Family M49


Summary Holotypes Alignment Tree Genomes Structure Literature H-seq M-seq

Summary for family M49

NamePeptidase family M49 (dipeptidyl-peptidase III family)
Family type peptidaseM49.001 - dipeptidyl-peptidase III (Rattus norvegicus), MEROPS Accession MER0003564 (peptidase unit: 425-663)
Content of familyFamily M49 contains a dipeptidylpeptidase.
History Identifier created: MEROPS 5.00 (20 April 2000)
Catalytic typeMetallo
Active site residuesH450 E451 H455 E508 
Active siteDPPIII (M49.001)binds a single zinc ion by means of two histidine ligands within an HEXXXH motif. In this motif the distance between the histidines is extended by one residue compared the HEXXH zinc-binding motif found in peptidases from clan MA. The histidines were shown to be metal ligands and the glutamate important for activity by site-directed mutagenesis (Fukasawa et al., 1999). Additionally, the third zinc ligand was shown to be glutamate in the same study. However, some members of family M49, notably from bacteria such as Colwelia possess the more usual HEXXH motif. The third zinc ligand occurs within a motif that has been described as EECRAE (Baral et al., 2008), and the glutamates at the ends of this motif are important for orientating the imidazolium rings of the histidine zinc-ligands. The second of these glutamates is replaced by aspartate in some members of the family.
Activities and specificitiesDPPIII releases N-terminal dipeptides sequentially from a peptide. Angiotensins II and III, Leu-enkephalin, prolactin and alpha-melanocyte-stimulating hormone are readily cleaved, whereas tripeptides are poor substrates and angiotensin I and polypeptides of more than ten residues are not cleaved. In addition, proline is not accepted in P1 or P1" . The recommended synthetic substrate is Arg-ArgNHMec (Chen & Barrett, 2004).
InhibitorsDPPIII is inhibited by metal chelators such as 1,10-phenanthroline, EDTA and EGTA. The reducing agents dithiothreitol and 2-mercaptoethanol also are inhibitory, probably because the thiol groups bind the metal ion. However, DPPIII is also reported to be inhibited by some compounds that are normally selective for peptidases of other catalytic types, and for this reason the catalytic type of DPPIII was obscure until the sequence was derived. Sulfhydryl-blocking reagents such as p-chloromercuribenzoate, N-ethylmaleimide and iodoacetamide inhibit, with the degree of inhibition depending on the species, and the thiol group of Cys176 (see the Alignment) has been implicated in the catalytic mechanism (Li et al., 2000). The serine peptidase inhibitor DFP is a potent inhibitor of rat DDPIII (Ohkubo et al., 1999). The peptides spinorphin and its derivative tynorphin are also inhibitory (Yamamoto et al., 2000).
Molecular structureThe tertiary structure has been determined for DPPIII from Saccharomyces cerevisiae (Baral et al., 2008) and human (<%Dobrovetsky et al., 2009[]%>). The structure shows two domains, with the peptidase unit confined to the predominantly C-terminal domain. This domain is a bundle of ten helices and shows similarity to structures of thimet oligopeptidase (M03.001) and thermolysin (M04.001), hence family M49 is included in clan MA subclan MA(E). DPPIII is a cytoplasmic protein and is synthesized without signal or activation peptides. Plant homologues with an HEXXH zinc-binding motif contain a Nudix box and in addition to being dipeptidyl-peptidases, also hydrolase isopentenyl diphosphate (Karacic et al., 2016).
Basis of clan assignmentFor members of this family active site residues occur in the motifs HEXXXH (which is unlike that in any other family) or HEXXH
Distribution of family Bacteria details  
Archaea -  
Protozoa details  
Fungi details  
Plants details  
Animals details  
Viruses -  
Biological functionsDPPIII is a widely-distributed soluble, cytosolic enzyme that is probably a housekeeping peptidase important for the catabolism of intracellular peptides. Levels of DPPIII are elevated in retroplacental serum compared to normal serum, indicating that it may participate in the increased angiotensin hydrolysis seen during pregnancy (Shimamori et al., 1986).
Pharmaceutical and biotech relevanceDPP III may work jointly with thimet oligopeptidase (M03.001) and tripeptidyl-peptidase I (S53.003) in the destruction of antigenic peptides.
Statistics for family M49Sequences:1076
Identifiers with PDB entries:2
Downloadable files Sequence library (FastA format)
Sequence alignment (FastA format)
Phylogenetic tree (Newick format)
Peptidases and Homologues MEROPS ID Structure
dipeptidyl-peptidase IIIM49.001Yes
similar to dipeptidyl-peptidase III (Rattus norvegicus)M49.002-
dipeptidyl-peptidase IIIBM49.003-
dipeptidyl-peptidase III (Saccharomyces-type)M49.004Yes
Nudix hydrolase 3M49.005-
Mername-AA164 proteinM49.972-
protein similar to dipeptidylpeptidase III (Rattus norvegicus)M49.973-
CG7415 g.p. (Drosophila melanogaster)M49.A01-
DDB_G0273563 g.p. (Dictyostelium discoideum)M49.A02-
LOC138971 g.p. (Homo sapiens)M49.P01-
family M49 non-peptidase homologuesnon-peptidase homologue-
family M49 unassigned peptidasesunassigned-