Name | Peptidase family S9 (prolyl oligopeptidase family) |
Family type peptidase | S09.001 - prolyl oligopeptidase (Sus scrofa), MEROPS Accession MER0000392 (peptidase unit: 428-710) |
Content of family | Peptidase family S9 contains a varied set of serine-dependent peptidases. |
History |
Identifier created: Biochem.J. 290:205-218 (1993) Family S9 was first assembled by Rawlings et al., 1991, when it was realised that the newly determined prolyl oligopeptidase (S09.001) protein sequence was homologous to those of dipeptidyl-peptidase IV (DPP-IV; S09.003) and acylaminoacyl-peptidase (S09.004). Each of these is the type-example for a subfamily (S9A, S9B and S9C, respectively). Recently, a fourth subfamily (S9D) has been added to the family, containing glutamyl endopeptidase (S09.021). |
Catalytic type | Serine |
Active site | The active site residues are in the order Ser, Asp, His in the sequence. The motifs around the active site Ser are characteristic for each subfamily: GGSXGGLL, where X is typically Asn or Ala (S9A), GWSYGGY (S9B), GGSYGG (S9C) and GGHSYGAFMT (S9D). |
Activities and specificities | Most members of the family show restricted specificities and are active mainly on oligopeptides, consistent with the steric hindrance of the catalytic site by the beta-propeller domain at the N-terminus (Fulop et al., 1998). An exception is the reported activity of fibroblast activation protein alpha (as seprase) on gelatin (Kelly, 1999). Although many peptidases in the family cleave prolyl bond, there are exceptions, such as oligopeptidase B (S09.010) which cleaves Arg and Lys bonds; acylaminoacyl-peptidase which is an omega-peptidase releasing an N-acylated amino acid from an oligopeptide blocked by a acetyl, chloroacetyl, formyl or carbamyl group (Jones et al., 1986); and glutamyl endopeptidase cleaves the synthetic substrate Z-Leu-Leu-Glu-naphthylamide (Yamauchi et al., 2001). Prolyl oligopeptidase is thiol-dependent. |
Inhibitors | Members of the family are sensitive to DFP, like most serine peptidases. DPP-IV is poorly inhibited by PMSF (Kenny et al., 1976). There are no known naturally-occuring protein inhibitors. |
Molecular structure | Tertiary structures have been solved for prolyl oligopeptidase (S09.001) and DPP-IV (S09.003). Each structure shows a multi-domain protein, with an N-terminal eight-bladed beta-propeller and a C-terminal peptidase unit. The structure of the peptidase unit is an alpha/beta/alpha sandwich and is similar to the fold of acetylcholinesterase, carboxylesterase, lipase, serine carboxypeptidases of family S10 (S10), prolyl aminopeptidase (S33.001), and many other enzymes. This fold has been described as 'alpha/beta-hydrolase' because most proteins with this fold are hydrolytic enzymes. Prolyl oligopeptidase (S09.001) and oligopeptidase B (S09.010) are monomers both in solution and in crystal structure, whereas dipeptidyl peptidase IV (S09.003) is a dimer, and mammalian acylaminoacyl-peptidase (S09.004) is a homotetramer (Kiss et al., 2004). |
Clan | SC |
Basis of clan assignment | Protein fold of the peptidase unit for members of this family resembles that of serine carboxypeptidase D, the type example of clan SC. |
Peptidases and Homologues |
MEROPS ID |
Structure |
dipeptidyl-peptidase IV (eukaryote) | S09.003 | Yes |
dipeptidyl aminopeptidase A | S09.005 | - |
dipeptidyl aminopeptidase B (fungus) | S09.006 | Yes |
fibroblast activation protein alpha subunit | S09.007 | Yes |
dipeptidyl peptidase 4 (Aspergillus-type) | S09.008 | - |
dipeptidyl-peptidase 4 (bacteria-type 1) | S09.009 | Yes |
dipeptidyl-peptidase 4 (bacteria-type 2) | S09.013 | Yes |
DPF-3 peptidase | S09.016 | - |
prolyl tripeptidyl peptidase | S09.017 | Yes |
dipeptidyl-peptidase 8 | S09.018 | Yes |
dipeptidyl-peptidase 9 | S09.019 | Yes |
omega peptidase (Drosophila melanogaster) | S09.069 | - |
Xaa-Pro dipeptidylpeptidase | S09.073 | - |
S-formylglutathione hydrolase FrmB (Escherichi coli) | S09.940 | Yes |
At5g24260 (Arabidopsis thaliana) | S09.A03 | - |
F14F18_80 protein (Arabidopsis thaliana) | S09.A58 | - |
CG11034 protein (Drosophila melanogaster) | S09.A64 | - |
CG11319 (Drosophila melanogaster) | S09.A65 | - |
dpf-2 g.p. (Caenorhabditis elegans) | S09.A74 | - |
K02F2.1 protein (Caenorhabditis elegans) | S09.A75 | - |
dpf-1 g.p. (Caenorhabditis elegans) | S09.A76 | - |
dipeptidyl aminopeptidase C14C4.15c (Schizosaccharomyces pombe) | S09.A93 | - |
bem46 g.p. (Schizosaccharomyces pombe) | S09.A94 | - |
Subfamily S9B non-peptidase homologues | non-peptidase homologue | - |
Subfamily S9B unassigned peptidases | unassigned | - |
Peptidases and Homologues |
MEROPS ID |
Structure |
acylaminoacyl-peptidase | S09.004 | - |
dipeptidyl-peptidase 5 | S09.012 | - |
sphingopyxin I lasso peptide isopeptidase | S09.032 | - |
lasso peptide isopeptidase (Asticcacaulis-type) | S09.035 | Yes |
FLJ1 putative peptidase | S09.051 | - |
Mername-AA194 putative peptidase | S09.052 | - |
Mername-AA195 putative peptidase | S09.053 | - |
Mername-AA197 putative peptidase | S09.055 | - |
dipeptidyl-peptidase IV, membrane-type (protistan) | S09.056 | - |
apsC g.p. (Aspergillus niger N400) | S09.057 | - |
C14orf29 protein | S09.061 | - |
acylaminoacyl peptidase (Aeropyrum-type) | S09.070 | Yes |
trilobed protease | S09.071 | Yes |
tyrosyl aminopeptidase (Raphanus-type) | S09.074 | - |
dipeptidyl-peptidase 5 (Porphyromonas sp.) | S09.075 | - |
lysophosphatidylserine lipase ABHD12 | S09.939 | - |
BSU33620 g.p. (Bacillus subtilis) and similar | S09.946 | Yes |
brefeldin A esterase | S09.951 | Yes |
1700122C07Rik protein (Mus musculus) | S09.963 | - |
protein 9430007A20RIK (Mus musculus) | S09.968 | - |
carboxylesterase-related protein | S09.986 | - |
At4g24760 (Arabidopsis thaliana) | S09.A04 | - |
At3g48690 (Arabidopsis thaliana) | S09.A09 | - |
At5g23530 (Arabidopsis thaliana) | S09.A10 | Yes |
At5g16080 (Arabidopsis thaliana) | S09.A12 | - |
At3g48700 (Arabidopsis thaliana) | S09.A13 | - |
At1g68620 (Arabidopsis thaliana) | S09.A15 | - |
At3g01690 (Arabidopsis thaliana) | S09.A20 | - |
At1g13610 (Arabidopsis thaliana) | S09.A23 | - |
At5g20520 (Arabidopsis thaliana)-type peptidase | S09.A24 | - |
At5g38220 (Arabidopsis thaliana) | S09.A25 | - |
At5g14390 (Arabidopsis thaliana)-type peptidase | S09.A27 | - |
At2g24320 (Arabidopsis thaliana) | S09.A28 | - |
At1g32190 (Arabidopsis thaliana)-type peptidase | S09.A30 | - |
At3g30380 (Arabidopsis thaliana) | S09.A32 | - |
At4g31020 (Arabidopsis thaliana)-type peptidase | S09.A33 | - |
At1g66900 (Arabidopsis thaliana)-type peptidase | S09.A34 | - |
YqiA protein (Escherichi coli) | S09.A40 | Yes |
aes protein (acetyl esterase) (Escherichi coli) | S09.A47 | Yes |
PFC0950c g.p. (Plasmodium falciparum) | S09.A66 | - |
CG11935 protein (Drosophila melanogaster) | S09.A67 | - |
CG18642 (Drosophila melanogaster) | S09.A68 | - |
CG15111 protein (Drosophila melanogaster) | S09.A69 | - |
dpf-6 g.p. (Caenorhabditis elegans) | S09.A77 | Yes |
Y97E10AL.2 (Caenorhabditis elegans) | S09.A78 | - |
T07H6.1 g.p. (Caenorhabditis elegans) | S09.A79 | - |
F01D5.8 g.p. (Caenorhabditis elegans) | S09.A80 | - |
K04G2.2 g.p. (Caenorhabditis elegans) | S09.A81 | - |
dpf-4 g.p. (Caenorhabditis elegans) | S09.A83 | - |
F01D5.7 g.p. (Caenorhabditis elegans) | S09.A84 | - |
PFD0185c g.p. (Plasmodium falciparum) | S09.A95 | - |
DDB_G0281415 g.p. (Dictyostelium discoideum) | S09.A96 | - |
vegetative specific protein h5 (Dictyostelium discoideum) | S09.A97 | - |
BSU23640 g.p. (Bacillus subtilis) | S09.B04 | - |
PF3D7_0805000 g.p. (Plasmodium falciparum) | S09.B05 | - |
Subfamily S9C non-peptidase homologues | non-peptidase homologue | Yes |
Subfamily S9C unassigned peptidases | unassigned | - |
Peptidases and Homologues |
MEROPS ID |
Structure |
bat5 peptidase | S09.022 | - |
D230019K24Rik peptidase (Mus musculus) | S09.023 | - |
Mername-AA264 putative peptidase (LP_1002 protein) (Lactobacillus plantarum) | S09.024 | Yes |
lysophospholipase II (Homo sapiens) | S09.025 | - |
predicted hydrolase of the alpha/beta-hydrolase fold (Homo sapiens) | S09.027 | - |
AlbD protein (Pantoea dispersa) | S09.031 | - |
hypothetical protein | S09.062 | - |
protein bat5 | S09.065 | - |
Mername-AA240 putative peptidase (Mus musculus) | S09.068 | - |
puromycin hydrolase | S09.072 | Yes |
highly similar to acyl-protein thioesterase 1 (Homo sapiens) | S09.941 | Yes |
esterase/lipase (Homo sapiens) | S09.942 | Yes |
acyl-CoA thioesterase 4 (Homo sapiens) | S09.943 | Yes |
acyl-coenzyme A thioesterase 6 (Homo sapiens) | S09.944 | - |
hypothetical esterase/lipase/thioesterase | S09.945 | - |
esterase 6 (Drosophila melanogaster) | S09.947 | Yes |
para-nitrobenzyl esterase (Bacillus subtilis) | S09.948 | Yes |
cephalosporin C deacetylase | S09.949 | Yes |
acyl-protein thioesterase 1 (Schizosaccharomyces pombe) | S09.952 | - |
carboxylesterase 6 (Rattus norvegicus) | S09.953 | - |
carboxylesterase homologue (Rattus norvegicus) | S09.954 | - |
carboxylesterase homologue (Rattus norvegicus) | S09.955 | - |
carboxylesterase homologue (Rattus norvegicus) | S09.956 | - |
carboxylesterase homologue (Rattus norvegicus) | S09.957 | - |
hypothetical protein flj40219 | S09.958 | - |
hypothetical protein flj37464 | S09.959 | - |
hypothetical protein flj33678 | S09.960 | - |
2210023G05RIK protein | S09.961 | - |
BC026374 protein (Mus musculus) | S09.962 | - |
liver carboxylesterase | S09.964 | - |
liver carboxylesterase 4 (rodent) | S09.965 | - |
carboxylesterase rl1 (Rattus norvegicus) | S09.969 | - |
putative carboxylesterase (Rattus norvegicus) | S09.970 | - |
carboxylesterase ES31 (Mus musculus) | S09.971 | - |
putative carboxylesterasec | S09.972 | - |
dipeptidylpeptidase homologue DPP6 | S09.973 | Yes |
dipeptidylpeptidase homologue DPP10 | S09.974 | Yes |
carboxylesterase homologue (Mus musculus) | S09.975 | - |
protein similar to Mus musculus chromosome 20 open reading frame 135 | S09.976 | - |
kynurenine formamidase | S09.977 | - |
thyroglobulin precursor | S09.978 | - |
acetylcholinesterase | S09.979 | Yes |
cholinesterase | S09.980 | Yes |
carboxylesterase D1 | S09.981 | - |
liver carboxylesterase | S09.982 | Yes |
carboxylesterase 3 | S09.983 | - |
carboxylesterase 2 | S09.984 | - |
bile salt-dependent lipase | S09.985 | Yes |
neuroligin 3 | S09.987 | - |
neuroligin 4, X-linked | S09.988 | Yes |
neuroligin 4, Y-linked | S09.989 | - |
esterase D | S09.990 | Yes |
arylacetamide deacetylase | S09.991 | - |
KIAA1363-like protein | S09.992 | - |
hormone-sensitive lipase | S09.993 | - |
neuroligin 1 | S09.994 | Yes |
neuroligin 2 | S09.995 | Yes |
liver carboxylesterase 1 | S09.996 | - |
carboxylesterase 2 | S09.997 | - |
9030624L02RIK-like protein | S09.998 | - |
carboxylesterase | S09.999 | - |
At3g27320 (Arabidopsis thaliana)-type peptidase | S09.A05 | - |
At5g25770 (Arabidopsis thaliana) | S09.A06 | - |
At2g45600 (Arabidopsis thaliana) | S09.A07 | - |
At5g14310 (Arabidopsis thaliana) | S09.A08 | - |
At2g45610 (Arabidopsis thaliana) | S09.A11 | - |
At5g62180 (Arabidopsis thaliana) | S09.A14 | - |
At5g19630 (Arabidopsis thaliana) | S09.A16 | - |
At3g47590 (Arabidopsis thaliana) | S09.A17 | - |
At2g19550 (Arabidopsis thaliana) | S09.A18 | - |
At1g29840 (Arabidopsis thaliana) | S09.A19 | - |
At1g26120 (Arabidopsis thaliana)-type peptidase | S09.A21 | - |
At5g15860 (Arabidopsis thaliana)-type peptidase | S09.A26 | - |
At4g17150 (Arabidopsis thaliana)-type peptidase | S09.A29 | - |
At3g47560 (Arabidopsis thaliana) | S09.A31 | - |
hypothetical ORF Ynl320wp (Saccharomyces cerevisiae) | S09.A35 | - |
YfhR protein (Escherichi coli) | S09.A36 | - |
YeiG protein (Escherichi coli) | S09.A39 | - |
YieL protein (Escherichi coli) | S09.A41 | - |
YpfH protein (Escherichi coli) | S09.A43 | - |
YjfP protein (Escherichi coli) | S09.A46 | - |
Gm438 protein (Mus musculus) | S09.A48 | - |
acyl-coenzyme A:N-acyltransferase 1 | S09.A49 | - |
acyl-coenzyme A amino acid N-acyltransferase 2 | S09.A50 | - |
acyl-coenzyme A thioesterase 5 | S09.A51 | - |
acyl-coenzyme A thioesterase 2, mitochondrial | S09.A52 | - |
mCG4926 protein (Mus musculus) | S09.A53 | - |
mCG51558 protein (Mus musculus) | S09.A54 | - |
At3G15650 protein (Arabidopsis thaliana) | S09.A55 | - |
At5G20060 protein (Arabidopsis thaliana) | S09.A56 | Yes |
At3G19970 protein (Arabidopsis thaliana) | S09.A57 | - |
MDB19.2 protein (Arabidopsis thaliana) | S09.A59 | - |
acyl-coenzyme A thioesterase 4 | S09.A60 | - |
acyl-coenzyme A thioesterase 6 | S09.A61 | - |
F16b3.4 protein (Arabidopsis thaliana) | S09.A62 | - |
AT14896 protein (Drosophila melanogaster) | S09.A63 | - |
CG7529 protein (Drosophila melanogaster) | S09.A71 | - |
CG9542 protein (Drosophila melanogaster) | S09.A72 | Yes |
Y43f8a.3 g.p. (Caenorhabditis elegans) | S09.A82 | - |
F27c8.6 g.p. (Caenorhabditis elegans) | S09.A85 | - |
F16F9.4 g.p. (Caenorhabditis elegans) | S09.A86 | - |
T28C12.4a g.p. (Caenorhabditis elegans) | S09.A87 | - |
T28C12.5 g.p. (Caenorhabditis elegans) | S09.A88 | - |
acetylcholinesterase (Caenorhabditis elegans) | S09.A89 | - |
ZC376.2 g.p. (Caenorhabditis elegans) | S09.A90 | - |
Y71G12A.4 g.p. (Caenorhabditis elegans) | S09.A91 | - |
YDL057W g.p. (Saccharomyces cerevisiae) | S09.A98 | - |
SPCC417.12 (Schizosaccharomyces pombe) | S09.A99 | - |
SPAPB1A11.02 g.p. (Schizosaccharomyces pombe) | S09.B01 | - |
DDB_G0288631 g.p. (Dictyostelium discoideum) | S09.B03 | - |
ytmA g.p. (Bacillus subtilis) | S09.B06 | - |
yjcH g.p. (Bacillus subtilis) | S09.B07 | - |
K05B2.4 g.p. (Caenorhabditis elegans) | S09.B09 | - |
C31H5.6 g.p. (Caenorhabditis elegans) | S09.B10 | - |
si:dkey-183c16.7 g.p. (Brachydanio rerio) | S09.B11 | - |
si:dkeyp-89c11.2 g.p. (Brachydanio rerio) | S09.B12 | - |
hCG1647005 | S09.B13 | - |
Family S9 non-peptidase homologues | non-peptidase homologue | Yes |
Family S9 unassigned peptidases | unassigned | Yes |