Expanding the enzyme universe through a marriage of chemistry and evolution

Abstract

For more than twenty years this laboratory has used directed evolution to modify enzymes. It is now widely accepted that directed evolution can change substrate specificity or reaction selectivity in desired ways, even if it sometimes remains difficult in practice. It is no longer surprising that enzymes adapt readily by accumulating beneficial mutations. And why should it be, since this is how Nature tailors them for myriad biological roles? More difficult to grasp is how Nature discovers new enzyme functions, particularly new catalytic activities. We know that the biological world's diverse catalytic repertoire is the product of evolution by natural selection, but we have little understanding of how Nature's tinkering generates new functions. Sometimes we are (un)lucky enough to catch them in the act - e.g., the acquisition of antibiotic resistance or the ability to degrade man-made toxins. But for the vast majority of activities, the fossil record is nonexistent or too sparse to tell the molecular story. This leaves us without much guidance for evolving new enzymes in the laboratory. Consequently we are forced to contaminate our evolution experiments with knowledge - e.g., computational design [1, 2] - in order to jumpstart the discovery process.