Identification and prioritization of novel uncharacterized peptidases for biochemical characterization.

Genome sequencing projects are generating enormous amounts of biological data that require analysis, which in turn identifies genes and proteins that require characterization. Enzymes that act on proteins are especially difficult to characterize because of the time required to distinguish one from another. This is particularly true of peptidases, the enzymes that activate, inactivate and degrade proteins. This article aims to identify clusters of sequences each of which represents the species variants of a single putative peptidase that is widely distributed and is thus merits biochemical characterization. The MEROPS database maintains large collections of sequences, references, substrate cleavage positions and inhibitor interactions of peptidases and their homologues. MEROPS also maintains a hierarchical classification of peptidase homologues, in which sequences are clustered as species variants of a single peptidase; homologous sequences are assembled into a family; and families are clustered into a clan. For each family, an alignment and a phylogenetic tree are generated. By assigning an identifier to a peptidase that has been biochemically characterized from a particular species (called a holotype), the identifier can be automatically extended to sequences from other species that cluster with the holotype. This permits transference of annotation from the holotype to other members of the cluster. By extending this concept to all peptidase homologues (including those of unknown function that have not been characterized) from model organisms representing all the major divisions of cellular life, clusters of sequences representing putative peptidases can also be identified. The 42 most widely distributed of these putative peptidases have been identified and discussed here and are prioritized as ideal candidates for biochemical characterization. Database URL: http://merops.sanger.ac.uk.