An evolutionary biochemist's perspective on promiscuity

Abstract

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.

Keywords: enzyme; molecular evolution; promiscuity; substrate ambiguity.

Figure 1

A heat map summarizing the activities of 23 haloacid dehalogenase-like proteins from E. coli with 80 physiological substrates. Activities are given in units of μmol/min/mg of protein. Red boxes indicate proteins that are discussed in the text. Reproduced from J. Biol. Chem. 281, 36149–36161 (2006).

Figure 2

A comparison of the binding of the physiological ligand (biotin) and a non-physiological ligand (8-oxodeoxyguanosine) to avidin. Biotin (A,C) (PDB 2AVI) and 8-oxodeoxyguanosine (B,D) (PDB 2A5B) are shown in the binding pocket of avidin. The flexible loop that closes over the ligand in the biotin-avidin complex is shown in yellow. Cyan, carbon; blue, nitrogen; red, oxygen. C) and d) depict the surface versions of the images shown in a) and b), respectively. Figure was prepared using MacPyMol.

Figure 3

Some transcription factors are more specific than others. Comparison of the affinities of four C-terminally tagged eukaryotic transcription factors belonging to the basic helix-loop-helix (bHLH) family to target DNAs containing all sequence permutations of the four-nucleotide binding site. A) human MAX isoform A; B) human MAX isoform B; C) yeast Pho4p; and D) yeast Cbf1p. The x-axis indicates the final three nucleotides in the sequence. The first nucleotide is indicated by the color of the bar. Reproduced with permission from Science 315, 233–237 (2007).