Family C15
Summary for family C15
| Name | Peptidase family C15 (pyroglutamyl peptidase I family) |
|---|
| Family type peptidase | C15.001 - pyroglutamyl-peptidase I (prokaryote) (Bacillus amyloliquefaciens), MEROPS Accession MER0001424 (peptidase unit: 1-215) |
| Content of family | Peptidase family C15 contains omega peptidases that release an N-terminal pyroglutamate residue. |
| History |
Identifier created: Methods Enzymol. 244:461-486 (1994)
There are two pyroglutamyl-peptidases in mammals; pyroglutamyl-peptidase I (PGP-I) is a cysteine peptidase and member of family C15, whereas pyroglutamyl-peptidase II (PGP-II; M01.008) is a metallopeptidase in family M1. |
| Catalytic type | Cysteine |
| Active site residues | E81 C144 H168 |
| Active site | There is a catalytic triad which occurs in the order Glu, Cys, His in the sequence. The nucleophilic Cys is located at the end of a helix whereas the His, which acts as a general base, is on a strand (see Structure for C15.001). |
| Activities and specificities | The only known activity is removal of a pyroglutamate (pGlu) residue from the N-terminus of a peptide. Typical synthetic substrates are pGlu NHMec and pGluNHNap. A thiol-reducing agent such as mercaptoethanol or dithiothreitol is required in the assay. Although pGlu is released from a variety of polypeptides, there is some selectivity for the residue in P1". Selectivity can be organism-dependent: for example pGluPro is cleaved by KlebsiellaPGP-I, but not by the peptidases from Pseudomonas or Bacillus. Optimal activity is seen at pH 7-9. The bacterial peptidases are heat sensitive, but peptidases from archaea are active at 90 degrees Celsius. |
| Inhibitors | PGP-I is inhibited by iodoacetamide, iodoacetate, benarthin and pyrizinostatin (Aoyagi et al., 1992; Aoyagi et al., 1992). Specific synthetic inhibitors of mammalian PGP-I include N,alpha-benzyloxycarbonyl-L-pyroglutamyl chloromethane and pyroglutamyl diazomethane (Fujiwara et al., 1980; Wilk etal, 1985). |
| Molecular structure | The tertiary structure has been solved for the enzymes from bacteria and archaea, and shows an alpha-beta-alpha sandwich (Singleton et al., 1999). The fold is unlike that of any other cysteine peptidase, hence pyroglutamyl-peptidase I is the type structure for clan CF. There are structural similarities detectable by the DALI algorithm between members of clan CF and three clans of metallopeptidases, MC, MF and MH, and all four peptidase clans are included in the phosphorylase/hydrolase-like fold by the SCOP database. The mammalian and bacterial peptidases are monomeric, but the archaean enzyme exists as a homotetramer. |
| Clan | CF |
| Basis of clan assignment | Type family of clan CF. |
| Biological functions | The enzyme is intracellular and soluble. Mammalian PGP-I has been shown to release pGlu from thyrotropin-releasing hormone, luteinizing hormone releasing hormone, neurotensin, bombesin and leukopyrokinin (Dando et al., 2003), but the physiological significance of this is unclear. For thyrotropin-releasing hormone at least, PGP-II appears to be the main peptidase responsible for catabolism (Cummins & O"Connor, 1998). |
| Pharmaceutical and biotech relevance | The enzyme is used in manual protein sequencing to remove N-terminal pGlu residues which block the Edman degradation. It is also used to confirm the presence of a pGlu residue. |
| Statistics for family C15 | Sequences: | 2475 |
| Identifiers: | 9 |
| Identifiers with PDB entries: | 1 |
| Downloadable files |
Sequence library (FastA format) |
| Sequence alignment (FastA format) |
| Phylogenetic tree (Newick format) |
| Peptidases and Homologues |
MEROPS ID |
Structure |
| pyroglutamyl-peptidase I (prokaryote) | C15.001 | Yes |
| pyroglutamyl-peptidase I (chordate) | C15.010 | - |
| Mername-AA073 peptidase | C15.011 | - |
| pyroglutamyl-peptidase I (Trypanosoma-type) | C15.012 | - |
| At1g23430/At1g23440 (Arabidopsis thaliana) | C15.A01 | - |
| At1g56700 (Arabidopsis thaliana) | C15.A02 | - |
| CG32147 g.p. (Drosophila melanogaster) | C15.A03 | - |
| M04C9.3 g.p. (Caenorhabditis elegans) | C15.A04 | - |
| DDB_G0267498 (Dictyostelium discoideum) | C15.A05 | - |
| Family C15 non-peptidase homologues | non-peptidase homologue | - |
| Family C15 unassigned peptidases | unassigned | - |
