Redefining the coenzyme A transferase superfamily with a large set of manually annotated proteins

The coenzyme A (CoA) transferases are a superfamily of proteins central to the metabolism of acetyl-CoA and other CoA thioesters. They are diverse group, catalyzing over a 100 biochemical reactions and spanning all three domains of life. A deeply rooted idea, proposed two decades ago, is these enzymes fall into three families (I, II, and III). Here we find they fall into different families, which we achieve by analyzing all CoA transferases characterized to date. We manually annotated 94 CoA transferases with functional information (including rates of catalysis for 208 reactions) from 97 publications. This represents all enzymes we could find in the primary literature, and it is double the number annotated in four protein databases (BRENDA, KEGG, MetaCyc, UniProt). We found family I transferases are not closely related to each other in terms of sequence, structure, and reactions catalyzed. This family is not even monophyletic. These problems are solved by regrouping the three families into six, including one family with many non-CoA transferases. The problem (and solution) became apparent only by analyzing our large set of manually annotated proteins. It would have been missed if we had used the small number of proteins annotated in UniProt and other databases. Our work is important to understanding the biology of CoA transferases. It also warns investigators doing phylogenetic analyses of proteins to go beyond information in databases.