How to Recruit a Promiscuous Enzyme to Serve a New Function

Promiscuous enzymes can be recruited to serve new functions when a genetic or environmental change makes catalysis of a novel reaction important for fitness or even survival. Subsequently, gene duplication and divergence can lead to evolution of an efficient and specialized new enzyme. Every organism likely has thousands of promiscuous enzyme activities that provide a vast reservoir of catalytic potential. However, much of this potential may not be accessible. We compiled kinetic parameters for promiscuous reactions catalyzed by 108 enzymes. The median value of k_cat/K_M is a very modest 31 M^-1 s^-1. Based upon the fluxes through metabolic pathways in E. coli, we estimate that many, if not most, promiscuous activities are too inefficient to impact fitness. However, mutations can elevate the level of an insufficient promiscuous activity by increasing enzyme expression, improving k_cat/K_M, or altering concentrations of the promiscuous and native substrates and allosteric regulators. Particularly in large bacterial populations, stochastic mutations may provide a viable pathway for recruitment of even inefficient promiscuous activities.