ID   DPEP1_PIG               Reviewed;         409 AA.
AC   P22412;
DT   01-AUG-1991, integrated into UniProtKB/Swiss-Prot.
DT   01-AUG-1991, sequence version 1.
DT   24-JAN-2024, entry version 154.
DE   RecName: Full=Dipeptidase 1;
DE            EC=3.4.13.19 {ECO:0000269|PubMed:8045301, ECO:0000269|PubMed:8823187};
DE   AltName: Full=Beta-lactamase {ECO:0000305};
DE            EC=3.5.2.6 {ECO:0000250|UniProtKB:P31428};
DE   AltName: Full=Microsomal dipeptidase;
DE   AltName: Full=Renal dipeptidase;
DE   Flags: Precursor;
GN   Name=DPEP1; Synonyms=RDP;
OS   Sus scrofa (Pig).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Laurasiatheria; Artiodactyla; Suina; Suidae; Sus.
OX   NCBI_TaxID=9823;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA], PARTIAL PROTEIN SEQUENCE, AND GLYCOSYLATION AT
RP   ASN-57.
RC   TISSUE=Kidney cortex;
RX   PubMed=2173907; DOI=10.1042/bj2710755;
RA   Rached E., Hooper N.M., James P., Semenza G., Turner A.J., Mantei N.;
RT   "cDNA cloning and expression in Xenopus laevis oocytes of pig renal
RT   dipeptidase, a glycosyl-phosphatidylinositol-anchored ectoenzyme.";
RL   Biochem. J. 271:755-760(1990).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RA   Satoh S., Koyama S., Ohtuka K., Keida Y., Niwa M., Kohsaka M.;
RT   "Purification and cDNA cloning for porcine renal dipeptidase.";
RL   Submitted (SEP-1992) to the EMBL/GenBank/DDBJ databases.
RN   [3]
RP   PROTEIN SEQUENCE OF 17-39.
RX   PubMed=2137335; DOI=10.1042/bj2650429;
RA   Hooper N.M., Keen J.N., Turner A.J.;
RT   "Characterization of the glycosyl-phosphatidylinositol-anchored human renal
RT   dipeptidase reveals that it is more extensively glycosylated than the pig
RT   enzyme.";
RL   Biochem. J. 265:429-433(1990).
RN   [4]
RP   CATALYTIC ACTIVITY, MUTAGENESIS OF HIS-235; ASP-285; HIS-286; ASP-288 AND
RP   HIS-289, SUBCELLULAR LOCATION, FUNCTION, AND ACTIVITY REGULATION.
RX   PubMed=8045301; DOI=10.1016/0014-5793(94)00637-7;
RA   Keynan S., Hooper N.M., Turner A.J.;
RT   "Directed mutagenesis of pig renal membrane dipeptidase. His219 is critical
RT   but the DHXXH motif is not essential for zinc binding or catalytic
RT   activity.";
RL   FEBS Lett. 349:50-54(1994).
RN   [5]
RP   INTERCHAIN DISULFIDE BOND, MUTAGENESIS OF CYS-87; CYS-109; CYS-170;
RP   CYS-242; CYS-274 AND CYS-377, CATALYTIC ACTIVITY, SUBUNIT, AND ACTIVITY
RP   REGULATION.
RX   PubMed=8823187; DOI=10.1021/bi961193z;
RA   Keynan S., Habgood N.T., Hooper N.M., Turner A.J.;
RT   "Site-directed mutagenesis of conserved cysteine residues in porcine
RT   membrane dipeptidase. Cys-361 alone is involved in disulfide-linked
RT   dimerization.";
RL   Biochemistry 35:12511-12517(1996).
RN   [6]
RP   GPI-ANCHOR AT SER-384, AND IDENTIFICATION BY MASS SPECTROMETRY.
RX   PubMed=16689534; DOI=10.1021/ac0517949;
RA   Omaetxebarria M.J., Hagglund P., Elortza F., Hooper N.M., Arizmendi J.M.,
RA   Jensen O.N.;
RT   "Isolation and characterization of glycosylphosphatidylinositol-anchored
RT   peptides by hydrophilic interaction chromatography and MALDI tandem mass
RT   spectrometry.";
RL   Anal. Chem. 78:3335-3341(2006).
CC   -!- FUNCTION: Hydrolyzes a wide range of dipeptides (PubMed:8045301,
CC       PubMed:8823187). Hydrolyzes the conversion of leukotriene D4 to
CC       leukotriene E4. Hydrolyzes cystinyl-bis-glycine (cys-bis-gly) formed
CC       during glutathione degradation. Possesses also beta lactamase activity
CC       and hydrolytically inactivates beta-lactam antibiotics (By similarity).
CC       {ECO:0000250|UniProtKB:P31428, ECO:0000269|PubMed:8045301,
CC       ECO:0000269|PubMed:8823187}.
CC   -!- FUNCTION: Independently of its dipeptidase activity, acts as an
CC       adhesion receptor for neutrophil recruitment from bloodstream into
CC       inflamed lungs and liver. {ECO:0000250|UniProtKB:P31428}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=an L-aminoacyl-L-amino acid + H2O = 2 an L-alpha-amino acid;
CC         Xref=Rhea:RHEA:48940, ChEBI:CHEBI:15377, ChEBI:CHEBI:59869,
CC         ChEBI:CHEBI:77460; EC=3.4.13.19; Evidence={ECO:0000255|PROSITE-
CC         ProRule:PRU10073, ECO:0000269|PubMed:8045301,
CC         ECO:0000269|PubMed:8823187};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=H2O + leukotriene D4 = glycine + leukotriene E4;
CC         Xref=Rhea:RHEA:48616, ChEBI:CHEBI:15377, ChEBI:CHEBI:57305,
CC         ChEBI:CHEBI:57462, ChEBI:CHEBI:63166;
CC         Evidence={ECO:0000250|UniProtKB:P31428};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=2 H2O + L-cystine-bis-glycine = 2 glycine + L-cystine;
CC         Xref=Rhea:RHEA:60520, ChEBI:CHEBI:15377, ChEBI:CHEBI:35491,
CC         ChEBI:CHEBI:57305, ChEBI:CHEBI:143812;
CC         Evidence={ECO:0000250|UniProtKB:P31428};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=a beta-lactam + H2O = a substituted beta-amino acid;
CC         Xref=Rhea:RHEA:20401, ChEBI:CHEBI:15377, ChEBI:CHEBI:35627,
CC         ChEBI:CHEBI:140347; EC=3.5.2.6;
CC         Evidence={ECO:0000250|UniProtKB:P31428};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=glycyldehydrophenylalanine + H2O = 2,3-didehydrophenylalanine
CC         + glycine; Xref=Rhea:RHEA:62704, ChEBI:CHEBI:15377,
CC         ChEBI:CHEBI:57305, ChEBI:CHEBI:145925, ChEBI:CHEBI:145926;
CC         Evidence={ECO:0000269|PubMed:8045301, ECO:0000269|PubMed:8823187};
CC   -!- COFACTOR:
CC       Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC         Evidence={ECO:0000250|UniProtKB:P16444, ECO:0000255|PROSITE-
CC         ProRule:PRU10073};
CC   -!- ACTIVITY REGULATION: Inhibited by L-penicillamine (By similarity).
CC       Inhibited by cilastatin (PubMed:8823187, PubMed:8045301).
CC       {ECO:0000250|UniProtKB:P16444, ECO:0000269|PubMed:8045301,
CC       ECO:0000269|PubMed:8823187}.
CC   -!- SUBUNIT: Homodimer; disulfide-linked. {ECO:0000269|PubMed:8823187}.
CC   -!- SUBCELLULAR LOCATION: Apical cell membrane; Lipid-anchor, GPI-anchor
CC       {ECO:0000269|PubMed:16689534}. Cell projection, microvillus membrane;
CC       Lipid-anchor, GPI-anchor {ECO:0000269|PubMed:16689534}. Cell membrane
CC       {ECO:0000269|PubMed:8045301}; Lipid-anchor, GPI-anchor
CC       {ECO:0000269|PubMed:8045301}. Note=Brush border membrane.
CC       {ECO:0000250|UniProtKB:P31429}.
CC   -!- SIMILARITY: Belongs to the metallo-dependent hydrolases superfamily.
CC       Peptidase M19 family. {ECO:0000255|PROSITE-ProRule:PRU10073}.
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DR   EMBL; X53730; CAA37762.1; -; mRNA.
DR   EMBL; D13142; BAA02433.1; -; mRNA.
DR   PIR; JS0759; JS0759.
DR   RefSeq; NP_999273.1; NM_214108.1.
DR   AlphaFoldDB; P22412; -.
DR   SMR; P22412; -.
DR   STRING; 9823.ENSSSCP00000019823; -.
DR   BindingDB; P22412; -.
DR   ChEMBL; CHEMBL2626; -.
DR   DrugCentral; P22412; -.
DR   MEROPS; M19.001; -.
DR   GlyCosmos; P22412; 2 sites, No reported glycans.
DR   iPTMnet; P22412; -.
DR   PaxDb; 9823-ENSSSCP00000019823; -.
DR   PeptideAtlas; P22412; -.
DR   Ensembl; ENSSSCT00025034816.1; ENSSSCP00025014499.1; ENSSSCG00025025766.1.
DR   Ensembl; ENSSSCT00035005011.1; ENSSSCP00035001713.1; ENSSSCG00035004024.1.
DR   Ensembl; ENSSSCT00045014623.1; ENSSSCP00045010144.1; ENSSSCG00045008656.1.
DR   Ensembl; ENSSSCT00065097843.1; ENSSSCP00065042890.1; ENSSSCG00065071207.1.
DR   GeneID; 397196; -.
DR   KEGG; ssc:397196; -.
DR   CTD; 1800; -.
DR   eggNOG; KOG4127; Eukaryota.
DR   InParanoid; P22412; -.
DR   OrthoDB; 5476406at2759; -.
DR   BioCyc; MetaCyc:MONOMER-9981; -.
DR   Reactome; R-SSC-2142691; Synthesis of Leukotrienes (LT) and Eoxins (EX).
DR   Reactome; R-SSC-5423646; Aflatoxin activation and detoxification.
DR   PRO; PR:P22412; -.
DR   Proteomes; UP000008227; Unplaced.
DR   Proteomes; UP000314985; Unplaced.
DR   Proteomes; UP000694570; Unplaced.
DR   Proteomes; UP000694571; Unplaced.
DR   Proteomes; UP000694720; Unplaced.
DR   Proteomes; UP000694722; Unplaced.
DR   Proteomes; UP000694723; Unplaced.
DR   Proteomes; UP000694724; Unplaced.
DR   Proteomes; UP000694725; Unplaced.
DR   Proteomes; UP000694726; Unplaced.
DR   Proteomes; UP000694727; Unplaced.
DR   Proteomes; UP000694728; Unplaced.
DR   GO; GO:0045177; C:apical part of cell; ISS:UniProtKB.
DR   GO; GO:0016324; C:apical plasma membrane; IEA:UniProtKB-SubCell.
DR   GO; GO:0005789; C:endoplasmic reticulum membrane; IDA:UniProtKB.
DR   GO; GO:0005615; C:extracellular space; IDA:UniProtKB.
DR   GO; GO:0031528; C:microvillus membrane; IEA:UniProtKB-SubCell.
DR   GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR   GO; GO:0098552; C:side of membrane; IEA:UniProtKB-KW.
DR   GO; GO:0008800; F:beta-lactamase activity; ISS:UniProtKB.
DR   GO; GO:0043027; F:cysteine-type endopeptidase inhibitor activity involved in apoptotic process; ISS:UniProtKB.
DR   GO; GO:0016805; F:dipeptidase activity; IDA:UniProtKB.
DR   GO; GO:0034235; F:GPI anchor binding; IDA:UniProtKB.
DR   GO; GO:0042802; F:identical protein binding; IDA:UniProtKB.
DR   GO; GO:0070573; F:metallodipeptidase activity; ISS:UniProtKB.
DR   GO; GO:0072341; F:modified amino acid binding; ISS:UniProtKB.
DR   GO; GO:0008270; F:zinc ion binding; ISS:UniProtKB.
DR   GO; GO:0016999; P:antibiotic metabolic process; ISS:UniProtKB.
DR   GO; GO:0071277; P:cellular response to calcium ion; IDA:UniProtKB.
DR   GO; GO:0032869; P:cellular response to insulin stimulus; IDA:UniProtKB.
DR   GO; GO:0071732; P:cellular response to nitric oxide; IDA:UniProtKB.
DR   GO; GO:0071466; P:cellular response to xenobiotic stimulus; ISS:UniProtKB.
DR   GO; GO:0006751; P:glutathione catabolic process; ISS:UniProtKB.
DR   GO; GO:0006507; P:GPI anchor release; IDA:UniProtKB.
DR   GO; GO:0050667; P:homocysteine metabolic process; ISS:UniProtKB.
DR   GO; GO:1901749; P:leukotriene D4 catabolic process; ISS:UniProtKB.
DR   GO; GO:0006691; P:leukotriene metabolic process; ISS:UniProtKB.
DR   GO; GO:0043066; P:negative regulation of apoptotic process; ISS:UniProtKB.
DR   GO; GO:0030336; P:negative regulation of cell migration; ISS:UniProtKB.
DR   GO; GO:0043154; P:negative regulation of cysteine-type endopeptidase activity involved in apoptotic process; ISS:UniProtKB.
DR   GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW.
DR   CDD; cd01301; rDP_like; 1.
DR   Gene3D; 3.20.20.140; Metal-dependent hydrolases; 1.
DR   InterPro; IPR000180; Dipep_AS.
DR   InterPro; IPR032466; Metal_Hydrolase.
DR   InterPro; IPR008257; Pept_M19.
DR   PANTHER; PTHR10443:SF38; DIPEPTIDASE 1; 1.
DR   PANTHER; PTHR10443; MICROSOMAL DIPEPTIDASE; 1.
DR   Pfam; PF01244; Peptidase_M19; 1.
DR   SUPFAM; SSF51556; Metallo-dependent hydrolases; 1.
DR   PROSITE; PS00869; RENAL_DIPEPTIDASE_1; 1.
DR   PROSITE; PS51365; RENAL_DIPEPTIDASE_2; 1.
PE   1: Evidence at protein level;
KW   Cell membrane; Cell projection; Dipeptidase; Direct protein sequencing;
KW   Disulfide bond; Glycoprotein; GPI-anchor; Hydrolase; Lipid metabolism;
KW   Lipoprotein; Membrane; Metal-binding; Metalloprotease; Protease;
KW   Reference proteome; Signal; Zinc.
FT   SIGNAL          1..16
FT                   /evidence="ECO:0000269|PubMed:2137335"
FT   CHAIN           17..384
FT                   /note="Dipeptidase 1"
FT                   /id="PRO_0000018656"
FT   PROPEP          385..409
FT                   /note="Removed in mature form"
FT                   /evidence="ECO:0000250|UniProtKB:P16444"
FT                   /id="PRO_0000018657"
FT   BINDING         36
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="1"
FT                   /ligand_note="catalytic"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU10073"
FT   BINDING         38
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="1"
FT                   /ligand_note="catalytic"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU10073"
FT   BINDING         141
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="1"
FT                   /ligand_note="catalytic"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU10073"
FT   BINDING         141
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="2"
FT                   /ligand_note="catalytic"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU10073"
FT   BINDING         168
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU10073"
FT   BINDING         214
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="2"
FT                   /ligand_note="catalytic"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU10073"
FT   BINDING         235
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="2"
FT                   /ligand_note="catalytic"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU10073"
FT   BINDING         246
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU10073"
FT   BINDING         304
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU10073"
FT   LIPID           384
FT                   /note="GPI-anchor amidated serine"
FT                   /evidence="ECO:0000269|PubMed:16689534"
FT   CARBOHYD        57
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000269|PubMed:2173907"
FT   CARBOHYD        279
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   DISULFID        87..170
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU10073"
FT   DISULFID        242..274
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU10073"
FT   DISULFID        377
FT                   /note="Interchain"
FT                   /evidence="ECO:0000269|PubMed:8823187"
FT   MUTAGEN         87
FT                   /note="C->G: Does not affect dimerization. Does not affect
FT                   dipeptidase activity."
FT                   /evidence="ECO:0000269|PubMed:8823187"
FT   MUTAGEN         109
FT                   /note="C->A: Does not affect dimerization. Does not affect
FT                   dipeptidase activity."
FT                   /evidence="ECO:0000269|PubMed:8823187"
FT   MUTAGEN         170
FT                   /note="C->G: Does not affect dimerization. Does not affect
FT                   dipeptidase activity."
FT                   /evidence="ECO:0000269|PubMed:8823187"
FT   MUTAGEN         235
FT                   /note="H->R,K,L: Complete abolition of dipeptidase
FT                   activity. Does not affect cell membrane localization."
FT                   /evidence="ECO:0000269|PubMed:8045301"
FT   MUTAGEN         242
FT                   /note="C->A: Does not affect dimerization. Does not affect
FT                   dipeptidase activity."
FT                   /evidence="ECO:0000269|PubMed:8823187"
FT   MUTAGEN         274
FT                   /note="C->G: Does not affect dimerization. Does not affect
FT                   dipeptidase activity."
FT                   /evidence="ECO:0000269|PubMed:8823187"
FT   MUTAGEN         285
FT                   /note="D->A: Does not affect dipeptidase activity."
FT                   /evidence="ECO:0000269|PubMed:8045301"
FT   MUTAGEN         286
FT                   /note="H->L,Q,K: Does not affect dipeptidase activity."
FT                   /evidence="ECO:0000269|PubMed:8045301"
FT   MUTAGEN         288
FT                   /note="D->A: Does not affect dipeptidase activity."
FT                   /evidence="ECO:0000269|PubMed:8045301"
FT   MUTAGEN         289
FT                   /note="H->R: Does not affect dipeptidase activity."
FT                   /evidence="ECO:0000269|PubMed:8045301"
FT   MUTAGEN         377
FT                   /note="C->G: Abolished disulfide-linked dimerization. Does
FT                   not affect dipeptidase activity."
FT                   /evidence="ECO:0000269|PubMed:8823187"
SQ   SEQUENCE   409 AA;  44700 MW;  926B7F0044FA055F CRC64;
     MWTSWWLWPL VAVCAADQFR DLAVRIMQDT PVIDGHNDLP WQLLNLFNNQ LQDPGANLSS
     LAHTHTNIPK LKAGFVGGQF WSAYVPCDTQ NRDAVKRTLE QIDVIQRMCQ AYPETFACVT
     SSTGIRQAFR EGKVASLVGV EGGHSIDSSL GVLRALYHLG MRYMTLTHSC NTPWADNWLV
     DTGDDKAQSQ GLSHFGQSVV KEMNRLGVMI DLAHVSVATM RAALKLSQAP VIFSHSSAYS
     LCPHRRNVPD DVLQLVKETG SLVMVNFYND YVSCSAKANL SQVADHLDHI KKVAGAAAVG
     FGGDYDGVSR VPSGLEDVSK YPDLVAELLR RQWTEAEVRG ALADNLLRVF EAVEQASNHA
     QVPGEEPIPL GQLEASCRTN YGYSAAPSLH LPPGSLLASL VPLLLLSLP
//