The disclosure provides systems, methods, reagents, apparatuses, vectors, and host cells for the discovery and evolution of metabolic pathways that produce small molecules that modulate enzyme function.

Provided are high-throughput screens for biologically active modulators of a target enzyme that mimic or recreate natural processes of diversification and selection. In some embodiments, the platform comprises one or more expression systems including without limitation (i) a two-hybrid system that, when expressed in a cell, links survival of the cell to the modulation of a therapeutic target, and (ii) a metabolic system that enables the biosynthesis of structurally varied modulators of the therapeutic agent.