The ligases are a small set of enzymes with functions that are critical for life. Their functions include (but are not limited to) the attachment of amino acid residues onto the corresponding tRNA, DNA repair and coenzyme A decorations.

The subclass level of the EC number, namely, the type of bond formed between the two substrates, is the primary discriminator between the overall chemical transformations. Further detailed examination can produce interesting insights but does not offer more in the means of more detailed automatic classification.

Many examples exist of ligases that have evolved both divergently and convergently, with examples of ligases that have evolved to work on different substrates using the same chemistry and occasional examples where there is an apparent change of chemistry in the reaction mechanism itself. We show a single example (the acyl-coenzyme A superfamily) in which divergent evolution has occurred to perform different overall bond formations utilising the same basic mechanistic approach.

Our systematic and automatic approach to comparing and analysing enzyme reactions and the evolution of the associated enzyme sequences provides a robust route to better understand how these ligase enzymes have evolved all the complex chemistries needed for life in diverse environment.