Family C25


Summary Holotypes Alignment Tree Genomes Structure Literature

Summary for family C25

NamePeptidase family C25 (gingipain family)
Family type peptidaseC25.001 - gingipain RgpA (Porphyromonas gingivalis), MEROPS Accession MER0001351 (peptidase unit: 228-578)
Content of familyPeptidase family C25 contains cysteine endopeptidases from bacteria, notably gingipain R (C25.001) and gingipain K (C25.002).
History Identifier created: Perspect.Drug Discov.Des. 6:1-11 (1996)
The proteolytic activity of Porphyromonas gingivalis (formerly Bacteroides gingivalis) was characterised by Carlsson et al. (1984), and the peptidase was first termed gingivain (Shah et al., 1991 and then gingipain. Gingipain proved to comprise two peptidases, which are termed gingipain-R (C25.001) and gingipain-K (C25.002) in MEROPS (Potempa & Travis, 1995). Porphyromonas gingivalis is a black-pigmented bacterium that is one of the causal organisms of periodontitis (Imamura et al., 1994). The amino acid sequences of the gingipains show that they belong to a distinct family of cysteine peptidases, C25 in MEROPS.
Catalytic typeCysteine
Active site residuesH438 C471 
Active siteThere is a His/Cys catalytic dyad, in a sequence motif characteristic of clan CD (Chen et al., 1998) (see the Alignment).
Activities and specificitiesGingipains R and K are endopeptidases with specificity for arginyl and lysyl bonds, respectively. Like other cysteine peptidases, they require reducing conditions for activity. They are maximally active at approximately neutral pH.
InhibitorsGeneral inhibitors of cysteine peptidases such as iodoacetamide, iodoacetic acid and N-ethylmaleimide, inactivate the enzymes slowly at rather high concentrations (10 mM). E-64 inhibits gingipain R only in a competitive, reversible manner, probably acting as an arginine analogue. Gingipain R, but not gingipain K, is also sensitive to inhibition by leupeptin and antipain. Peptidyl chloromethanes with a P1 Arg residue are extremely efficient irreversible inhibitors of gingipain R, and can be used for active site titration (Potempa et al., 1997). A nanomolar inhibitor of gingipain K has been described (Curtis et al., 2002).
Molecular structureThe crystal structure of gingipain R shows a 435-residue, single-polypeptide chain organized into a catalytic domain and an immunoglobulin-like, hemagglutinin domain. The catalytic domain is divided into two subdomains comprising four- and six-stranded beta-sheets sandwiched between alpha-helices. Each subdomain has topological similarities to the p20-p10 heterodimer of caspase-1 (C14.001). The second subdomain contains the Cys/His catalytic dyad and a nearby Glu. The S1 specificity pocket contains an Asp residue that is believed to be responsible for the specificity preference for Arg in P1 (Eichinger et al., 1999).
Basis of clan assignmentProtein fold of the peptidase unit for members of this family resembles that of caspase 1, the type example for clan CD.
Distribution of family Bacteria details  
Archaea details  
Protozoa -  
Fungi -  
Plants -  
Animals -  
Viruses -  
Biological functionsGingipains R and K are secreted by the bacterium Porphyromonas gingivalis. The bacterium is a major pathogen in periodontal disease, and the many ways in which the activities of the gingipains may contribute to the disease processes have been reviewed by Imamura et al. (2004). These enzymes are also involved in the hemagglutinating activity of the organisms (Tokuda et al., 1996).
Pharmaceutical and biotech relevanceThe evidence for the roles of gingipains in periodontal disease makes them potential drug targets (Bialas et al., 2006; Matsushita et al., 2006).
ReviewsBialas et al. (2006); Matsushita et al. (2006)
Statistics for family C25Sequences:466
Identifiers with PDB entries:3
Downloadable files Sequence library (FastA format)
Sequence alignment (FastA format)
Phylogenetic tree (Newick format)
Peptidases and Homologues MEROPS ID Structure
gingipain RgpAC25.001-
gingipain KgpC25.002Yes
gingipain RgpBC25.003Yes
PG0026 peptidase (Porphyromonas-type)C25.004-
family C25 non-peptidase homologuesnon-peptidase homologue-
family C25 unassigned peptidasesunassignedYes