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1 Centre for Protein Engineering, Cambridge CB2 2HQ, United Kingdom
2 Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot 76 100, Israel
Reprint requests to: Dr. Dan S. Tawfik, Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot 76 100, Israel; e-mail: tawfik{at}weizmann.ac.il; fax: +972-8-934-4118.
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.
Keywords: Promiscuous; promiscuity; substrate ambiguity; cross-reactivity; catalytic antibody; serum albumin; directed evolution; enzyme evolution; medium effects
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