An evolutionary biochemist's perspective on promiscuity

•Promiscuous enzymes catalyze physiologically irrelevant secondary reactions.•Promiscuous activities are not always inefficient.•The concept of promiscuity can be easily extended to noncatalytic proteins.•Promiscuous functions can be the starting point for the evolution of new functions.•Promiscuous functions are used for a wide range of biotechnological applications.

Evolutionary biochemists define enzyme promiscuity as the ability to catalyze secondary reactions that are physiologically irrelevant, either because they are too inefficient to affect fitness or because the enzyme never encounters the substrate. Promiscuous activities are common because evolution of a perfectly specific active site is both difficult and unnecessary; natural selection ceases when the performance of a protein is ‘good enough’ that it no longer affects fitness. Although promiscuous functions are accidental and physiologically irrelevant, they are of great importance because they provide opportunities for the evolution of new functions in nature and in the laboratory, as well as targets for therapeutic drugs and tools for a wide range of technological applications.