Figure 4.

Genetically encoded medicinal chemistry. Shown is an ancestral TOMM produced by a basic biosynthetic cluster consisting of a precursor peptide (A, black arrow), dehydrogenase (B, yellow arrow), cyclodehydratase (C, green arrow), and docking protein (D, blue arrow). Core peptide mutations (black and white striped arrow) and/or altered regiospecificity/chemospecificity of the biosynthetic machinery provide one route to diversify the ancestral TOMM. This not only changes the number and position of cyclized residues, but also can alter the physicochemical properties of the final product. Another method to structurally diversify the TOMM involves the acquisition of ancillary enzymes (X and Y) that carryout additional posttranslational modifications (orange hexagon and red triangle) to diversify the TOMM scaffold. This can result in an entirely new function, relative to the ancestral TOMM.