AMPL_RAT
ID AMPL_RAT Reviewed; 519 AA.
AC Q68FS4;
DT 23-JAN-2007, integrated into UniProtKB/Swiss-Prot.
DT 11-OCT-2004, sequence version 1.
DT 03-AUG-2022, entry version 117.
DE RecName: Full=Cytosol aminopeptidase {ECO:0000305};
DE EC=3.4.11.1 {ECO:0000269|PubMed:12675513};
DE AltName: Full=Cysteinylglycine-S-conjugate dipeptidase {ECO:0000305|PubMed:12675513};
DE EC=3.4.13.23 {ECO:0000269|PubMed:12675513};
DE AltName: Full=Leucine aminopeptidase 3 {ECO:0000312|RGD:1307985};
DE Short=LAP-3;
DE AltName: Full=Leucyl aminopeptidase {ECO:0000303|PubMed:12675513};
DE Short=LAP {ECO:0000303|PubMed:12675513};
DE AltName: Full=Peptidase S {ECO:0000250|UniProtKB:P28838};
DE AltName: Full=Proline aminopeptidase {ECO:0000250|UniProtKB:P28839};
DE EC=3.4.11.5 {ECO:0000250|UniProtKB:P28839};
DE AltName: Full=Prolyl aminopeptidase {ECO:0000312|RGD:1307985};
GN Name=Lap3 {ECO:0000312|RGD:1307985};
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Testis;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [2]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=6108111; DOI=10.1016/0006-291x(80)90050-9;
RA Rankin B.B., McIntyre T.M., Curthoys N.P.;
RT "Brush border membrane hydrolysis of S-benzyl-cysteine-p-nitroanilide, and
RT activity of aminopeptidase M.";
RL Biochem. Biophys. Res. Commun. 96:991-996(1980).
RN [3]
RP PROTEIN SEQUENCE OF 69-79; 85-103; 189-200; 283-294; 322-342; 369-384;
RP 441-455; 458-469; 477-496 AND 506-513, AND IDENTIFICATION BY MASS
RP SPECTROMETRY.
RC STRAIN=Sprague-Dawley; TISSUE=Hippocampus, and Spinal cord;
RA Lubec G., Afjehi-Sadat L., Diao W.;
RL Submitted (APR-2007) to UniProtKB.
RN [4]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, AND SUBCELLULAR
RP LOCATION.
RX PubMed=12675513; DOI=10.1515/bc.2003.023;
RA Joesch C., Klotz L.O., Sies H.;
RT "Identification of cytosolic leucyl aminopeptidase (EC 3.4.11.1) as the
RT major cysteinylglycine-hydrolyzing activity in rat liver.";
RL Biol. Chem. 384:213-218(2003).
RN [5]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-42 AND SER-54, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22673903; DOI=10.1038/ncomms1871;
RA Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C.,
RA Olsen J.V.;
RT "Quantitative maps of protein phosphorylation sites across 14 different rat
RT organs and tissues.";
RL Nat. Commun. 3:876-876(2012).
CC -!- FUNCTION: Cytosolic metallopeptidase that catalyzes the removal of
CC unsubstituted N-terminal hydrophobic amino acids from various peptides
CC (PubMed:6108111, PubMed:12675513). The presence of Zn(2+) ions is
CC essential for the peptidase activity, and the association with other
CC cofactors can modulate the substrate spectificity of the enzyme (By
CC similarity). For instance, in the presence of Mn(2+), it displays a
CC specific Cys-Gly hydrolyzing activity of Cys-Gly-S-conjugates (By
CC similarity). Involved in the metabolism of glutathione and in the
CC degradation of glutathione S-conjugates, which may play a role in the
CC control of the cell redox status (PubMed:12675513).
CC {ECO:0000250|UniProtKB:P00727, ECO:0000269|PubMed:12675513,
CC ECO:0000269|PubMed:6108111}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=Release of an N-terminal amino acid, Xaa-|-Yaa-, in which Xaa
CC is preferably Leu, but may be other amino acids including Pro
CC although not Arg or Lys, and Yaa may be Pro. Amino acid amides and
CC methyl esters are also readily hydrolyzed, but rates on arylamides
CC are exceedingly low.; EC=3.4.11.1;
CC Evidence={ECO:0000269|PubMed:12675513};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=an S-substituted L-cysteinylglycine + H2O = an S-substituted
CC L-cysteine + glycine; Xref=Rhea:RHEA:60444, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:57305, ChEBI:CHEBI:58717, ChEBI:CHEBI:143103;
CC EC=3.4.13.23; Evidence={ECO:0000269|PubMed:12675513};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:60445;
CC Evidence={ECO:0000305|PubMed:12675513};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + L-cysteinylglycine = glycine + L-cysteine;
CC Xref=Rhea:RHEA:28783, ChEBI:CHEBI:15377, ChEBI:CHEBI:35235,
CC ChEBI:CHEBI:57305, ChEBI:CHEBI:61694;
CC Evidence={ECO:0000269|PubMed:12675513};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:28784;
CC Evidence={ECO:0000305|PubMed:12675513};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + S-benzyl-L-cysteinylglycine = glycine + S-benzyl-L-
CC cysteine; Xref=Rhea:RHEA:62568, ChEBI:CHEBI:15377, ChEBI:CHEBI:57305,
CC ChEBI:CHEBI:145802, ChEBI:CHEBI:145803;
CC Evidence={ECO:0000269|PubMed:6108111};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:62569;
CC Evidence={ECO:0000305|PubMed:6108111};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=Release of N-terminal proline from a peptide.; EC=3.4.11.5;
CC Evidence={ECO:0000250|UniProtKB:P28839};
CC -!- COFACTOR:
CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC Evidence={ECO:0000250|UniProtKB:P00727};
CC Name=Mn(2+); Xref=ChEBI:CHEBI:29035;
CC Evidence={ECO:0000250|UniProtKB:P00727};
CC Note=Binds two metal ions per subunit. Two metal binding sites with
CC different affinities are located in the enzyme active site and can be
CC occupied in vitro by different metals: site 1 is occupied by Zn(2+),
CC Mn(2+), Mg(2+) or Co(2+), while the tight binding site 2 can be
CC occupied by only Zn(2+) or Co(2+). One Zn(2+) ion is tightly bound to
CC site 2 and essential for enzyme activity in vivo, while site 1 can be
CC occupied by different metals to give different enzymatic activities.
CC Mn(2+) is required for Cys-Gly hydrolysis activity. A third metal
CC binding site may serve a structural role, possibly stabilizing part of
CC the interface between the N-terminal and the catalytic domain.
CC {ECO:0000250|UniProtKB:P00727};
CC -!- ACTIVITY REGULATION: Bimane-S-cysteinylglycine-hydrolyzing activity is
CC inhibited by o-phenanthroline or bestatin, and is activated by the
CC addition of zinc chloride. {ECO:0000269|PubMed:12675513}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC Vmax=1.6 umol/min/mg enzyme for peptidase activity with S-benzyl-
CC cysteine-p-nitroanilide {ECO:0000269|PubMed:6108111};
CC Vmax=11.9 umol/min/mg enzyme for peptidase activity with Leucine-p-
CC nitroanilide {ECO:0000269|PubMed:6108111};
CC Vmax=9.4 umol/min/mg enzyme for peptidase activity with Alanine-p-
CC nitroanilide {ECO:0000269|PubMed:6108111};
CC -!- SUBUNIT: Homohexamer. {ECO:0000250|UniProtKB:P00727}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:12675513}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative initiation; Named isoforms=2;
CC Name=1;
CC IsoId=Q68FS4-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q68FS4-2; Sequence=VSP_022633;
CC -!- SIMILARITY: Belongs to the peptidase M17 family. {ECO:0000305}.
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DR EMBL; BC079381; AAH79381.1; -; mRNA.
DR RefSeq; NP_001011910.1; NM_001011910.1. [Q68FS4-1]
DR AlphaFoldDB; Q68FS4; -.
DR SMR; Q68FS4; -.
DR STRING; 10116.ENSRNOP00000004770; -.
DR MEROPS; M17.001; -.
DR iPTMnet; Q68FS4; -.
DR PhosphoSitePlus; Q68FS4; -.
DR jPOST; Q68FS4; -.
DR PaxDb; Q68FS4; -.
DR PRIDE; Q68FS4; -.
DR Ensembl; ENSRNOT00000004770; ENSRNOP00000004770; ENSRNOG00000003289. [Q68FS4-1]
DR GeneID; 289668; -.
DR KEGG; rno:289668; -.
DR CTD; 51056; -.
DR RGD; 1307985; Lap3.
DR eggNOG; KOG2597; Eukaryota.
DR GeneTree; ENSGT00530000063255; -.
DR HOGENOM; CLU_013734_1_2_1; -.
DR InParanoid; Q68FS4; -.
DR OMA; MKNTGPR; -.
DR OrthoDB; 562530at2759; -.
DR PhylomeDB; Q68FS4; -.
DR TreeFam; TF314954; -.
DR BioCyc; MetaCyc:MON-10001; -.
DR BRENDA; 3.4.13.23; 5301.
DR PRO; PR:Q68FS4; -.
DR Proteomes; UP000002494; Chromosome 14.
DR Bgee; ENSRNOG00000003289; Expressed in jejunum and 19 other tissues.
DR Genevisible; Q68FS4; RN.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005829; C:cytosol; IEA:Ensembl.
DR GO; GO:0030496; C:midbody; IEA:Ensembl.
DR GO; GO:0005654; C:nucleoplasm; IEA:Ensembl.
DR GO; GO:0005802; C:trans-Golgi network; IDA:MGI.
DR GO; GO:0004180; F:carboxypeptidase activity; IEA:RHEA.
DR GO; GO:0030145; F:manganese ion binding; IEA:InterPro.
DR GO; GO:0070006; F:metalloaminopeptidase activity; IEA:InterPro.
DR GO; GO:0008233; F:peptidase activity; ISO:RGD.
DR GO; GO:0006508; P:proteolysis; IBA:GO_Central.
DR CDD; cd00433; Peptidase_M17; 1.
DR Gene3D; 3.40.220.10; -; 1.
DR HAMAP; MF_00181; Cytosol_peptidase_M17; 1.
DR InterPro; IPR011356; Leucine_aapep/pepB.
DR InterPro; IPR043472; Macro_dom-like.
DR InterPro; IPR000819; Peptidase_M17_C.
DR InterPro; IPR023042; Peptidase_M17_leu_NH2_pept.
DR InterPro; IPR008283; Peptidase_M17_N.
DR PANTHER; PTHR11963; PTHR11963; 1.
DR Pfam; PF00883; Peptidase_M17; 1.
DR Pfam; PF02789; Peptidase_M17_N; 1.
DR PRINTS; PR00481; LAMNOPPTDASE.
DR SUPFAM; SSF52949; SSF52949; 1.
DR PROSITE; PS00631; CYTOSOL_AP; 1.
PE 1: Evidence at protein level;
KW Acetylation; Alternative initiation; Aminopeptidase; Cytoplasm;
KW Direct protein sequencing; Hydrolase; Magnesium; Manganese; Metal-binding;
KW Phosphoprotein; Protease; Reference proteome; Zinc.
FT CHAIN 1..519
FT /note="Cytosol aminopeptidase"
FT /id="PRO_0000274146"
FT ACT_SITE 294
FT /evidence="ECO:0000250|UniProtKB:P00727"
FT ACT_SITE 368
FT /evidence="ECO:0000250|UniProtKB:P00727"
FT BINDING 202
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="3"
FT /ligand_note="structural"
FT /evidence="ECO:0000250|UniProtKB:P00727"
FT BINDING 203
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="3"
FT /ligand_note="structural"
FT /evidence="ECO:0000250|UniProtKB:P00727"
FT BINDING 282
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P00727"
FT BINDING 282
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000250|UniProtKB:P00727"
FT BINDING 287
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000250|UniProtKB:P00727"
FT BINDING 287
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P00727"
FT BINDING 287
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000250|UniProtKB:P00727"
FT BINDING 287
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000250|UniProtKB:P00727"
FT BINDING 292
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P00727"
FT BINDING 294
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P00727"
FT BINDING 303
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="3"
FT /ligand_note="structural"
FT /evidence="ECO:0000250|UniProtKB:P00727"
FT BINDING 305
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P00727"
FT BINDING 305
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000250|UniProtKB:P00727"
FT BINDING 364
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000250|UniProtKB:P00727"
FT BINDING 364
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P00727"
FT BINDING 364
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000250|UniProtKB:P00727"
FT BINDING 366
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000250|UniProtKB:P00727"
FT BINDING 366
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000250|UniProtKB:P00727"
FT BINDING 366
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000250|UniProtKB:P00727"
FT MOD_RES 42
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 45
FT /note="N6-succinyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q9CPY7"
FT MOD_RES 54
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 61
FT /note="N6-succinyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q9CPY7"
FT MOD_RES 103
FT /note="N6-succinyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q9CPY7"
FT MOD_RES 180
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9CPY7"
FT MOD_RES 194
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P28838"
FT MOD_RES 221
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P28838"
FT MOD_RES 221
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:Q9CPY7"
FT MOD_RES 238
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P28838"
FT MOD_RES 455
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:Q9CPY7"
FT MOD_RES 455
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:Q9CPY7"
FT MOD_RES 476
FT /note="N6-succinyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q9CPY7"
FT MOD_RES 489
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:Q9CPY7"
FT MOD_RES 489
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:Q9CPY7"
FT VAR_SEQ 1..31
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000305"
FT /id="VSP_022633"
SQ SEQUENCE 519 AA; 56150 MW; 0D4DFDC93D0CFF9D CRC64;
MYLLPLPAAA RVALRRLGVR GLWDRGLSTA DMTKGLVLGI YSKDKDDDVP QFTSAGENFN
KLVSGRLREM LNISGPPLKA GKTRTFYGLH QDFPSVVVVG LGKRSAGVDD QENWHEGKEN
IRAAVAAGCR QVQDLELPSV EVDPCGDAQA AAEGAVLGLY EYDDLKQKKK VAVSAKLHGS
GDLEAWEKGV LFASGQNLAR QLMESPANEM TPTRFAEVIE KNLKSASSKT EVHIRTKSWI
EEQEMGSFLS VAKGSEEPPV FLEIHYTGSP NATEAPLVFV GKGITFDSGG ISIKASANMD
LMRADMGGAA TICSAIVSAA KLNLPINIIG LAPLCENMPS GKANKPGDVV RARNGKTIQV
DNTDAEGRLI LADALCYAHT FNPKVIINAA TLTGAMDVAL GSGATGVFTN SSWLWNKLFE
ASVETGDRVW RMPLFEHYTR QVIDCQLADV NNLGKYRSAG ACTAAAFLRE FVTHTKWAHL
DIAGVMTNKD EIPYLRKGMS GRPTRTLIEF LLRFSKDSS
