Paradigms of convergent evolution in enzymes.

There are many occurrences of enzymes catalysing the same reaction but having significantly different structures. Leveraging the comprehensive information on enzymes stored in the Mechanism and Catalytic Site Atlas (M-CSA), we present a collection of 34 cases for which there is sufficient evidence of functional convergence without an evolutionary link. For each case, we compare enzymes which have identical Enzyme Commission numbers (i.e. catalyse the same reaction), but different identifiers in the CATH data resource (i.e. different folds). We focus on similarities between their sequences, structures, active site geometries, cofactors and catalytic mechanisms. These features are then assessed to evaluate whether all the evidence for these structurally diverse proteins supports their independent evolution to catalyse the same chemical reaction. Our approach combines published literature information with knowledge-based computational resources from, amongst others, M-CSA, PDBe and PDBsum, supported by tailor-made software to explore active site structures and assess similarities in mechanism. We find that there are multiple types of convergent functional evolution observed to date, and it is necessary to investigate sequence, structure, active site geometry and enzyme mechanisms to describe such convergence accurately.