Family S28


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

Summary for family S28

Family type peptidaseS28.001 - lysosomal Pro-Xaa carboxypeptidase (Homo sapiens), MEROPS Accession MER0000446 (peptidase unit: 46-496)
Content of familyPeptidase family S28 contains exopeptidases that hydrolyse prolyl bonds, and are known only from eukaryotes.
History Identifier created: Methods Enzymol. 244:19-61 (1994)
Amongst the first reports of lysosomal Pro-Xaa carboxypeptidase (S28.001) was that of Matsunaga et al. (1969), and dipeptidyl-peptidase II (DPP II, S28.002) was first described by McDonald et al. (1968).
Catalytic typeSerine
Active site residuesS179 D430 H455 
Active siteThe Ser, Asp, His catalytic triad has been determined from the crystal structure of human lysosomal Pro-Xaa carboxypeptidase. The substrate specificity of Pro-Xaa carboxypeptidase is explained by an extended active-site cleft that can accommodate proline substrates with multiple N-terminal residues (Soisson et al., 2010).
Activities and specificitiesThe lysosomal Pro-Xaa carboxypeptidase is unusual amongst carboxypeptidases in its selectivity for cleavage of the -ProXaa bond, in which Xaa is C-terminal. In a study with a large set of synthetic substrates, DPP II proved most active on lysine or isoleucine in P2, and proline in P1 (Leiting et al., 2003); its pH optimum being about 5.7. Dipeptidyl-peptidase IV (DPP IV, S09.003) has somewhat similar specificity, also with a strong preference for Pro in P1, but has a much broader specificity in P2, and a higher pH optimum (pH 7.8: Leiting et al., 2003). The putative peptidase activity of the thymus-specific serine peptidase (S28.003) has yet to be characterised.
InhibitorsLys thiazolidide (Ki 150 nM) is an effective inhibitor of DPP II, but inhibits DPP IV almost as strongly (Leiting et al., 2003). A highly-selective, sub-nanomolar inhibitor of DPP II has been described by Senten et al. (2004).
Molecular structureThe tertiary structure has been solved for human lysosomal Pro-Xaa carboxypeptidase and shows a peptidase domain with a typical alpha/beta-hydrolase fold, plus a novel helical structure domain that caps the active site (Soisson et al., 2010).
Basis of clan assignmentPredicted active site residues for members of this family and family S10 occur in the same order in the sequence: S, D, H.
Distribution of family Bacteria details  
Archaea -  
Protozoa details  
Fungi details  
Plants details  
Animals details  
Viruses details  
Biological functionsPro-Xaa carboxypeptidase inactivates angiotensin II by cleavage of the C-terminal -ProPhe bond, and this may be physiologically significant. It is also reported that recombinant Pro-Xaa carboxypeptidase associated with H-kininogen is an activator of plasma prekallikrein (S01.212) (Shariat-Madar et al., 2004).
Pharmaceutical and biotech relevanceThe substrate specificity of DPP II, somewhat similar to that of DPP IV, will require it to be taken into account in any attempts to develop inhibitors of DPP IV as therapeutic agents.
Statistics for family S28Sequences:3644
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
lysosomal Pro-Xaa carboxypeptidaseS28.001Yes
dipeptidyl-peptidase IIS28.002Yes
thymus-specific serine peptidaseS28.003-
acid prolyl endopeptidase (Aspergillus sp.)S28.004-
PRO1 g.p. (Plasmodiophora brassicae)S28.005-
At2g24280 (Arabidopsis thaliana)S28.A01-
AT5g65760 (Arabidopsis thaliana)S28.A02-
At5g22860 (Arabidopsis thaliana)S28.A03-
At4g36190 (Arabidopsis thaliana)S28.A04-
At2g18080 (Arabidopsis thaliana)S28.A05-
IP20428 protein (Drosophila melanogaster)S28.A06-
CG3734 protein (Drosophila melanogaster)S28.A07-
CG3739 protein (Drosophila melanogaster)S28.A08-
CG18493 protein (Drosophila melanogaster)S28.A09-
CG9953 protein (Drosophila melanogaster)S28.A10-
K12H4.7 g.p. (Caenorhabditis elegans)S28.A11-
F19C7.4 g.p. (Caenorhabditis elegans)S28.A12-
C26B9.5 g.p. (Caenorhabditis elegans)S28.A13-
F56F10.1 g.p. (Caenorhabditis elegans)S28.A14-
pcp-2 g.p. (Caenorhabditis elegans)S28.A15-
pcp-4 g.p. (Caenorhabditis elegans)S28.A16-
pcp-1 g.p. (Caenorhabditis elegans)S28.A17-
F19C7.2 g.p. (Caenorhabditis elegans)S28.A18-
C46C2.4 g.p. (Caenorhabditis elegans)S28.A19-
pcp-3 g.p. (Caenorhabditis elegans)S28.A20-
pcp-5 g.p. (Caenorhabditis elegans)S28.A21-
DDB_G0278299 g.p. (Dictyostelium discoideum)S28.A22-
DDB_G0292476 g.p. (Dictyostelium discoideum)S28.A23-
DDB_G0290139 g.p. (Dictyostelium discoideum)S28.A24-
DDB_G0290409 g.p. (Dictyostelium discoideum)S28.A25-
At4g36195 g.p. (Arabidopsis thaliana)S28.A26-
family S28 non-peptidase homologuesnon-peptidase homologue-
family S28 unassigned peptidasesunassigned-