ALIGNMENT PHYLOGENY OF THE PAPAIN SUPERFAMILY OF CYSTEINE PROTEASES

An alignment/phylogeny of the papain superfamily of cysteine proteases was created using an initial structure-based alignment followed by su ccessive iterations of sequence alignment and phylogenetic inference. The iterative approach resulted in significant improvements in the ali gnment/phylogeny There were three groups of cysteine proteases that we re distantly related and which could be aligned against each other onl y in the active site regions: the papain group, which included such st ereotypical cysteine proteases as cathepsins B, C, H, L and S; and the bleomycin hydrolase and calpain groups. There was one bacterial seque nce in each of the bleomycin hydrolase and calpain groups. The former probably arose by lateral gene transfer, the latter possibly by direct evolution from an ancestral protease predating the eukaryote/prokaryo te divergence. The phylogeny of the papain group indicated that many f amilies diverged almost simultaneously early during eukaryotic evoluti on. In mammals there are at least 12 distinct families of cysteine pro teases, possibly many more, including at least two as yet uncharacteri zed enzymes.