPERATURE alpha-L-ARABINOFURANOSIDASE, AND METHOD FOR PREPARING GINSENDOSIDE COMPOUND K

Abstract

Disclosed are a composition for production of ginsenoside compound K using a high temperature-?-glycosidase and a high temperature-?-L-arabinofuranosidase, and a method for preparing ginsenoside compound k. The composition for producing ginsenoside compound k and the method for preparing ginsenoside compound k according to one aspect of the present invention allow high temperature-?glycosidase and high temperature-a-L-arabinofuranosidase to exhibit stable activity even at high temperatures, thereby increasing a reaction rate. The composition for producing ginsenoside compound k and the method for preparing ginsenoside compound k according to one aspect of the present invention allow a large quantity of ginsenoside compound k to be produced in a short time, thereby exhibiting an effect of producing a high yield, and thus can be utilized industrially.

Claims

1. A composition for production of ginsenoside compound K comprising a high temperature-?-glycosidase and a high temperature-?-L-arabinofuranosidase.

2. The composition for production of ginsenoside compound K according to claim 1, wherein the high temperature-?-glycosidase is a ?-glycosidase of Sulfolobus solfataricus, and the high temperature-?-L-arabinofuranosidase is an ?-L-arabinofuranosidase of Thermotoga petrophila.

3. The composition for production of ginsenoside compound K according to claim 1, wherein the content of the high temperature-?-L-arabinofuranosidase is 1 part by weight or more based on 100 parts by weight of the high temperature-?-glycosidase.

4. The composition for production of ginsenoside compound K according to claim 1, wherein the content of the high temperature-?-L-arabinofuranosidase is 2.5 parts by weight or more based on 100 parts by weight of the high temperature-?-glycosidase.

5. The composition for production of ginsenoside compound K according to claim 2, wherein the high temperature-?-glycosidase is an enzyme consisting of the amino acid sequence of SEQ ID NO: 2 and the high temperature-?-L-arabinofuranosidase is an enzyme consisting of the amino acid sequence of SEQ ID NO: 4.

6. A method for preparing the composition for production of ginsenoside compound K according to claim 1, wherein the method comprises expression in E. coli transformed with a vector comprising the base sequence of SEQ ID NO: 3; and a vector comprising the base sequences of SEQ ID NO: 13 and SEQ ID NO: 14.

7. A method for preparing ginsenoside compound K, comprising the step of fermenting a saponin-containing material comprising at least one of ginsenoside Rb 1, ginsenoside Rb2, ginsenoside Rc, and ginsenoside Rd with a high temperature-?-glycosidase and a high temperature-?-L-arabinofuranosidase.

8. The method for preparing ginsenoside compound K according to claim 7, wherein the step of fermentation is fermentation using the composition for production of ginsenoside compound K according to claim 1.

9. The method for preparing ginsenoside compound K according to claim 7, wherein the step of fermentation is applying each of a high temperature-?-glycosidase and a high temperature-?-L-arabinofuranosidase.

10. The method for preparing ginsenoside compound K according to claim 9, wherein the high temperature-?-glycosidase is a ?-glycosidase of Sulfolobus solfataricus, and the high temperature-?-L-arabinofuranosidase is an ?-L-arabinofuranosidase of Thermotoga petrophila.

11. The method for preparing ginsenoside compound K according to claim 9, wherein the high temperature-?-L-arabinofuranosidase is applied in an amount of 1 part by weight or more based on 100 parts by weight of the high temperature-?-glycosidase.

12. The method for preparing ginsenoside compound K according to claim 7, wherein the saponin-containing material is red ginseng extract.

13. The method for preparing ginsenoside compound K according to claim 7, wherein the fermentation is fermentation at a temperature of 70? C. to 95? C.

14. The method for preparing ginsenoside compound K according to claim 7, wherein the fermentation is fermentation at a temperature of 80? C. to 90? C.

Description

BRIEF DESCRIPTION OF DRAWINGS

[0028] FIG. 1 shows the results of Test Example 1 regarding ?-L-arabinofuranosidases in cell debris, enzyme suspension and purified enzyme liquid when ?-L-arabinofuranosidases derived from Thermotoga petrophila were expressed in various host strains and coexpressed with chaperone.

[0029] FIG. 2 shows the decrease of compound Mc when the concentration of ?-L-arabinofuranosidase was varied while the concentration of high temperature-?-glycosidase was fixed at 2 mg/ml and red ginseng extract was used as a substrate.

[0030] FIG. 3 shows the production of ginsenoside compound K by 2 mg/ml of high temperature-?-glycosidase when red ginseng extract was used as a substrate.

[0031] FIG. 4 shows the production of ginsenoside compound K by 2 mg/ml of ?-glycosidase and 0.05 mg/ml of ?-L-arabinofuranosidase when red ginseng extract was used as a substrate.

DESCRIPTION OF EMBODIMENTS

Embodiments

[0032] Hereinafter, the present invention will be described in detail.

[0033] In one aspect, the present invention provides a composition for production of ginsenoside compound K comprising a high temperature-?-glycosidase and a high temperature-?-L-arabinofuranosidase.

[0034] As used herein, the term high temperature enzyme refers to an enzyme that exhibits optimum activity at a high temperature of 70-95? C., rather than an intermediate temperature of 10-50? C., which is the optimum temperature for enzyme activity.

[0035] In one aspect of the present invention, the high temperature-?-glycosidase may be a ?-glycosidase of Sulfolobus solfataricus, and the high temperature-?-L-arabinofuranosidase may be an ?-L-arabinofuranosidase of Thermotoga petrophila.

[0036] In one aspect of the present invention, the high temperature-?-glycosidase and the high temperature-?-L-arabinofuranosidase of the present invention are obtained from Sulfolobus solfataricus and Thermotoga petrophila, which are high temperature organisms, by 1) directly isolating them from these strains and purifying them or 2) cloning the genes of each of the enzymes from the strains, expressing them in a recombinant expression vector, and purifying them. The method for obtaining the enzymes from microorganisms is a conventional method in the art (Sambrook, J. and Russell, D. W. Molecular Cloning 3rd Ed. Cold Spring Harbor Laboratory, 2001).

[0037] When the ?-glycosidase obtained by a conventional method is applied to red ginseng extract, ginsenoside Rc and compound Mc among protopanaxadiol-type saponins are left, which limits the production yield of ginsenoside compound K (FIG. 3). Thus, in one aspect, the present invention provides a method for converting all the protopanaxadiol-type saponins in red ginseng extract or tiny-sized ginseng extract to compound K by applying ?-L-arabinofuranosidase simultaneously.

[0038] In one aspect of the present invention, ?-L-arabinofuranosidase derived from Thermotoga petrophila exhibited about 17 times higher activity than ?-L-arabinofuranosidase derived from Caldicellulosiruptor saccharolyticus, which has been conventionally used in the production of ginsenoside compound K. Also, its expression pattern was enhanced by host cell selection and the introduction of chaperone (FIG. 1).

[0039] In one aspect of the present invention, the content of the high temperature-?-L-arabinofuranosidase may be 1 part by weight or more based on 100 parts by weight of the high temperature-?-glycosidase.

[0040] Specifically, the content of the temperature-?-L-arabinofuranosidase may be 1 part by weight or more, 1.5 parts by weight or more, 2.0 parts by weight or more, 2.1 parts by weight or more, 2.2 parts by weight or more, 2.3 parts by weight or more, 2.4 parts by weight or more, 2.5 parts by weight or more, 2.6 parts by weight or more, 2.7 parts by weight or more, 2.8 parts by weight or more, or 3.0 parts by weight or more based on 100 parts by weight of the high temperature-?-glycosidase. Also, the content of the high temperature-?-L-arabinofuranosidase may be 5.0 parts by weight or less, 4.5 parts by weight or less, or 4.0 parts by weight or less based on 100 parts by weight of the high temperature-?-glycosidase.

[0041] The high temperature-?-L-arabinofuranosidase can achieve the maximum generation of compound K economically while minimizing the concentration of the enzyme, when the weight ratio of the high temperature-?-glycosidase is within the above range.

[0042] Preferably, the content of the temperature-?-L-arabinofuranosidase may be 2 parts by weight or more based on 100 parts by weight of the high temperature-?-glycosidase.

[0043] More preferably, the content of the high temperature-?-L-arabinofuranosidase may be 2.5 parts by weight or more based on 100 parts by weight of the high temperature-?-glycosidase. In one aspect of the present invention, when red ginseng extract is used as a substrate, all of the remaining compounds Mc are converted to compounds K at a concentration ratio of ?-glycosidase derived from Thermotoga petrophila and ?-L-arabinofuranosidase derived from Sulfolobus solfataricus of 40:1 (FIG. 2).

[0044] As described above, the composition for production of ginsenoside compound K comprising a high temperature-?-glycosidase and a high temperature-?-L-arabinofuranosidase according to one aspect of the present invention controls the reaction rate rapidly at a high temperature of 85? C. and thereby achieves the effect of producing ginsenoside compound K in a short time at a high yield and using a low enzyme concentration, when reacted with a mixture of ginsenosides Rb1, Rb2, Rc, and Rd, which are major diol-type saponins in red ginseng extract, in a mixed solution of a buffer solution and an aqueous solvent.

[0045] In one aspect of the present invention, the high temperature-?-glycosidase may be an enzyme consisting of the amino acid sequence of SEQ ID NO: 2, and the high temperature-?-L-arabinofuranosidase may be an enzyme consisting of the amino acid sequence of SEQ ID NO: 4.

[0046] In one aspect of the invention, the method may be a method for preparing a composition for production of ginsenoside compound K, comprising expression in E. coli transformed with a vector comprising the base sequence of SEQ ID NO: 3; and a vector comprising the base sequences of SEQ ID NO: 13 and SEQ ID NO: 14. The vector comprising the base sequences of SEQ ID NO: 13 and SEQ ID NO: 14 may be chaperone pGrp7.

[0047] In another aspect, the present invention provides a method for preparing ginsenoside compound K, comprising the step of fermenting a saponin-containing material comprising at least one of ginsenoside Rb1, ginsenoside Rb2, ginsenoside Rc, and ginsenoside Rd with a high temperature-?-glycosidase and a temperature-?-L-arabinofuranosidase.

[0048] In another aspect of the present invention, the step of fermentation may be fermentation using the composition for production of ginsenoside compound K according to any one of the aspects of the present invention.

[0049] In another aspect of the invention, the step of fermentation may be applying each of a high temperature-?-glycosidase and a high temperature-?-L-arabinofuranosidase. In another aspect of the present invention, the high temperature-?-glycosidase may be a ?-glycosidase of Sulfolobus solfataricus, and the high temperature-?-L-arabinofuranosidase may be an ?-L-arabinofuranosidase of Thermotoga petrophila. In another aspect of the present invention, the high temperature-?-L-arabinofuranosidase may be applied in an amount of 1 part by weight or more based on 100 parts by weight of the high temperature-?-glycosidase. Specifically, the content of the high temperature-?-L-arabinofuranosidase may be 1 part by weight or more, 1.5 parts by weight or more, 2.0 parts by weight or more, 2.1 parts by weight or more, 2.2 parts by weight or more, 2.3 parts by weight or more, 2.4 parts by weight or more, 2.5 parts by weight or more, 2.6 parts by weight or more, 2.7 parts by weight or more, 2.8 parts by weight or more, or 3.0 parts by weight or more based on 100 parts by weight of the high temperature-?-glycosidase. Also, the content of the high temperature-?-L-arabinofuranosidase may be 5.0 parts by weight or less, 4.5 parts by weight or less, or 4.0 parts by weight or less based on 100 parts by weight of the high temperature-?-glycosidase.

[0050] In one embodiment of the present invention, a) PCR is performed with genomic DNA of Sulfolobus solfataricus and Thermotoga petrophila and their respective primers to amplify the DNA fragments comprising each of high temperature-?-glycosidase and high temperature-?-L-arabinofuranosidase genes; b) the amplified DNA fragments comprising each of high temperature-?-glycosidase and high temperature-?-L-arabinofuranosidase gene are treated with restriction enzymes and each of them is cloned into plasmid vectors pET-24a(+) and pET-21a(+) to construct recombinant expression vectors pET-24a(+)/?-glycosidase and pET-21a(+)/?-L-arabinofuranosidase; c) E. coli ER2566 is transformed with the vectors according to a conventional transformation method; d) E. coli transformed with each of high temperature-?-glycosidase genes and high temperature ?-L-arabinofuranosidase genes is cultured; e) gene expression is induced during culture to produce a high temperature-?-glycosidase and a high temperature-?-L-arabinofuranosidase; and f) the expressed high temperature-?-glycosidase and high temperature-?-L-arabinofuranosidase proteins are isolated and obtained.

[0051] The pET-21a(+)/?-L-arabinofuranosidase in the above step c) may be transformed together with the chaperone vector pGro7 into BL21(DE3), which shows the highest expression among various strains such as E. coli ER2566, BL21(DE3), JM109 and Origami B, as a host.

[0052] The process of isolating the high temperature (?-glucosidase and high temperature-?-L-arabinofuranosidase proteins expressed in the above step f) may consist of the steps of: (a) lysing the culture solution of microorganisms; (b) centrifuging the cell lysate to obtain a supernatant; (c) subjecting the supernatant to heat treatment at a high temperature and centrifuging the resultant; and (d) filtering the thus-obtained supernatant to isolate an enzyme liquid.

[0053] In the above step (a), preferably, cells are lysed at a pressure of about 15,000 lb/in.sup.2 using a device such as a French press. In the above step (c), preferably, the cell supernatant is subjected to heat treatment at a temperature of 75? C. for about 10 minutes. In the above step (d), preferably, the filtration is performed using a filter paper of about 0.45 ?m.

[0054] Also, the substrate may be ginsenosides Rb1, Rb2, Rc, and Rd, which are diol-type saponins in red ginseng extract, and may be used as a mixture in the preparation of ginsenoside compound K. The reaction solvent may be a buffer solution such as Mcllvaine buffer.

[0055] As described above, the reaction between the high temperature-?-glycosidase and high temperature-?-L-arabinofuranosidase and the substrate in the reaction solvent is performed preferably at a pH of 5.0 to 7.0 and a temperature of 70 to 95? C., more preferably at a pH of 6.0 and a temperature of 85? C.

[0056] The method for preparing ginsenoside compound K using a high temperature-?-glycosidase and a high temperature-?-L-arabinofuranosidase according to the present invention allows a high temperature-?-glycosidase derived from Sulfolobus solfataricus and a high temperature-?-L-arabinofuranosidase derived from Thermotoga petrophila to exhibit stable activity even at high temperatures, thereby increasing a reaction rate. As a result, it allows a large quantity of ginsenoside compound k to be produced in a short time, thereby exhibiting an effect of producing a high yield, and thus can be utilized industrially.

[0057] In another aspect of the present invention, the saponin-containing material may be red ginseng extract.

[0058] In another aspect of the present invention, the fermentation may be performed at a temperature of 70? C. to 95? C. Specifically, the fermentation temperature may be 70? C. or more, 72? C. or more, 74? C. or more, 76? C. or more, 78? C. or more, 80? C. or more, 82? C. or more, or 84? C. or more. Also, the fermentation temperature may be 95? C. or less, 93? C. or less, 91? C. or less, 90? C. or less, 88? C. or less, 86? C. or less, or 84? C. or less. When the temperature is within the above range, the production yield of ginsenoside K is excellent.

[0059] Hereinafter, preferred examples of the present invention will be described to facilitate understanding of the present invention. However, the following examples are provided only to facilitate understanding of the present invention, and the scope of the present invention is not limited thereto.

Example 1

[0060] Preparation of a Recombinant Expression Vector Comprising a High Temperature-?-glycosidase Coding Base Sequence or a High Temperature-?-L-arabinofuranosidase Coding Base Sequence, and a Transformed Microorganism

[0061] In order to prepare a high temperature-?-glycosidase, a ?-glycosidase gene derived from Sulfolobus solfataricus was isolated. Also, in order to prepare a high temperature-?-L-arabinofuranosidase, an ?-L-arabinofuranosidase gene derived from Thermotoga petrophila was isolated.

[0062] Specifically, Sulfolobus solfataricus and Thermotoga petrophila, whose base sequence and amino acid sequence are already specified, were selected and the genomic DNA of each was extracted. The Sulfolobus solfataricus used was DSM 1617 purchased from the DSMZ (Germany), and the Thermotoga petrophila used was DSM 13995 purchased from the DSMZ (Germany).

[0063] Also, primers were prepared using the base sequence of the ?-glycosidase gene of Sulfolobus solfataricus (GenBank Accession No. M34696) and the base sequence of the ?-L-arabinofuranosidase gene of Thermotoga petrophila (GenBank Accession No. ABQ46651, respectively.

[0064] The DNA base sequence of the ?-glycosidase of Sulfolobus solfataricus was as shown in SEQ ID NO: 1, and the amino acid sequence thereof was as shown in SEQ ID NO: 2.

[0065] The DNA base sequence of the ?-L-arabinofuranosidase of Thermotoga petrophila was as shown in SEQ ID NO: 3, and the amino acid sequence thereof was as shown in SEQ ID NO: 4.

[0066] The forward and reverse primers for the ?-glycosidase of Sulfolobus solfataricus were as shown in SEQ ID NO: 5 and SEQ ID NO: 6, respectively.

[0067] In addition, the forward and reverse primers for ?-L-arabinofuranosidase of Thermotoga petrophila were as shown in SEQ ID NO: 7 and SEQ ID NO: 8, respectively.

[0068] Polymerase chain reaction (PCR) was performed using the genomic DNA and primers to amplify the base sequences of the corresponding genes. After the respective genes were obtained in large quantities by the above procedure, they were inserted into plasmid vectors pET-24a(+) and pET-21a to prepare recombinant expression vectors pET-24a(+)/?-glycosidase and pET-21a/?-L-arabinofuranosidase.

[0069] The plasmid vector pET-24a(+) was as shown in SEQ ID NO: 9.

[0070] The plasmid vector pET-21a was as shown in SEQ ID NO: 10.

[0071] The recombinant expression vector pET-24a(+)/?-glycosidase was as shown in SEQ ID NO: 11.

[0072] The recombinant expression vector pET-21a/?-L-arabinofuranosidase was as shown in SEQ ID NO: 12.

[0073] Also, the thus-prepared recombinant expression vectors were transformed into E. coli strain ER2566 by a conventional transformation method. pET-21a/?-L-arabinofuranosidase was also transformed into E. coli strains BL21(DE3), JM109 and Origami B.

[0074] The E. coli strains ER2566 and BL21(DE3) were purchased from New England Biolabs (NEB).

[0075] The E. coli strain JM109 was purchased from Takara.

[0076] The E. coli strain Origami B was purchased from Novagen.

[0077] BL21(DE3), which among them exhibited the highest expression, as a host was transformed with pET-21a/?-L-arabinofuranosidase and the chaperone vector pGro7, which was a commercial chaperone vector purchased from Takara. The chaperone vector pGro7, which was an independent plasmid, was co-transformed with the pET-21a/?-L-arabinofuranosidase vector into the strain BL21(DE3).

[0078] The chaperone vector pGro7 was a vector that simultaneously expresses GroEL and GroES genes. The GroEL gene was as shown in SEQ ID NO: 13, and the GroES gene was as shown in SEQ ID NO: 14. A schematic diagram of the chaperon pGro7 vector is shown in FIG. 5.

[0079] The transformed recombinant E. coli is referred to as E. coli strain ER2566 pET-24a(+)/?-glycosidase, E. coli strains ER2566, BL21(DE3), JM109, and Origami B pET-21a/?-L-arabinofuranosidase, and E. coli strain BL21(DE3) pET-21a/?-L-arabinofuranosidase-pGro7.

[0080] The transformed E. coli was added with 20% glycerine solution and stored frozen before culture.

Example 2

Expression and Purification of a High Temperature-?-Glycosidase and a High Temperature-?-L-Arabinofuranosidase

[0081] In order to mass produce ?-glycosidase and ?-L-arabinofuranosidase, the frozen E. coli strain ER2566 pET-24a(+)/?-glycosidase, E. coli strains ER2566, BL21(DE3), JM109, and Origami B pET-21a/?-L-arabinofuranosidase, and E. coli strain BL21(DE3) pET-21a/?-L-arabinofuranosidase-pGro7 each were seeded into a 250 ml flask containing 50 ml of LB medium, and then subjected to shaking culture in a shaking incubator at 37? C. until the absorbance at 600 nm reached 2.0. Then, the culture solution was added to a 21 Erlenmeyer flask containing 500 ml of LB medium and cultured until the absorbance at 600 nm reached 0.8. During the process, the stirring speed was 200 rpm and the culture temperature was 37? C. The resultant was added with 0.1 mM IPTG (isopropyl-beta-thiogalactoside) to induce production of the overexpressed enzyme. The stirring speed was adjusted to 150 rpm and the culture temperature was adjusted to 16? C.

[0082] In order to purify the thus-obtained high temperature-?-glycosidase and high temperature-?-L-arabinofuranosidase, the cultures of the transformed strains were centrifuged at 4,000?g for 4 to 30 minutes. Then, the cell solutions were lysed using a French press at 15,000 lb/in.sup.2. The cell lysates were centrifuged again at 13,000?g for 4 to 20 minutes and subjected to heat treatment at a high temperature of 75? C. for 10 minutes. The thus-obtained heat-treated product was centrifuged again at 13,000?g for 4 to 20 minutes. The resultant supernatant was filtered with a 0.45 ?m filter paper and isolated as an enzyme liquid which can be used for the production of ginsenoside compound K.

Test Example 1

Determination of the Expression Level of ?-L-Arabinofuranosidase

[0083] The expression levels of the ?-L-arabinofuranosidase enzyme liquids isolated from various host strains, the enzyme suspensions before subjected to heat treatment, and the cell debris obtained by centrifugation according to Example 2 were qualitatively compared through SDS-PAGE analysis.

[0084] As a result, as shown in FIG. 1, it was found from the cell debris that ?-L-arabinofuranosidase expressed in the E. coli strain BL21(DE3) (well No. 2) was most expressed. Also, it was found from the purified enzyme liquid and the enzyme suspension that in the case of coexpression using chaperone pGro7 in the E. coli strain BL21(DE3) (well No. 4), ?-L-arabinofuranosidase reached the highest concentration, and the expression of ?-L-arabinofuranosidase of relatively high solubility was enhanced.

Test Example 2

Experiment on the Optimum Ratio of High Temperature-?-Glycosidase and High Temperature-?-L-Arabinofuranosidase

[0085] It was found that when the high temperature-?-glycosidase isolated in Example 2 was applied to red ginseng extract, ginsenoside Rc and compound Mc among protopanaxadiol-type saponins were left, which limited the production yield of ginsenoside compound K (FIG. 3).

[0086] In order to convert the residual ginsenoside Rc and compound Mc into compound K, ?-L-arabinofuranosidase was added for co-treatment with ?-glycosidase, and then the compound K production was compared.

[0087] The high temperature-?-glycosidase isolated in Example 2 was added with varying concentration of ?-L-arabinofuranosidase, which was confirmed to have enhanced expression in Test Example 1, and the optimum ratio of the enzymes was determined in the following manner. The two enzymes were reacted with red ginseng extract and compared for the degree of compound K production.

[0088] In order to determine the optimum concentration ratio of ?-glycosidase and ?-L-arabinofuranosidase, red ginseng extract containing about 7.5 mg/ml of protopanaxadiol-type saponins, 50 mM Mcilvaine buffer solution (pH 6.0), and a mixture of the two enzymes were applied.

[0089] When 2 mg/ml of ?-glycosidase alone was applied to red ginseng extract as a substrate, it was found that most of ginsenosides Rd disappeared after 12 hours as shown in FIG. 3.

[0090] The concentration of ?-L-arabinofuranosidase at which all of compounds Mc (C-Mc) are converted was determined by varying the concentration of ?-L-arabinofuranosidase with the concentration of ?-glycosidase fixed at 2 mg/ml. Specifically, the concentration of ?-L-arabinofuranosidase was decreased from 0.1 mg/ml to 0.0032 mg/ml. As a result, as shown in FIG. 2, it was found that when ?-L-arabinofuranosidase at a concentration of 0.05 mg/ml or more was applied with the concentration of ?-glycosidase fixed at 2 mg/ml, all of the compounds Mc were converted.

Example 3

[0091] Production of Ginsenoside Compound K using High Temperature-?-Glycosidase and High Temperature ?-L-Arabinofuranosidase

[0092] In order to develop a method for preparing ginsenoside compound K using the high temperature-?-glycosidase of Example 2 and the ?-L-arabinofuranosidase with enhanced expression in Test Example 1, the production of ginsenoside compound K over time was measured using red ginseng extract and tiny-sized ginseng extract at an optimum ratio of the enzymes in each substrate as determined above.

[0093] The test results are shown in FIG. 4. FIG. 4 is a graph showing the production of ginsenoside compound K by 2.0 mg/ml of ?-glycosidase and 0.05 mg/ml of ?-L-arabinofuranosidase of the present invention in red ginseng extract containing about 7.5 mg/ml of protopanaxadiol-type saponins as a substrate. FIG. 4 shows that after 12 hours, all of the materials were converted to produce 4.2 mg/ml of ginsenoside compound K (C-K).

[0094] Until now, a suspension of ?-glycosidase (2.3 mg/ml) from Sulfolobus solfataricus and ?-L-arabinofuranosidase (0.39 mg/ml) from Thermotoga petrophila has been found to achieve the highest productivity in production of ginsenoside compound K. It has been reported that the use of the suspension in red ginseng extract containing about 7.5 mg/ml of protopanaxadiol-type saponins resulted in production of 4.2 mg/ml of ginsenoside compound K for 12 hours (Kyung-Chul Shin et al. 2015, Compound K Production from Red Ginseng Extract by ?-Glycosidase from Sulfolobus solfataricus Supplemented with ?-L-arabinofuranosidase from Caldicellulosiruptor saccharolyticus. PLoS One. 28;10(12):e0145876.).

[0095] Upon comparing the above case and the present invention, in the case of using the high temperature-?-glycosidase and the high temperature-?-L-arabinofuranosidase according to one aspect of the present invention, the total enzyme concentration was about 1.3 times lower than in the case of using the two enzymes, and the concentration of ?-L-arabinofuranosidase among them was 8 times lower than the above case, and the productivity increased by about 1.2 times. Thus, it was confirmed that the productivity per enzyme concentration in this experiment was 1.3 times higher than the above case.

TABLE-US-00001 SequenceListingFreeText SEQIDNO:1 ggatcaatactaggaggagtagcatataattacgttacacaattttataacccaatatat 60 tcaatagaccttatgcttatcctatcctctattctaagattctcggtatctcccctattc 120 ttgaccataaaagatactcgctcaaagcttaaataatattaatcataaataaagtcatgt 180 actcatttccaaatagctttaggtttggttggtcccaggccggatttcaatcagaaatgg 240 gaacaccagggtcagaagatccaaatactgactggtataaatgggttcatgatccagaaa 300 acatggcagcgggattagtaagtggagatctaccagaaaatgggccaggctactggggaa 360 actataagacatttcacgataatgcacaaaaaatgggattaaaaatagctagactaaatg 420 tggaatggtctaggatatttcctaatccattaccaaggccacaaaactttgatgaatcaa 480 aacaagatgtgacagaggttgagataaacgaaaacgagttaaagagacttgacgagtacg 540 ctaataaagacgcattaaaccattacagggaaatattcaaggatcttaaaagtagaggac 600 tttactttatactaaacatgtatcattggccattacctctatggttacacgacccaataa 660 gagtaagaagaggagattttactggaccaagtggttggctaagtactagaacagtttacg 720 aattcgctagattctcagcttatatagcttggaaattcgatgatctagtggatgagtact 780 caacaatgaatgaacctaacgttgttggaggtttaggatacgttggtgttaagtccggtt 840 ttcccccaggatacctaagctttgaactttcccgtagggcaatgtataacatcattcaag 900 ctcacgcaagagcgtatgatgggataaagagtgtttctaaaaaaccagttggaattattt 960 acgctaatagctcattccagccgttaacggataaagatatggaagcggtagagatggctg 1020 aaaatgataatagatggtggttctttgatgctataataagaggtgagatcaccagaggaa 1080 acgagaagattgtaagagatgacctaaagggtagattggattggattggagttaattatt 1140 acactaggactgttgtgaagaggactgaaaagggatacgttagcttaggaggttacggtc 1200 acggatgtgagaggaattctgtaagtttagcgggattaccaaccagcgacttcggctggg 1260 agttcttcccagaaggtttatatgacgttttgacgaaatactggaatagatatcatctct 1320 atatgtacgttactgaaaatggtattgcggatgatgccgattatcaaaggccctattatt 1380 tagtatctcacgtttatcaagttcatagagcaataaatagtggtgcagatgttagagggt 1440 atttacattggtctctagctgataattacgaatgggcttcaggattctctatgaggtttg 1500 gtctgttaaaggtcgattacaacactaagagactatactggagaccctcagcactagtat 1560 atagggaaatcgccacaaatggcgcaataactgatgaaatagagcacttaaatagcgtac 1620 ctccagtaaagccattaaggcactaaactttctcaagtctcactataccaaatgagtttt 1680 cttttaatcttattctaatctcattttcattagattgcaatactttcataccttctatat 1740 tatttattttgtaccttttgggatc 1765 SEQIDNO:2 MetTyrSerPheProAsnSerPheArgPheGlyTrpSerGlnAlaGly PheGlnSerGluMetGlyThrProGlySerGluAspProAsnThrAsp TrpTyrLysTrpValHisAspProGluAsnMetAlaAlaGlyLeuVal SerGlyAspLeuProGluAsnGlyProGlyTyrTrpGlyAsnTyrLys ThrPheHisAspAsnAlaGlnLysMetGlyLeuLysIleAlaArgLeu AsnValGluTrpSerArgIlePheProAsnProLeuProArgProGln AsnPheAspGluSerLysGlnAspValThrGluValGluIleAsnGlu AsnGluLeuLysArgLeuAspGluTyrAlaAsnLysAspAlaLeuAsn HisTyrArgGluIlePheLysAspLeuLysSerArgGlyLeuTyrPhe IleLeuAsnMetTyrHisTrpProLeuProLeuTrpLeuHisAspPro IleArgValArgArgGlyAspPheThrGlyProSerGlyTrpLeuSer ThrArgThrValTyrGluPheAlaArgPheSerAlaTyrIleAlaTrp LysPheAspAspLeuValAspGluTyrSerThrMetAsnGluProAsn ValValGlyGlyLeuGlyTyrValGlyValLysSerGlyPheProPro GlyTyrLeuSerPheGluLeuSerArgArgAlaMetTyrAsnIleIle GlnAlaHisAlaArgAlaTyrAspGlyIleLysSerValSerLysLys ProValGlyIleIleTyrAlaAsnSerSerPheGlnProLeuThrAsp LysAspMetGluAlaValGluMetAlaGluAsnAspAsnArgTrpTrp PhePheAspAlaIleIleArgGlyGluIleThrArgGlyAsnGluLys IleValArgAspAspLeuLysGlyArgLeuAspTrpIleGlyValAsn TyrTyrThrArgThrValValLysArgThrGluLysGlyTyrValSer LeuGlyGlyTyrGlyHisGlyCysGluArgAsnSerValSerLeuAla GlyLeuProThrSerAspPheGlyTrpGluPhePheProGluGlyLeu TyrAspValLeuThrLysTyrTrpAsnArgTyrHisLeuTyrMetTyr ValThrGluAsnGlyIleAlaAspAspAlaAspTyrGlnArgProTyr TyrLeuValSerHisValTyrGlnValHisArgAlaIleAsnSerGly AlaAspValArgGlyTyrLeuHisTrpSerLeuAlaAspAsnTyrGlu TrpAlaSerGlyPheSerMetArgPheGlyLeuLeuLysValAspTyr AsnThrLysArgLeuTyrTrpArgProSerAlaLeuValTyrArgGlu IleAlaThrAsnGlyAlaIleThrAspGluIleGluHisLeuAsnSer ValProProValLysProLeuArgHis SEQIDNO:3 atgtcctacaggatagtggttgatccaaaaaaagttgtcaagccgattagtagacacatc 60 tacggtcatttcacggaacatctgggaaggtgtatctacggcggaatttatgaagaaggt 120 tctccgctctccgatgaaaggggtttcagaaaggacgttctggaggctgtaaagaggata 180 aaagttccgaacttgagatggcccggtggaaactttgtgtcgaactaccactgggaagac 240 ggaataggtcccaaagatcagaggcctgtcaggttcgatctcgcctggcaacaggaagag 300 acgaatagatttggaacggacgaattcattgagtactgtcgtgagataggagcagaacct 360 tacatcagtataaacatgggaactggaacactcgacgaagctctccactggcttgaatac 420 tgcaatggaaagggtaatacctactacgctcaactcagaagaaagtacggtcatccagaa 480 ccttacaacgtaaagttctggggaataggcaacgagatgtacggggaatggcaggtaggc 540 cacatgacggcggacgaatacgcaagagccgccaaagaatacacgaaatggatgaaggtt 600 ttcgatcctacaattaaagcgatcgccgtgggctgtgacgaccctatatggaatctcagg 660 gttcttcaagaagcaggtgatgtgattgacttcatatcctaccatttctacacagggtcc 720 gaggattactacgaaacagtttccacggtttaccttctcaaagaaagactcatcggagtg 780 aaaaagctcattgatatggtggatactgctagaaagagaggtgtcaaaatcgcccttgat 840 gaatggaacgtatggtacagagtgtccgataacaagctcgaagaaccttacgatctcaaa 900 gatggtatctttgcatgtggagtgcttgtacttcttcaaaagatgagcgacatagtccca 960 cttgccaatctcgcacagcttgtaaacgcccttggagctatacacaccgagaaagacggt 1020 ctcattctcacacccgtttacaaggcttttgaactcatcgtgaatcattccggagaaaag 1080 cttgtcaagacccatgttgaatcggagacttacaacatagaaggagtcatgttcatcaac 1140 aaaatgcctttctctgtcgagaacgcaccgttccttgatgccgccgcttccatctcagaa 1200 gatggcaagaaacttttcatcgctgttgtaaactacaggaaagaagacgctttgaaggtt 1260 ccaatcagagtggaaggtctgggacagaaaaaagccaccgtttatacactcacaggtccg 1320 gacgtgaacgcgagaaacaccatggaaaatccgaacgtcgttgatattacctccgaaacc 1380 atcaccgttgacaccgaatttgaacacacgtttaaaccattctcttgcagtgtgattgag 1440 gtagaattggagtaa 1455 SEQIDNO:4 MetSerTyrArgIleValValAspProLysLysValValLysProIle SerArgHisIleTyrGlyHisPheThrGluHisLeuGlyArgCysIle TyrGlyGlyIleTyrGluGluGlySerProLeuSerAspGluArgGly PheArgLysAspValLeuGluAlaValLysArgIleLysValProAsn LeuArgTrpProGlyGlyAsnPheValSerAsnTyrHisTrpGluAsp GlyIleGlyProLysAspGlnArgProValArgPheAspLeuAlaTrp GlnGlnGluGluThrAsnArgPheGlyThrAspGluPheIleGluTyr CysArgGluIleGlyAlaGluProTyrIleSerIleAsnMetGlyThr GlyThrLeuAspGluAlaLeuHisTrpLeuGluTyrCysAsnGlyLys GlyAsnThrTyrTyrAlaGlnLeuArgArgLysTyrGlyHisProGlu ProTyrAsnValLysPheTrpGlyIleGlyAsnGluMetTyrGlyGlu TrpGlnValGlyHisMetThrAlaAspGluTyrAlaArgAlaAlaLys GluTyrThrLysTrpMetLysValPheAspProThrIleLysAlaIle AlaValGlyCysAspAspProIleTrpAsnLeuArgValLeuGlnGlu AlaGlyAspValIleAspPheIleSerTyrHisPheTyrThrGlySer GluAspTyrTyrGluThrValSerThrValTyrLeuLeuLysGluArg LeuIleGlyValLysLysLeuIleAspMetValAspThrAlaArgLys ArgGlyValLysIleAlaLeuAspGluTrpAsnValTrpTyrArgVal SerAspAsnLysLeuGluGluProTyrAspLeuLysAspGlyIlePhe AlaCysGlyValLeuValLeuLeuGlnLysMetSerAspIleValPro LeuAlaAsnLeuAlaGlnLeuValAsnAlaLeuGlyAlaIleHisThr GluLysAspGlyLeuIleLeuThrProValTyrLysAlaPheGluLeu IleValAsnHisSerGlyGluLysLeuValLysThrHisValGluSer GluThrTyrAsnIleGluGlyValMetPheIleAsnLysMetProPhe SerValGluAsnAlaProPheLeuAspAlaAlaAlaSerIleSerGlu AspGlyLysLysLeuPheIleAlaValValAsnTyrArgLysGluAsp AlaLeuLysValProIleArgValGluGlyLeuGlyGlnLysLysAla ThrValTyrThrLeuThrGlyProAspValAsnAlaArgAsnThrMet GluAsnProAsnValValAspIleThrSerGluThrIleThrValAsp ThrGluPheGluHisThrPheLysProPheSerCysSerValIleGlu ValGluLeuGlu SEQIDNO:5 catatgtactcatttccaaatagc 24 SEQIDNO:6 ctcgagttagtgccttaatggctttac 27 SEQIDNO:7 catatgatgtcctacaggatagtggttgatc 31 SEQIDNO:8 ctcgagctccaattctacctcaatcac 27 SEQIDNO:9 atccggatatagttcctcctttcagcaaaaaacccctcaagacccgtttagaggccccaa 60 ggggttatgctagttattgctcagcggtggcagcagccaactcagcttcctttcgggctt 120 tgttagcagccggatctcagtggtggtggtggtggtgctcgagtgcggccgcaagcttgt 180 cgacggagctcgaattcggatccgcgacccatttgctgtccaccagtcatgctagccata 240 tgtatatctccttcttaaagttaaacaaaattatttctagaggggaattgttatccgctc 300 acaattcccctatagtgagtcgtattaatttcgcgggatcgagatctcgatcctctacgc 360 cggacgcatcgtggccggcatcaccggcgccacaggtgcggttgctggcgcctatatcgc 420 cgacatcaccgatggggaagatcgggctcgccacttcgggctcatgagcgcttgtttcgg 480 cgtgggtatggtggcaggccccgtggccgggggactgttgggcgccatctccttgcatgc 540 accattccttgcggcggcggtgctcaacggcctcaacctactactgggctgcttcctaat 600 gcaggagtcgcataagggagagcgtcgagatcccggacaccatcgaatggcgcaaaacct 660 ttcgcggtatggcatgatagcgcccggaagagagtcaattcagggtggtgaatgtgaaac 720 cagtaacgttatacgatgtcgcagagtatgccggtgtctcttatcagaccgtttcccgcg 780 tggtgaaccaggccagccacgtttctgcgaaaacgcgggaaaaagtggaagcggcgatgg 840 cggagctgaattacattcccaaccgcgtggcacaacaactggcgggcaaacagtcgttgc 900 tgattggcgttgccacctccagtctggccctgcacgcgccgtcgcaaattgtcgcggcga 960 ttaaatctcgcgccgatcaactgggtgccagcgtggtggtgtcgatggtagaacgaagcg 1020 gcgtcgaagcctgtaaagcggcggtgcacaatcttctcgcgcaacgcgtcagtgggctga 1080 tcattaactatccgctggatgaccaggatgccattgctgtggaagctgcctgcactaatg 1140 ttccggcgttatttcttgatgtctctgaccagacacccatcaacagtattattttctccc 1200 atgaagacggtacgcgactgggcgtggagcatctggtcgcattgggtcaccagcaaatcg 1260 cgctgttagcgggcccattaagttctgtctcggcgcgtctgcgtctggctggctggcata 1320 aatatctcactcgcaatcaaattcagccgatagcggaacgggaaggcgactggagtgcca 1380 tgtccggttttcaacaaaccatgcaaatgctgaatgagggcatcgttcccactgcgatgc 1440 tggttgccaacgatcagatggcgctgggcgcaatgcgcgccattaccgagtccgggctgc 1500 gcgttggtgcggatatctcggtagtgggatacgacgataccgaagacagctcatgttata 1560 tcccgccgttaaccaccatcaaacaggattttcgcctgctggggcaaaccagcgtggacc 1620 gcttgctgcaactctctcagggccaggcggtgaagggcaatcagctgttgcccgtctcac 1680 tggtgaaaagaaaaaccaccctggcgcccaatacgcaaaccgcctctccccgcgcgttgg 1740 ccgattcattaatgcagctggcacgacaggtttcccgactggaaagcgggcagtgagcgc 1800 aacgcaattaatgtaagttagctcactcattaggcaccgggatctcgaccgatgcccttg 1860 agagccttcaacccagtcagctccttccggtgggcgcggggcatgactatcgtcgccgca 1920 cttatgactgtcttctttatcatgcaactcgtaggacaggtgccggcagcgctctgggtc 1980 attttcggcgaggaccgctttcgctggagcgcgacgatgatcggcctgtcgcttgcggta 2040 ttcggaatcttgcacgccctcgctcaagccttcgtcactggtcccgccaccaaacgtttc 2100 ggcgagaagcaggccattatcgccggcatggcggccccacgggtgcgcatgatcgtgctc 2160 ctgtcgttgaggacccggctaggctggcggggttgccttactggttagcagaatgaatca 2220 ccgatacgcgagcgaacgtgaagcgactgctgctgcaaaacgtctgcgacctgagcaaca 2280 acatgaatggtcttcggtttccgtgtttcgtaaagtctggaaacgcggaagtcagcgccc 2340 tgcaccattatgttccggatctgcatcgcaggatgctgctggctaccctgtggaacacct 2400 acatctgtattaacgaagcgctggcattgaccctgagtgatttttctctggtcccgccgc 2460 atccataccgccagttgtttaccctcacaacgttccagtaaccgggcatgttcatcatca 2520 gtaacccgtatcgtgagcatcctctctcgtttcatcggtatcattacccccatgaacaga 2580 aatcccccttacacggaggcatcagtgaccaaacaggaaaaaaccgcccttaacatggcc 2640 cgctttatcagaagccagacattaacgcttctggagaaactcaacgagctggacgcggat 2700 gaacaggcagacatctgtgaatcgcttcacgaccacgctgatgagctttaccgcagctgc 2760 ctcgcgcgtttcggtgatgacggtgaaaacctctgacacatgcagctcccggagacggtc 2820 acagcttgtctgtaagcggatgccgggagcagacaagcccgtcagggcgcgtcagcgggt 2880 gttggcgggtgtcggggcgcagccatgacccagtcacgtagcgatagcggagtgtatact 2940 ggcttaactatgcggcatcagagcagattgtactgagagtgcaccatatatgcggtgtga 3000 aataccgcacagatgcgtaaggagaaaataccgcatcaggcgctcttccgcttcctcgct 3060 cactgactcgctgcgctcggtcgttcggctgcggcgagcggtatcagctcactcaaaggc 3120 ggtaatacggttatccacagaatcaggggataacgcaggaaagaacatgtgagcaaaagg 3180 ccagcaaaaggccaggaaccgtaaaaaggccgcgttgctggcgtttttccataggctccg 3240 cccccctgacgagcatcacaaaaatcgacgctcaagtcagaggtggcgaaacccgacagg 3300 actataaagataccaggcgtttccccctggaagctccctcgtgcgctctcctgttccgac 3360 cctgccgcttaccggatacctgtccgcctttctcccttcgggaagcgtggcgctttctca 3420 tagctcacgctgtaggtatctcagttcggtgtaggtcgttcgctccaagctgggctgtgt 3480 gcacgaaccccccgttcagcccgaccgctgcgccttatccggtaactatcgtcttgagtc 3540 caacccggtaagacacgacttatcgccactggcagcagccactggtaacaggattagcag 3600 agcgaggtatgtaggcggtgctacagagttcttgaagtggtggcctaactacggctacac 3660 tagaaggacagtatttggtatctgcgctctgctgaagccagttaccttcggaaaaagagt 3720 tggtagctcttgatccggcaaacaaaccaccgctggtagcggtggtttttttgtttgcaa 3780 gcagcagattacgcgcagaaaaaaaggatctcaagaagatcctttgatcttttctacggg 3840 gtctgacgctcagtggaacgaaaactcacgttaagggattttggtcatgaacaataaaac 3900 tgtctgcttacataaacagtaatacaaggggtgttatgagccatattcaacgggaaacgt 3960 cttgctctaggccgcgattaaattccaacatggatgctgatttatatgggtataaatggg 4020 ctcgcgataatgtcgggcaatcaggtgcgacaatctatcgattgtatgggaagcccgatg 4080 cgccagagttgtttctgaaacatggcaaaggtagcgttgccaatgatgttacagatgaga 4140 tggtcagactaaactggctgacggaatttatgcctcttccgaccatcaagcattttatcc 4200 gtactcctgatgatgcatggttactcaccactgcgatccccgggaaaacagcattccagg 4260 tattagaagaatatcctgattcaggtgaaaatattgttgatgcgctggcagtgttcctgc 4320 gccggttgcattcgattcctgtttgtaattgtccttttaacagcgatcgcgtatttcgtc 4380 tcgctcaggcgcaatcacgaatgaataacggtttggttgatgcgagtgattttgatgacg 4440 agcgtaatggctggcctgttgaacaagtctggaaagaaatgcataaacttttgccattct 4500 caccggattcagtcgtcactcatggtgatttctcacttgataaccttatttttgacgagg 4560 ggaaattaataggttgtattgatgttggacgagtcggaatcgcagaccgataccaggatc 4620 ttgccatcctatggaactgcctcggtgagttttctccttcattacagaaacggctttttc 4680 aaaaatatggtattgataatcctgatatgaataaattgcagtttcatttgatgctcgatg 4740 agtttttctaagaattaattcatgagcggatacatatttgaatgtatttagaaaaataaa 4800 caaataggggttccgcgcacatttccccgaaaagtgccacctgaaattgtaaacgttaat 4860 attttgttaaaattcgcgttaaatttttgttaaatcagctcattttttaaccaataggcc 4920 gaaatcggcaaaatcccttataaatcaaaagaatagaccgagatagggttgagtgttgtt 4980 ccagtttggaacaagagtccactattaaagaacgtggactccaacgtcaaagggcgaaaa 5040 accgtctatcagggcgatggcccactacgtgaaccatcaccctaatcaagttttttgggg 5100 tcgaggtgccgtaaagcactaaatcggaaccctaaagggagcccccgatttagagcttga 5160 cggggaaagccggcgaacgtggcgagaaaggaagggaagaaagcgaaaggagcgggcgct 5220 agggcgctggcaagtgtagcggtcacgctgcgcgtaaccaccacacccgccgcgcttaat 5280 gcgccgctacagggcgcgtcccattcgcca 5310 SEQIDNO:10 tggcgaatgggacgcgccctgtagcggcgcattaagcgcggcgggtgtggtggttacgcg 60 cagcgtgaccgctacacttgccagcgccctagcgcccgctcctttcgctttcttcccttc 120 ctttctcgccacgttcgccggctttccccgtcaagctctaaatcgggggctccctttagg 180 gttccgatttagtgctttacggcacctcgaccccaaaaaacttgattagggtgatggttc 240 acgtagtgggccatcgccctgatagacggtttttcgccctttgacgttggagtccacgtt 300 ctttaatagtggactcttgttccaaactggaacaacactcaaccctatctcggtctattc 360 ttttgatttataagggattttgccgatttcggcctattggttaaaaaatgagctgattta 420 acaaaaatttaacgcgaattttaacaaaatattaacgtttacaatttcaggtggcacttt 480 tcggggaaatgtgcgcggaacccctatttgtttatttttctaaatacattcaaatatgta 540 tccgctcatgagacaataaccctgataaatgcttcaataatattgaaaaaggaagagtat 600 gagtattcaacatttccgtgtcgcccttattcccttttttgcggcattttgccttcctgt 660 ttttgctcacccagaaacgctggtgaaagtaaaagatgctgaagatcagttgggtgcacg 720 agtgggttacatcgaactggatctcaacagcggtaagatccttgagagttttcgccccga 780 agaacgttttccaatgatgagcacttttaaagttctgctatgtggcgcggtattatcccg 840 tattgacgccgggcaagagcaactcggtcgccgcatacactattctcagaatgacttggt 900 tgagtactcaccagtcacagaaaagcatcttacggatggcatgacagtaagagaattatg 960 cagtgctgccataaccatgagtgataacactgcggccaacttacttctgacaacgatcgg 1020 aggaccgaaggagctaaccgcttttttgcacaacatgggggatcatgtaactcgccttga 1080 tcgttgggaaccggagctgaatgaagccataccaaacgacgagcgtgacaccacgatgcc 1140 tgcagcaatggcaacaacgttgcgcaaactattaactggcgaactacttactctagcttc 1200 ccggcaacaattaatagactggatggaggcggataaagttgcaggaccacttctgcgctc 1260 ggcccttccggctggctggtttattgctgataaatctggagccggtgagcgtgggtctcg 1320 cggtatcattgcagcactggggccagatggtaagccctcccgtatcgtagttatctacac 1380 gacggggagtcaggcaactatggatgaacgaaatagacagatcgctgagataggtgcctc 1440 actgattaagcattggtaactgtcagaccaagtttactcatatatactttagattgattt 1500 aaaacttcatttttaatttaaaaggatctaggtgaagatcctttttgataatctcatgac 1560 caaaatcccttaacgtgagttttcgttccactgagcgtcagaccccgtagaaaagatcaa 1620 aggatcttcttgagatcctttttttctgcgcgtaatctgctgcttgcaaacaaaaaaacc 1680 accgctaccagcggtggtttgtttgccggatcaagagctaccaactctttttccgaaggt 1740 aactggcttcagcagagcgcagataccaaatactgtccttctagtgtagccgtagttagg 1800 ccaccacttcaagaactctgtagcaccgcctacatacctcgctctgctaatcctgttacc 1860 agtggctgctgccagtggcgataagtcgtgtcttaccgggttggactcaagacgatagtt 1920 accggataaggcgcagcggtcgggctgaacggggggttcgtgcacacagcccagcttgga 1980 gcgaacgacctacaccgaactgagatacctacagcgtgagctatgagaaagcgccacgct 2040 tcccgaagggagaaaggcggacaggtatccggtaagcggcagggtcggaacaggagagcg 2100 cacgagggagcttccagggggaaacgcctggtatctttatagtcctgtcgggtttcgcca 2160 cctctgacttgagcgtcgatttttgtgatgctcgtcaggggggcggagcctatggaaaaa 2220 cgccagcaacgcggcctttttacggttcctggccttttgctggccttttgctcacatgtt 2280 ctttcctgcgttatcccctgattctgtggataaccgtattaccgcctttgagtgagctga 2340 taccgctcgccgcagccgaacgaccgagcgcagcgagtcagtgagcgaggaagcggaaga 2400 gcgcctgatgcggtattttctccttacgcatctgtgcggtatttcacaccgcatatatgg 2460 tgcactctcagtacaatctgctctgatgccgcatagttaagccagtatacactccgctat 2520 cgctacgtgactgggtcatggctgcgccccgacacccgccaacacccgctgacgcgccct 2580 gacgggcttgtctgctcccggcatccgcttacagacaagctgtgaccgtctccgggagct 2640 gcatgtgtcagaggttttcaccgtcatcaccgaaacgcgcgaggcagctgcggtaaagct 2700 catcagcgtggtcgtgaagcgattcacagatgtctgcctgttcatccgcgtccagctcgt 2760 tgagtttctccagaagcgttaatgtctggcttctgataaagcgggccatgttaagggcgg 2820 ttttttcctgtttggtcactgatgcctccgtgtaagggggatttctgttcatgggggtaa 2880 tgataccgatgaaacgagagaggatgctcacgatacgggttactgatgatgaacatgccc 2940 ggttactggaacgttgtgagggtaaacaactggcggtatggatgcggcgggaccagagaa 3000 aaatcactcagggtcaatgccagcgcttcgttaatacagatgtaggtgttccacagggta 3060 gccagcagcatcctgcgatgcagatccggaacataatggtgcagggcgctgacttccgcg 3120 tttccagactttacgaaacacggaaaccgaagaccattcatgttgttgctcaggtcgcag 3180 acgttttgcagcagcagtcgcttcacgttcgctcgcgtatcggtgattcattctgctaac 3240 cagtaaggcaaccccgccagcctagccgggtcctcaacgacaggagcacgatcatgcgca 3300 cccgtggggccgccatgccggcgataatggcctgcttctcgccgaaacgtttggtggcgg 3360 gaccagtgacgaaggcttgagcgagggcgtgcaagattccgaataccgcaagcgacaggc 3420 cgatcatcgtcgcgctccagcgaaagcggtcctcgccgaaaatgacccagagcgctgccg 3480 gcacctgtcctacgagttgcatgataaagaagacagtcataagtgcggcgacgatagtca 3540 tgccccgcgcccaccggaaggagctgactgggttgaaggctctcaagggcatcggtcgag 3600 atcccggtgcctaatgagtgagctaacttacattaattgcgttgcgctcactgcccgctt 3660 tccagtcgggaaacctgtcgtgccagctgcattaatgaatcggccaacgcgcggggagag 3720 gcggtttgcgtattgggcgccagggtggtttttcttttcaccagtgagacgggcaacagc 3780 tgattgcccttcaccgcctggccctgagagagttgcagcaagcggtccacgctggtttgc 3840 cccagcaggcgaaaatcctgtttgatggtggttaacggcgggatataacatgagctgtct 3900 tcggtatcgtcgtatcccactaccgagatatccgcaccaacgcgcagcccggactcggta 3960 atggcgcgcattgcgcccagcgccatctgatcgttggcaaccagcatcgcagtgggaacg 4020 atgccctcattcagcatttgcatggtttgttgaaaaccggacatggcactccagtcgcct 4080 tcccgttccgctatcggctgaatttgattgcgagtgagatatttatgccagccagccaga 4140 cgcagacgcgccgagacagaacttaatgggcccgctaacagcgcgatttgctggtgaccc 4200 aatgcgaccagatgctccacgcccagtcgcgtaccgtcttcatgggagaaaataatactg 4260 ttgatgggtgtctggtcagagacatcaagaaataacgccggaacattagtgcaggcagct 4320 tccacagcaatggcatcctggtcatccagcggatagttaatgatcagcccactgacgcgt 4380 tgcgcgagaagattgtgcaccgccgctttacaggcttcgacgccgcttcgttctaccatc 4440 gacaccaccacgctggcacccagttgatcggcgcgagatttaatcgccgcgacaatttgc 4500 gacggcgcgtgcagggccagactggaggtggcaacgccaatcagcaacgactgtttgccc 4560 gccagttgttgtgccacgcggttgggaatgtaattcagctccgccatcgccgcttccact 4620 ttttcccgcgttttcgcagaaacgtggctggcctggttcaccacgcgggaaacggtctga 4680 taagagacaccggcatactctgcgacatcgtataacgttactggtttcacattcaccacc 4740 ctgaattgactctcttccgggcgctatcatgccataccgcgaaaggttttgcgccattcg 4800 atggtgtccgggatctcgacgctctcccttatgcgactcctgcattaggaagcagcccag 4860 tagtaggttgaggccgttgagcaccgccgccgcaaggaatggtgcatgcaaggagatggc 4920 gcccaacagtcccccggccacggggcctgccaccatacccacgccgaaacaagcgctcat 4980 gagcccgaagtggcgagcccgatcttccccatcggtgatgtcggcgatataggcgccagc 5040 aaccgcacctgtggcgccggtgatgccggccacgatgcgtccggcgtagaggatcgagat 5100 ctcgatcccgcgaaattaatacgactcactataggggaattgtgagcggataacaattcc 5160 cctctagaaataattttgtttaactttaagaaggagatatacatatggctagcatgactg 5220 gtggacagcaaatgggtcgcggatccgaattcgagctccgtcgacaagcttgcggccgca 5280 ctcgagcaccaccaccaccaccactgagatccggctgctaacaaagcccgaaaggaagct 5340 gagttggctgctgccaccgctgagcaataactagcataaccccttggggcctctaaacgg 5400 gtcttgaggggttttttgctgaaaggaggaactatatccggat 5443 SEQIDNO:11 atccggatatagttcctcctttcagcaaaaaacccctcaagacccgtttagaggccccaa 60 ggggttatgctagttattgctcagcggtggcagcagccaactcagcttcctttcgggctt 120 tgttagcagccggatctcagtggtggtggtggtggtgctcgagggatcaatactaggagg 180 agtagcatataattacgttacacaattttataacccaatatattcaatagaccttatgct 240 tatcctatcctctattctaagattctcggtatctcccctattcttgaccataaaagatac 300 tcgctcaaagcttaaataatattaatcataaataaagtcatgtactcatttccaaatagc 360 tttaggtttggttggtcccaggccggatttcaatcagaaatgggaacaccagggtcagaa 420 gatccaaatactgactggtataaatgggttcatgatccagaaaacatggcagcgggatta 480 gtaagtggagatctaccagaaaatgggccaggctactggggaaactataagacatttcac 540 gataatgcacaaaaaatgggattaaaaatagctagactaaatgtggaatggtctaggata 600 tttcctaatccattaccaaggccacaaaactttgatgaatcaaaacaagatgtgacagag 660 gttgagataaacgaaaacgagttaaagagacttgacgagtacgctaataaagacgcatta 720 aaccattacagggaaatattcaaggatcttaaaagtagaggactttactttatactaaac 780 atgtatcattggccattacctctatggttacacgacccaataagagtaagaagaggagat 840 tttactggaccaagtggttggctaagtactagaacagtttacgaattcgctagattctca 900 gcttatatagcttggaaattcgatgatctagtggatgagtactcaacaatgaatgaacct 960 aacgttgttggaggtttaggatacgttggtgttaagtccggttttcccccaggataccta 1020 agctttgaactttcccgtagggcaatgtataacatcattcaagctcacgcaagagcgtat 1080 gatgggataaagagtgtttctaaaaaaccagttggaattatttacgctaatagctcattc 1140 cagccgttaacggataaagatatggaagcggtagagatggctgaaaatgataatagatgg 1200 tggttctttgatgctataataagaggtgagatcaccagaggaaacgagaagattgtaaga 1260 gatgacctaaagggtagattggattggattggagttaattattacactaggactgttgtg 1320 aagaggactgaaaagggatacgttagcttaggaggttacggtcacggatgtgagaggaat 1380 tctgtaagtttagcgggattaccaaccagcgacttcggctgggagttcttcccagaaggt 1440 ttatatgacgttttgacgaaatactggaatagatatcatctctatatgtacgttactgaa 1500 aatggtattgcggatgatgccgattatcaaaggccctattatttagtatctcacgtttat 1560 caagttcatagagcaataaatagtggtgcagatgttagagggtatttacattggtctcta 1620 gctgataattacgaatgggcttcaggattctctatgaggtttggtctgttaaaggtcgat 1680 tacaacactaagagactatactggagaccctcagcactagtatatagggaaatcgccaca 1740 aatggcgcaataactgatgaaatagagcacttaaatagcgtacctccagtaaagccatta 1800 aggcactaaactttctcaagtctcactataccaaatgagttttcttttaatcttattcta 1860 atctcattttcattagattgcaatactttcataccttctatattatttattttgtacctt 1920 ttgggatccatatgtatatctccttcttaaagttaaacaaaattatttctagaggggaat 1980 tgttatccgctcacaattcccctatagtgagtcgtattaatttcgcgggatcgagatctc 2040 gatcctctacgccggacgcatcgtggccggcatcaccggcgccacaggtgcggttgctgg 2100 cgcctatatcgccgacatcaccgatggggaagatcgggctcgccacttcgggctcatgag 2160 cgcttgtttcggcgtgggtatggtggcaggccccgtggccgggggactgttgggcgccat 2220 ctccttgcatgcaccattccttgcggcggcggtgctcaacggcctcaacctactactggg 2280 ctgcttcctaatgcaggagtcgcataagggagagcgtcgagatcccggacaccatcgaat 2340 ggcgcaaaacctttcgcggtatggcatgatagcgcccggaagagagtcaattcagggtgg 2400 tgaatgtgaaaccagtaacgttatacgatgtcgcagagtatgccggtgtctcttatcaga 2460 ccgtttcccgcgtggtgaaccaggccagccacgtttctgcgaaaacgcgggaaaaagtgg 2520 aagcggcgatggcggagctgaattacattcccaaccgcgtggcacaacaactggcgggca 2580 aacagtcgttgctgattggcgttgccacctccagtctggccctgcacgcgccgtcgcaaa 2640 ttgtcgcggcgattaaatctcgcgccgatcaactgggtgccagcgtggtggtgtcgatgg 2700 tagaacgaagcggcgtcgaagcctgtaaagcggcggtgcacaatcttctcgcgcaacgcg 2760 tcagtgggctgatcattaactatccgctggatgaccaggatgccattgctgtggaagctg 2820 cctgcactaatgttccggcgttatttcttgatgtctctgaccagacacccatcaacagta 2880 ttattttctcccatgaagacggtacgcgactgggcgtggagcatctggtcgcattgggtc 2940 accagcaaatcgcgctgttagcgggcccattaagttctgtctcggcgcgtctgcgtctgg 3000 ctggctggcataaatatctcactcgcaatcaaattcagccgatagcggaacgggaaggcg 3060 actggagtgccatgtccggttttcaacaaaccatgcaaatgctgaatgagggcatcgttc 3120 ccactgcgatgctggttgccaacgatcagatggcgctgggcgcaatgcgcgccattaccg 3180 agtccgggctgcgcgttggtgcggatatctcggtagtgggatacgacgataccgaagaca 3240 gctcatgttatatcccgccgttaaccaccatcaaacaggattttcgcctgctggggcaaa 3300 ccagcgtggaccgcttgctgcaactctctcagggccaggcggtgaagggcaatcagctgt 3360 tgcccgtctcactggtgaaaagaaaaaccaccctggcgcccaatacgcaaaccgcctctc 3420 cccgcgcgttggccgattcattaatgcagctggcacgacaggtttcccgactggaaagcg 3480 ggcagtgagcgcaacgcaattaatgtaagttagctcactcattaggcaccgggatctcga 3540 ccgatgcccttgagagccttcaacccagtcagctccttccggtgggcgcggggcatgact 3600 atcgtcgccgcacttatgactgtcttctttatcatgcaactcgtaggacaggtgccggca 3660 gcgctctgggtcattttcggcgaggaccgctttcgctggagcgcgacgatgatcggcctg 3720 tcgcttgcggtattcggaatcttgcacgccctcgctcaagccttcgtcactggtcccgcc 3780 accaaacgtttcggcgagaagcaggccattatcgccggcatggcggccccacgggtgcgc 3840 atgatcgtgctcctgtcgttgaggacccggctaggctggcggggttgccttactggttag 3900 cagaatgaatcaccgatacgcgagcgaacgtgaagcgactgctgctgcaaaacgtctgcg 3960 acctgagcaacaacatgaatggtcttcggtttccgtgtttcgtaaagtctggaaacgcgg 4020 aagtcagcgccctgcaccattatgttccggatctgcatcgcaggatgctgctggctaccc 4080 tgtggaacacctacatctgtattaacgaagcgctggcattgaccctgagtgatttttctc 4140 tggtcccgccgcatccataccgccagttgtttaccctcacaacgttccagtaaccgggca 4200 tgttcatcatcagtaacccgtatcgtgagcatcctctctcgtttcatcggtatcattacc 4260 cccatgaacagaaatcccccttacacggaggcatcagtgaccaaacaggaaaaaaccgcc 4320 cttaacatggcccgctttatcagaagccagacattaacgcttctggagaaactcaacgag 4380 ctggacgcggatgaacaggcagacatctgtgaatcgcttcacgaccacgctgatgagctt 4440 taccgcagctgcctcgcgcgtttcggtgatgacggtgaaaacctctgacacatgcagctc 4500 ccggagacggtcacagcttgtctgtaagcggatgccgggagcagacaagcccgtcagggc 4560 gcgtcagcgggtgttggcgggtgtcggggcgcagccatgacccagtcacgtagcgatagc 4620 ggagtgtatactggcttaactatgcggcatcagagcagattgtactgagagtgcaccata 4680 tatgcggtgtgaaataccgcacagatgcgtaaggagaaaataccgcatcaggcgctcttc 4740 cgcttcctcgctcactgactcgctgcgctcggtcgttcggctgcggcgagcggtatcagc 4800 tcactcaaaggcggtaatacggttatccacagaatcaggggataacgcaggaaagaacat 4860 gtgagcaaaaggccagcaaaaggccaggaaccgtaaaaaggccgcgttgctggcgttttt 4920 ccataggctccgcccccctgacgagcatcacaaaaatcgacgctcaagtcagaggtggcg 4980 aaacccgacaggactataaagataccaggcgtttccccctggaagctccctcgtgcgctc 5040 tcctgttccgaccctgccgcttaccggatacctgtccgcctttctcccttcgggaagcgt 5100 ggcgctttctcatagctcacgctgtaggtatctcagttcggtgtaggtcgttcgctccaa 5160 gctgggctgtgtgcacgaaccccccgttcagcccgaccgctgcgccttatccggtaacta 5220 tcgtcttgagtccaacccggtaagacacgacttatcgccactggcagcagccactggtaa 5280 caggattagcagagcgaggtatgtaggcggtgctacagagttcttgaagtggtggcctaa 5340 ctacggctacactagaaggacagtatttggtatctgcgctctgctgaagccagttacctt 5400 cggaaaaagagttggtagctcttgatccggcaaacaaaccaccgctggtagcggtggttt 5460 ttttgtttgcaagcagcagattacgcgcagaaaaaaaggatctcaagaagatcctttgat 5520 cttttctacggggtctgacgctcagtggaacgaaaactcacgttaagggattttggtcat 5580 gaacaataaaactgtctgcttacataaacagtaatacaaggggtgttatgagccatattc 5640 aacgggaaacgtcttgctctaggccgcgattaaattccaacatggatgctgatttatatg 5700 ggtataaatgggctcgcgataatgtcgggcaatcaggtgcgacaatctatcgattgtatg 5760 ggaagcccgatgcgccagagttgtttctgaaacatggcaaaggtagcgttgccaatgatg 5820 ttacagatgagatggtcagactaaactggctgacggaatttatgcctcttccgaccatca 5880 agcattttatccgtactcctgatgatgcatggttactcaccactgcgatccccgggaaaa 5940 cagcattccaggtattagaagaatatcctgattcaggtgaaaatattgttgatgcgctgg 6000 cagtgttcctgcgccggttgcattcgattcctgtttgtaattgtccttttaacagcgatc 6060 gcgtatttcgtctcgctcaggcgcaatcacgaatgaataacggtttggttgatgcgagtg 6120 attttgatgacgagcgtaatggctggcctgttgaacaagtctggaaagaaatgcataaac 6180 ttttgccattctcaccggattcagtcgtcactcatggtgatttctcacttgataacctta 6240 tttttgacgaggggaaattaataggttgtattgatgttggacgagtcggaatcgcagacc 6300 gataccaggatcttgccatcctatggaactgcctcggtgagttttctccttcattacaga 6360 aacggctttttcaaaaatatggtattgataatcctgatatgaataaattgcagtttcatt 6420 tgatgctcgatgagtttttctaagaattaattcatgagcggatacatatttgaatgtatt 6480 tagaaaaataaacaaataggggttccgcgcacatttccccgaaaagtgccacctgaaatt 6540 gtaaacgttaatattttgttaaaattcgcgttaaatttttgttaaatcagctcatttttt 6600 aaccaataggccgaaatcggcaaaatcccttataaatcaaaagaatagaccgagataggg 6660 ttgagtgttgttccagtttggaacaagagtccactattaaagaacgtggactccaacgtc 6720 aaagggcgaaaaaccgtctatcagggcgatggcccactacgtgaaccatcaccctaatca 6780 agttttttggggtcgaggtgccgtaaagcactaaatcggaaccctaaagggagcccccga 6840 tttagagcttgacggggaaagccggcgaacgtggcgagaaaggaagggaagaaagcgaaa 6900 ggagcgggcgctagggcgctggcaagtgtagcggtcacgctgcgcgtaaccaccacaccc 6960 gccgcgcttaatgcgccgctacagggcgcgtcccattcgcca 7002 SEQIDNO:12 ggcgaatgggacgcgccctgtagcggcgcattaagcgcggcgggtgtggtggttacgcgc 60 agcgtgaccgctacacttgccagcgccctagcgcccgctcctttcgctttcttcccttcc 120 tttctcgccacgttcgccggctttccccgtcaagctctaaatcgggggctccctttaggg 180 ttccgatttagtgctttacggcacctcgaccccaaaaaacttgattagggtgatggttca 240 cgtagtgggccatcgccctgatagacggtttttcgccctttgacgttggagtccacgttc 300 tttaatagtggactcttgttccaaactggaacaacactcaaccctatctcggtctattct 360 tttgatttataagggattttgccgatttcggcctattggttaaaaaatgagctgatttaa 420 caaaaatttaacgcgaattttaacaaaatattaacgtttacaatttcaggtggcactttt 480 cggggaaatgtgcgcggaacccctatttgtttatttttctaaatacattcaaatatgtat 540 ccgctcatgagacaataaccctgataaatgcttcaataatattgaaaaaggaagagtatg 600 agtattcaacatttccgtgtcgcccttattcccttttttgcggcattttgccttcctgtt 660 tttgctcacccagaaacgctggtgaaagtaaaagatgctgaagatcagttgggtgcacga 720 gtgggttacatcgaactggatctcaacagcggtaagatccttgagagttttcgccccgaa 780 gaacgttttccaatgatgagcacttttaaagttctgctatgtggcgcggtattatcccgt 840 attgacgccgggcaagagcaactcggtcgccgcatacactattctcagaatgacttggtt 900 gagtactcaccagtcacagaaaagcatcttacggatggcatgacagtaagagaattatgc 960 agtgctgccataaccatgagtgataacactgcggccaacttacttctgacaacgatcgga 1020 ggaccgaaggagctaaccgcttttttgcacaacatgggggatcatgtaactcgccttgat 1080 cgttgggaaccggagctgaatgaagccataccaaacgacgagcgtgacaccacgatgcct 1140 gcagcaatggcaacaacgttgcgcaaactattaactggcgaactacttactctagcttcc 1200 cggcaacaattaatagactggatggaggcggataaagttgcaggaccacttctgcgctcg 1260 gcccttccggctggctggtttattgctgataaatctggagccggtgagcgtgggtctcgc 1320 ggtatcattgcagcactggggccagatggtaagccctcccgtatcgtagttatctacacg 1380 acggggagtcaggcaactatggatgaacgaaatagacagatcgctgagataggtgcctca 1440 ctgattaagcattggtaactgtcagaccaagtttactcatatatactttagattgattta 1500 aaacttcatttttaatttaaaaggatctaggtgaagatcctttttgataatctcatgacc 1560 aaaatcccttaacgtgagttttcgttccactgagcgtcagaccccgtagaaaagatcaaa 1620 ggatcttcttgagatcctttttttctgcgcgtaatctgctgcttgcaaacaaaaaaacca 1680 ccgctaccagcggtggtttgtttgccggatcaagagctaccaactctttttccgaaggta 1740 actggcttcagcagagcgcagataccaaatactgtccttctagtgtagccgtagttaggc 1800 caccacttcaagaactctgtagcaccgcctacatacctcgctctgctaatcctgttacca 1860 gtggctgctgccagtggcgataagtcgtgtcttaccgggttggactcaagacgatagtta 1920 ccggataaggcgcagcggtcgggctgaacggggggttcgtgcacacagcccagcttggag 1980 cgaacgacctacaccgaactgagatacctacagcgtgagctatgagaaagcgccacgctt 2040 cccgaagggagaaaggcggacaggtatccggtaagcggcagggtcggaacaggagagcgc 2100 acgagggagcttccagggggaaacgcctggtatctttatagtcctgtcgggtttcgccac 2160 ctctgacttgagcgtcgatttttgtgatgctcgtcaggggggcggagcctatggaaaaac 2220 gccagcaacgcggcctttttacggttcctggccttttgctggccttttgctcacatgttc 2280 tttcctgcgttatcccctgattctgtggataaccgtattaccgcctttgagtgagctgat 2340 accgctcgccgcagccgaacgaccgagcgcagcgagtcagtgagcgaggaagcggaagag 2400 cgcctgatgcggtattttctccttacgcatctgtgcggtatttcacaccgcatatatggt 2460 gcactctcagtacaatctgctctgatgccgcatagttaagccagtatacactccgctatc 2520 gctacgtgactgggtcatggctgcgccccgacacccgccaacacccgctgacgcgccctg 2580 acgggcttgtctgctcccggcatccgcttacagacaagctgtgaccgtctccgggagctg 2640 catgtgtcagaggttttcaccgtcatcaccgaaacgcgcgaggcagctgcggtaaagctc 2700 atcagcgtggtcgtgaagcgattcacagatgtctgcctgttcatccgcgtccagctcgtt 2760 gagtttctccagaagcgttaatgtctggcttctgataaagcgggccatgttaagggcggt 2820 tttttcctgtttggtcactgatgcctccgtgtaagggggatttctgttcatgggggtaat 2880 gataccgatgaaacgagagaggatgctcacgatacgggttactgatgatgaacatgcccg 2940 gttactggaacgttgtgagggtaaacaactggcggtatggatgcggcgggaccagagaaa 3000 aatcactcagggtcaatgccagcgcttcgttaatacagatgtaggtgttccacagggtag 3060 ccagcagcatcctgcgatgcagatccggaacataatggtgcagggcgctgacttccgcgt 3120 ttccagactttacgaaacacggaaaccgaagaccattcatgttgttgctcaggtcgcaga 3180 cgttttgcagcagcagtcgcttcacgttcgctcgcgtatcggtgattcattctgctaacc 3240 agtaaggcaaccccgccagcctagccgggtcctcaacgacaggagcacgatcatgcgcac 3300 ccgtggggccgccatgccggcgataatggcctgcttctcgccgaaacgtttggtggcggg 3360 accagtgacgaaggcttgagcgagggcgtgcaagattccgaataccgcaagcgacaggcc 3420 gatcatcgtcgcgctccagcgaaagcggtcctcgccgaaaatgacccagagcgctgccgg 3480 cacctgtcctacgagttgcatgataaagaagacagtcataagtgcggcgacgatagtcat 3540 gccccgcgcccaccggaaggagctgactgggttgaaggctctcaagggcatcggtcgaga 3600 tcccggtgcctaatgagtgagctaacttacattaattgcgttgcgctcactgcccgcttt 3660 ccagtcgggaaacctgtcgtgccagctgcattaatgaatcggccaacgcgcggggagagg 3720 cggtttgcgtattgggcgccagggtggtttttcttttcaccagtgagacgggcaacagct 3780 gattgcccttcaccgcctggccctgagagagttgcagcaagcggtccacgctggtttgcc 3840 ccagcaggcgaaaatcctgtttgatggtggttaacggcgggatataacatgagctgtctt 3900 cggtatcgtcgtatcccactaccgagatatccgcaccaacgcgcagcccggactcggtaa 3960 tggcgcgcattgcgcccagcgccatctgatcgttggcaaccagcatcgcagtgggaacga 4020 tgccctcattcagcatttgcatggtttgttgaaaaccggacatggcactccagtcgcctt 4080 cccgttccgctatcggctgaatttgattgcgagtgagatatttatgccagccagccagac 4140 gcagacgcgccgagacagaacttaatgggcccgctaacagcgcgatttgctggtgaccca 4200 atgcgaccagatgctccacgcccagtcgcgtaccgtcttcatgggagaaaataatactgt 4260 tgatgggtgtctggtcagagacatcaagaaataacgccggaacattagtgcaggcagctt 4320 ccacagcaatggcatcctggtcatccagcggatagttaatgatcagcccactgacgcgtt 4380 gcgcgagaagattgtgcaccgccgctttacaggcttcgacgccgcttcgttctaccatcg 4440 acaccaccacgctggcacccagttgatcggcgcgagatttaatcgccgcgacaatttgcg 4500 acggcgcgtgcagggccagactggaggtggcaacgccaatcagcaacgactgtttgcccg 4560 ccagttgttgtgccacgcggttgggaatgtaattcagctccgccatcgccgcttccactt 4620 tttcccgcgttttcgcagaaacgtggctggcctggttcaccacgcgggaaacggtctgat 4680 aagagacaccggcatactctgcgacatcgtataacgttactggtttcacattcaccaccc 4740 tgaattgactctcttccgggcgctatcatgccataccgcgaaaggttttgcgccattcga 4800 tggtgtccgggatctcgacgctctcccttatgcgactcctgcattaggaagcagcccagt 4860 agtaggttgaggccgttgagcaccgccgccgcaaggaatggtgcatgcaaggagatggcg 4920 cccaacagtcccccggccacggggcctgccaccatacccacgccgaaacaagcgctcatg 4980 agcccgaagtggcgagcccgatcttccccatcggtgatgtcggcgatataggcgccagca 5040 accgcacctgtggcgccggtgatgccggccacgatgcgtccggcgtagaggatcgagatc 5100 tcgatcccgcgaaattaatacgactcactataggggaattgtgagcggataacaattccc 5160 ctctagaaataattttgtttaactttaagaaggagatatacatatgatgtcctacaggat 5220 agtggttgatccaaaaaaagttgtcaagccgattagtagacacatctacggtcatttcac 5280 ggaacatctgggaaggtgtatctacggcggaatttatgaagaaggttctccgctctccga 5340 tgaaaggggtttcagaaaggacgttctggaggctgtaaagaggataaaagttccgaactt 5400 gagatggcccggtggaaactttgtgtcgaactaccactgggaagacggaataggtcccaa 5460 agatcagaggcctgtcaggttcgatctcgcctggcaacaggaagagacgaatagatttgg 5520 aacggacgaattcattgagtactgtcgtgagataggagcagaaccttacatcagtataaa 5580 catgggaactggaacactcgacgaagctctccactggcttgaatactgcaatggaaaggg 5640 taatacctactacgctcaactcagaagaaagtacggtcatccagaaccttacaacgtaaa 5700 gttctggggaataggcaacgagatgtacggggaatggcaggtaggccacatgacggcgga 5760 cgaatacgcaagagccgccaaagaatacacgaaatggatgaaggttttcgatcctacaat 5820 taaagcgatcgccgtgggctgtgacgaccctatatggaatctcagggttcttcaagaagc 5880 aggtgatgtgattgacttcatatcctaccatttctacacagggtccgaggattactacga 5940 aacagtttccacggtttaccttctcaaagaaagactcatcggagtgaaaaagctcattga 6000 tatggtggatactgctagaaagagaggtgtcaaaatcgcccttgatgaatggaacgtatg 6060 gtacagagtgtccgataacaagctcgaagaaccttacgatctcaaagatggtatctttgc 6120 atgtggagtgcttgtacttcttcaaaagatgagcgacatagtcccacttgccaatctcgc 6180 acagcttgtaaacgcccttggagctatacacaccgagaaagacggtctcattctcacacc 6240 cgtttacaaggcttttgaactcatcgtgaatcattccggagaaaagcttgtcaagaccca 6300 tgttgaatcggagacttacaacatagaaggagtcatgttcatcaacaaaatgcctttctc 6360 tgtcgagaacgcaccgttccttgatgccgccgcttccatctcagaagatggcaagaaact 6420 tttcatcgctgttgtaaactacaggaaagaagacgctttgaaggttccaatcagagtgga 6480 aggtctgggacagaaaaaagccaccgtttatacactcacaggtccggacgtgaacgcgag 6540 aaacaccatggaaaatccgaacgtcgttgatattacctccgaaaccatcaccgttgacac 6600 cgaatttgaacacacgtttaaaccattctcttgcagtgtgattgaggtagaattggagct 6660 cgagcaccaccaccaccaccactgagatccggctgctaacaaagcccgaaaggaagctga 6720 gttggctgctgccaccgctgagcaataactagcataaccccttggggcctctaaacgggt 6780 cttgaggggttttttgctgaaaggaggaactatatccggat 6821 SEQIDNO:13 atggcagctaaagacgtaaaattcggtaacgacgctcgtgtgaaaatgctgcgcggcgta 60 aacgtactggcagatgcagtgaaagttaccctcggtccgaaaggccgtaacgtagttctg 120 gataaatctttcggtgcaccgaccatcaccaaagatggtgtttccgttgctcgtgaaatc 180 gaactggaagacaagttcgaaaatatgggtgcgcagatggtgaaagaagttgcctccaaa 240 gcgaacgacgctgcaggcgacggtaccaccactgcaaccgtactggctcaggctatcatc 300 actgaaggtctgaaagctgttgctgcgggcatgaacccgatggacctgaaacgtggtatc 360 gacaaagcggttaccgctgcagttgaagaactgaaagcgctgtccgtaccgtgctctgat 420 tctaaagcgattgctcaggttggtaccatctccgctaactccgacgaaaccgtaggtaaa 480 ctgatcgcagaagcgatggacaaagtcggtaaagaaggcgttatcaccgttgaagacggt 540 accggtctgcaggacgaactggacgtggttgaaggtatgcagttcgaccgtggctacctg 600 tctccttacttcatcaacaagccggaaactggcgcagtagaactggaaagcccgttcatc 660 ctgctggctgacaagaaaatctccaacatccgcgaaatgctgccggttctggaagctgtt 720 gcaaaagcaggtaaaccgctgctgatcatcgctgaagatgtagaaggcgaagcgctggca 780 actctggttgttaacaccatgcgtggcatcgtgaaagtcgctgcggttaaagcaccgggc 840 ttcggcgatcgtcgtaaagctatgctgcaggatatcgcaaccctgactggcggtaccgtg 900 atctctgaagagatcggtatggagctggaaaaagcaaccctggaagacctgggtcaggct 960 aaacgtgttgtgatcaacaaagacaccaccactatcatcgatggcgtgggtgaagaagct 1020 gcaatccagggccgtgttgctcagatccgtcagcagattgaagaagcaacttctgactac 1080 gaccgtgaaaaactgcaggaacgcgtagcgaaactggcaggcggcgttgcagttatcaaa 1140 gtaggtgctgctaccgaagttgaaatgaaagagaaaaaagcacgcgttgaagatgccctg 1200 cacgcgacccgtgcagcggtagaagagggcgtggttgctggtggtggtgttgcgctgatc 1260 cgcgtagcgtctaaactggctgacctgcgtggtcagaacgaagaccagaacgtgggtatc 1320 aaagttgcactgcgtgcaatggaagctccgctgcgtcagatcgtattgaactgcggcgaa 1380 gaaccgtctgttgttgctaacaccgttaaaggcggcgacggcaactacggttacaacgca 1440 gcaaccgaagaatacggcaacatgatcgacatgggtatcctggatccaaccaaagtaact 1500 cgttctgctctgcagtacgcagcttctgtggctggcctgatgatcaccaccgagtgcatg 1560 gttaccgacctgccgaaaaacgatgcagctgacttaggcgctgctggcggtatgggcggc 1620 atgggtggcatgggcggcatgatgtaa 1647 SEQIDNO:14 atgaatattcgtccattgcatgatcgcgtgatcgtcaagcgtaaagaagttgaaactaaa 60 tctgctggcggcatcgttctgaccggctctgcagcggctaaatccacccgtggcgaagtg 120 ctggctgtcggcaatggccgtatccttgaaaatggcgaagtgaagccgctggatgtgaaa 180 gttggcgacatcgttattttcaacgatggctacggtgtgaaatctgagaagatcgacaat 240 gaagaagtgttgatcatgtccgaaagcgacattctggcaattgttgaagcgtaa 29