Promiscuous enzymes and serendipitous metabolic pathways

Although metabolic enzymes are usually highly efficient and specific, they often have inefficient promiscuous activities due to the reactive environments at active sites. Promiscuous activities can become important for fitness if the environment changes, and can provide a starting place for evolution of new enzymes. The evolutionary potential of promiscuous enzymes goes beyond this, however. Promiscuous activities can be patched together to form multi‐step “serendipitous” pathways. Mutations that increase expression or activity of enzymes in such pathways can elevate flux to physiologically significant levels. We have characterized a multi‐step serendipitous pathway that restores synthesis of PLP in E. coli when the normal pathway is blocked. Introduction of a serendipitous pathway into an existing metabolic network can lead to inhibitory cross‐talk due to interactions between metabolites and macromolecules that have not previously encountered one another. We have identified several adventitious interactions between this serendipitous pathway and the metabolic network that interfere with the function of the pathway and the fitness of the bacterium. These findings have important implications for evolutionary studies of the emergence of novel pathways in nature as well as genetic engineering of microbes for “green” manufacturing processes.