Enzyme Evolution in the Context of Cellular Metabolism


MARSDEN FUND (2019-2022)

Biochemistry textbooks tell us that enzymes are supremely active and specific catalysts. However, our recent work has shown that many microorganisms use decidedly unimpressive enzymes in essential roles. This implies that speed and specificity are not the dominant factors determining the evolutionary trajectories of enzymes. Instead, we hypothesise that the evolution of individual enzymes is dictated by the constraints of optimising flux through multi-step metabolic pathways. A further layer of complexity arises because environmental conditions alter the metabolic demands on a cell; mutations that are beneficial in one environment can be deleterious in another.

In this project, we are discovering what determines the evolutionary trajectories of enzymes that are embedded in the heart of the metabolic network. We are making every possible single-amino-acid mutation in each of two central metabolic enzymes. We are measuring the effects of these mutations on enzyme activity, and also on cell growth in almost 1,000 different environments. We will measure the flow of metabolites through pathways and individual enzyme-catalysed steps. Ultimately, we hope to gain a comprehensive and integrated understanding of how natural selection works, from enzyme to organism.