Catalytic and binding poly‐reactivities shared by two unrelated proteins: The potential role of promiscuity in enzyme evolution

Abstract

It is generally accepted that enzymes evolved via gene duplication of existing proteins. But duplicated genes can serve as a starting point for the evolution of a new function only if the protein they encode happens to exhibit some activity towards this new function. Although the importance of such catalytic promiscuity in enzyme evolution has been proposed, little is actually known regarding how common promiscuous catalytic activities are in proteins or their origins, magnitudes, and potential contribution to the survival of an organism. Here we describe a pattern of promiscuous activities in two completely unrelated proteins-serum albumins and a catalytic antibody (aldolase antibody 38C2). Despite considerable structural dissimilarities-in the shape of the cavities and the position of catalytic lysine residues-both active sites are able to catalyze the Kemp elimination, a model reaction for proton transfer from carbon. We also show that these different active sites can bind promiscuously an array of hydrophobic negatively charged ligands. We suggest that the basic active-site features of an apolar pocket and a lysine residue can act as a primitive active site allowing these promiscuous activities to take place. We also describe, by modelling product formation at different substrate concentrations, how promiscuous activities of this kind- inefficient and rudimentary as they are-can provide a considerable selective advantage and a starting point for the evolution of new functions.

TRIM21 is an IgG receptor that is structurally, thermodynamically, and kinetically conserved

“…In a general context, the three binding mechanisms illustrate the versatility of protein structure. We have previously commented that protein binding sites are intrinsically promiscuously active as result of their chemically heterogeneous nature (36). The present example illustrates how individual residues provide remarkable chemical and hence functional heterogeneity.…”

Genome-wide Analysis of Substrate Specificities of the Escherichia coli Haloacid Dehalogenase-like Phosphatase Family

“…Although specificity is considered a hallmark of enzymatic activity and certain enzymes can be extraordinarily specific, there has been growing appreciation that substrate specificities are perhaps broader than is generally accepted, and many enzymes exhibit considerable catalytic and substrate promiscuity (34 -36). Catalytic promiscuity (also called polyreactivity or moon-lighting activity) is defined as the ability of enzyme active sites to catalyze distinctly different chemical transformations (different types of bonds cleaved or formed or different catalytic mechanisms of bond making or breaking) (37,38). Substrate promiscuity (also called substrate ambiguity or cross-reactivity) is defined as the ability of enzymes to catalyze one chemical transformation on several structurally related substrates.…”

A structural model of latent evolutionary potentials underlying neutral networks in proteins

“…As far as protein function is concerned, enzymes have long been known to be promiscuous (James and Tawfik, 2001;Khersonsky et al, 2006). Promiscuity (polyreactivity) in function can be underlied by dynamic interconversions among energetically similar structures of a protein (James and Tawfik, 2003).…”