Enzyme Evolution

Abstract

Life involves an enormous diversity of coupled chemical reactions, almost none of which would occur in a biologically relevant time scale without catalysis. Enzymes are life catalysts, capable of enhancing the rates of biochemical reactions by many orders of magnitude. Modern natural enzymes are the complex outcome of evolution operating over a vast expanse of time. Plausibly, the overall process started ∼4 billion years ago when polypeptides that possibly served as cofactors of ribozymes in the RNA world acquired the capability to catalyse simple reactions. Likely, primordial enzymes were generalists that could catalyse various reactions with moderate efficiency. Diversification, specialisation and optimisation occurred subsequently over evolutionary history, probably coupled to successive gene duplication events. Advances in protein engineering and laboratory evolution have allowed some of the main stages in this evolutionary narrative to be reproduced in the laboratory and have demonstrated the fundamental role of conformational diversity in enzyme evolution. Key Concepts Modern natural enzymes are the complex outcome of evolution operating over ∼4 billion years. Most modern natural enzymes evolved from previously existing enzymes. To avoid detrimental effects on organismal fitness, the emergence of new enzymes from old enzymes is likely coupled to gene duplication. Directed evolution experiments allow the transformation of an old enzyme into a new enzyme to be reproduced in the laboratory. The evolutionary transformation of an old enzyme into a new enzyme likely occurs trough multifunctional intermediates. Unless we accept panspermia as an explanation for the origin of life on Earth, we must admit that, at some very early stage of life evolution on this planet, primordial enzymes emerged de novo in noncatalytic scaffolds. Recent work has shown that single mutations can generate emerging enzyme functionalities in previously noncatalytic scaffolds. Proteins in solution are best envisioned as ensembles of different conformations. Experimental and computational studies support that conformational diversity underlies enzyme ‘evolvability’, that is, the capability to evolve towards new functionalities. Our current understanding of enzyme evolution is not detailed enough to provide a reliable basis for rational enzyme design.