LKHA4_CAVPO
ID LKHA4_CAVPO Reviewed; 611 AA.
AC P19602;
DT 01-FEB-1991, integrated into UniProtKB/Swiss-Prot.
DT 23-JAN-2007, sequence version 3.
DT 03-AUG-2022, entry version 147.
DE RecName: Full=Leukotriene A-4 hydrolase;
DE Short=LTA-4 hydrolase;
DE EC=3.3.2.6 {ECO:0000250|UniProtKB:P09960};
DE AltName: Full=Leukotriene A(4) hydrolase;
DE AltName: Full=Tripeptide aminopeptidase LTA4H;
DE EC=3.4.11.4 {ECO:0000250|UniProtKB:P09960};
GN Name=LTA4H;
OS Cavia porcellus (Guinea pig).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Hystricomorpha; Caviidae;
OC Cavia.
OX NCBI_TaxID=10141;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=Hartley; TISSUE=Lung;
RX PubMed=7665088; DOI=10.1016/0378-1119(95)00179-a;
RA Minami M., Mutoh H., Ohishi N., Honda Z., Bito H., Shimizu T.;
RT "Amino-acid sequence and tissue distribution of guinea-pig leukotriene A4
RT hydrolase.";
RL Gene 161:249-251(1995).
RN [2]
RP PROTEIN SEQUENCE OF 2-21.
RC TISSUE=Liver;
RX PubMed=3391178; DOI=10.1111/j.1432-1033.1988.tb14156.x;
RA Haeggstroem J., Bergman T., Joernvall H., Raadmark O.;
RT "Guinea-pig liver leukotriene A4 hydrolase. Purification, characterization
RT and structural properties.";
RL Eur. J. Biochem. 174:717-724(1988).
RN [3]
RP PROTEIN SEQUENCE OF 2-21.
RC STRAIN=Hartley; TISSUE=Lung;
RX PubMed=2722767; DOI=10.1093/oxfordjournals.jbchem.a122650;
RA Bito H., Ohishi N., Miki I., Minami M., Tanabe T., Shimizu T., Seyama Y.;
RT "Leukotriene A4 hydrolase from guinea pig lung: the presence of two
RT catalytically active forms.";
RL J. Biochem. 105:261-264(1989).
CC -!- FUNCTION: Bifunctional zinc metalloenzyme that comprises both epoxide
CC hydrolase (EH) and aminopeptidase activities. Acts as an epoxide
CC hydrolase to catalyze the conversion of LTA4 to the pro-inflammatory
CC mediator leukotriene B4 (LTB4). Has also aminopeptidase activity, with
CC high affinity for N-terminal arginines of various synthetic
CC tripeptides. In addition to its pro-inflammatory EH activity, may also
CC counteract inflammation by its aminopeptidase activity, which
CC inactivates by cleavage another neutrophil attractant, the tripeptide
CC Pro-Gly-Pro (PGP), a bioactive fragment of collagen generated by the
CC action of matrix metalloproteinase-9 (MMP9) and prolylendopeptidase
CC (PREPL). Involved also in the biosynthesis of resolvin E1 and 18S-
CC resolvin E1 from eicosapentaenoic acid, two lipid mediators that show
CC potent anti-inflammatory and pro-resolving actions.
CC {ECO:0000250|UniProtKB:P09960}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + leukotriene A4 = leukotriene B4; Xref=Rhea:RHEA:22324,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:57461, ChEBI:CHEBI:57463; EC=3.3.2.6;
CC Evidence={ECO:0000250|UniProtKB:P09960};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:22325;
CC Evidence={ECO:0000250|UniProtKB:P09960};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(5S,6S)-epoxy-(18R)-hydroxy-(7E,9E,11Z,14Z,16E)-
CC eicosapentaenoate + H2O = resolvin E1; Xref=Rhea:RHEA:50272,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:91000, ChEBI:CHEBI:132219;
CC Evidence={ECO:0000250|UniProtKB:P09960};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:50273;
CC Evidence={ECO:0000250|UniProtKB:P09960};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(5S,6S)-epoxy-(18S)-hydroxy-(7E,9E,11Z,14Z,16E)-
CC eicosapentaenoate + H2O = 18S-resolvin E1; Xref=Rhea:RHEA:51988,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:134661, ChEBI:CHEBI:136057;
CC Evidence={ECO:0000250|UniProtKB:P09960};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:51989;
CC Evidence={ECO:0000250|UniProtKB:P09960};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=Release of the N-terminal residue from a tripeptide.;
CC EC=3.4.11.4; Evidence={ECO:0000250|UniProtKB:P09960};
CC -!- COFACTOR:
CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC Evidence={ECO:0000250|UniProtKB:P09960};
CC Note=Binds 1 zinc ion per subunit. {ECO:0000250|UniProtKB:P09960};
CC -!- ACTIVITY REGULATION: Inhibited by bestatin. The epoxide hydrolase
CC activity is restrained by suicide inactivation that involves binding of
CC LTA4 to Tyr-379. 4-(4-benzylphenyl)thiazol-2-amine (ARM1) selectively
CC inhibits the epoxide hydrolase activity.
CC {ECO:0000250|UniProtKB:P09960}.
CC -!- PATHWAY: Lipid metabolism; leukotriene B4 biosynthesis.
CC {ECO:0000250|UniProtKB:P09960}.
CC -!- SUBUNIT: Monomer. {ECO:0000250|UniProtKB:P09960}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:P09960}.
CC -!- PTM: Phosphorylation at Ser-416 inhibits leukotriene-A4 hydrolase
CC activity. activity. {ECO:0000250|UniProtKB:P09960}.
CC -!- SIMILARITY: Belongs to the peptidase M1 family. {ECO:0000305}.
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DR EMBL; D16669; BAA04077.1; -; mRNA.
DR PIR; JC4237; JC4237.
DR RefSeq; NP_001166450.1; NM_001172979.1.
DR AlphaFoldDB; P19602; -.
DR SMR; P19602; -.
DR STRING; 10141.ENSCPOP00000011748; -.
DR BindingDB; P19602; -.
DR ChEMBL; CHEMBL5786; -.
DR MEROPS; M01.004; -.
DR GeneID; 100135571; -.
DR KEGG; cpoc:100135571; -.
DR CTD; 4048; -.
DR eggNOG; KOG1047; Eukaryota.
DR InParanoid; P19602; -.
DR OrthoDB; 775595at2759; -.
DR BRENDA; 3.3.2.6; 1225.
DR UniPathway; UPA00878; -.
DR PRO; PR:P19602; -.
DR Proteomes; UP000005447; Unassembled WGS sequence.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0004177; F:aminopeptidase activity; ISS:UniProtKB.
DR GO; GO:0004301; F:epoxide hydrolase activity; ISS:UniProtKB.
DR GO; GO:0004463; F:leukotriene-A4 hydrolase activity; ISS:UniProtKB.
DR GO; GO:0008237; F:metallopeptidase activity; IEA:UniProtKB-KW.
DR GO; GO:0045148; F:tripeptide aminopeptidase activity; IEA:UniProtKB-EC.
DR GO; GO:0008270; F:zinc ion binding; ISS:UniProtKB.
DR GO; GO:0019370; P:leukotriene biosynthetic process; ISS:UniProtKB.
DR GO; GO:0043171; P:peptide catabolic process; ISS:UniProtKB.
DR GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW.
DR CDD; cd09599; M1_LTA4H; 1.
DR Gene3D; 1.10.390.10; -; 1.
DR Gene3D; 1.25.40.320; -; 1.
DR Gene3D; 2.60.40.1730; -; 1.
DR InterPro; IPR045357; Aminopeptidase_N-like_N.
DR InterPro; IPR042097; Aminopeptidase_N-like_N_sf.
DR InterPro; IPR016024; ARM-type_fold.
DR InterPro; IPR012777; LTA4H.
DR InterPro; IPR038502; M1_LTA-4_hydro/amino_C_sf.
DR InterPro; IPR034015; M1_LTA4H.
DR InterPro; IPR001930; Peptidase_M1.
DR InterPro; IPR015211; Peptidase_M1_C.
DR InterPro; IPR014782; Peptidase_M1_dom.
DR InterPro; IPR027268; Peptidase_M4/M1_CTD_sf.
DR PANTHER; PTHR45726; PTHR45726; 1.
DR Pfam; PF09127; Leuk-A4-hydro_C; 1.
DR Pfam; PF01433; Peptidase_M1; 1.
DR Pfam; PF17900; Peptidase_M1_N; 1.
DR PRINTS; PR00756; ALADIPTASE.
DR SMART; SM01263; Leuk-A4-hydro_C; 1.
DR SUPFAM; SSF48371; SSF48371; 1.
DR SUPFAM; SSF63737; SSF63737; 1.
DR TIGRFAMs; TIGR02411; leuko_A4_hydro; 1.
DR PROSITE; PS00142; ZINC_PROTEASE; 1.
PE 1: Evidence at protein level;
KW Acetylation; Cytoplasm; Direct protein sequencing; Hydrolase;
KW Leukotriene biosynthesis; Metal-binding; Metalloprotease; Phosphoprotein;
KW Protease; Reference proteome; Zinc.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000269|PubMed:2722767,
FT ECO:0000269|PubMed:3391178"
FT CHAIN 2..611
FT /note="Leukotriene A-4 hydrolase"
FT /id="PRO_0000095122"
FT ACT_SITE 297
FT /note="Proton acceptor"
FT /evidence="ECO:0000250|UniProtKB:P09960"
FT ACT_SITE 384
FT /note="Proton donor"
FT /evidence="ECO:0000250|UniProtKB:P09960"
FT BINDING 135..137
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P09960"
FT BINDING 267..272
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P09960"
FT BINDING 296
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000250|UniProtKB:P09960"
FT BINDING 300
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000250|UniProtKB:P09960"
FT BINDING 319
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000250|UniProtKB:P09960"
FT BINDING 564..566
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P09960"
FT SITE 376
FT /note="Essential for epoxide hydrolase activity, but not
FT for aminopeptidase activity"
FT /evidence="ECO:0000250|UniProtKB:P09960"
FT SITE 379
FT /note="Covalently modified during suicide inhibition by
FT leukotrienes"
FT /evidence="ECO:0000250|UniProtKB:P09960"
FT MOD_RES 73
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P09960"
FT MOD_RES 337
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P09960"
FT MOD_RES 414
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P09960"
FT MOD_RES 416
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P09960"
FT MOD_RES 573
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P09960"
SQ SEQUENCE 611 AA; 68971 MW; 8FBBA08E46B2804A CRC64;
MPEVVDTCSL ASPATVCRTK HLHLRCSVDF TRRALTGVAA LTIQSQEDNL RSLILDTKDL
TIEKVVINGQ EVKYALGEKQ SYKGSPMEIS LPIALSKNQE VVIEISFETS PKSSALQWLT
PEQTSGKEHP YLFSQCQAIH CRAFLPCQDT PSVKLTYTAE VSVPKELVAL MSAIRDGEAP
DPADPSRKIY KFSQKVPIPC YLIALVVGAL ESRKIGPRTL VWSEKEQVDK SAYEFSETES
MLKIAEDLGG PYVWGQYDRL VLPPSFSYGG MENPCLTFVT PTLLAGDKSL SNVIAHEISH
TWTGNLVTNK TWDHFWLNEG HTVYLERHIC GRLFGEKFRH FHALGGWGEL QNTVKTLGET
QAFTKLVVDL TDTDPDVAYS SVPYEKGFAL LFHLEQLLGG PEVFLGFLKA YVEKFSYKSI
TTDDWKNFLF SHFKDKVDIL NQVDWDAWLY SPGLPPIKPN YDMTLTNACI ALSQRWITAK
EKDLNTFSAT DLKDLSSHQV NEFLAQVLQR APLPLGHVKR MQEVYNCNAI NNSEIRFRWL
RLCIQSKWEE AIPLALKMAT EQGRMKFTRP LFKDLAAFDK SHDQAIQTYH AHKASMHPVT
AMLVGKDLKV E
