LKHA4_BOVIN
ID LKHA4_BOVIN Reviewed; 611 AA.
AC Q3SZH7;
DT 11-JUL-2006, integrated into UniProtKB/Swiss-Prot.
DT 23-JAN-2007, sequence version 3.
DT 03-AUG-2022, entry version 120.
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 Bos taurus (Bovine).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Artiodactyla; Ruminantia; Pecora; Bovidae;
OC Bovinae; Bos.
OX NCBI_TaxID=9913;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=Crossbred X Angus; TISSUE=Liver;
RG NIH - Mammalian Gene Collection (MGC) project;
RL Submitted (AUG-2005) to the EMBL/GenBank/DDBJ databases.
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; BC102852; AAI02853.1; -; mRNA.
DR RefSeq; NP_001029452.1; NM_001034280.1.
DR AlphaFoldDB; Q3SZH7; -.
DR SMR; Q3SZH7; -.
DR STRING; 9913.ENSBTAP00000021833; -.
DR MEROPS; M01.004; -.
DR PaxDb; Q3SZH7; -.
DR PRIDE; Q3SZH7; -.
DR Ensembl; ENSBTAT00000021833; ENSBTAP00000021833; ENSBTAG00000016415.
DR GeneID; 507130; -.
DR KEGG; bta:507130; -.
DR CTD; 4048; -.
DR VEuPathDB; HostDB:ENSBTAG00000016415; -.
DR VGNC; VGNC:31067; LTA4H.
DR eggNOG; KOG1047; Eukaryota.
DR GeneTree; ENSGT00940000156375; -.
DR HOGENOM; CLU_014505_0_0_1; -.
DR InParanoid; Q3SZH7; -.
DR OMA; YHPICRQ; -.
DR OrthoDB; 775595at2759; -.
DR TreeFam; TF300758; -.
DR UniPathway; UPA00878; -.
DR Proteomes; UP000009136; Chromosome 5.
DR Bgee; ENSBTAG00000016415; Expressed in duodenum and 103 other tissues.
DR ExpressionAtlas; Q3SZH7; baseline and differential.
DR GO; GO:0005829; C:cytosol; IBA:GO_Central.
DR GO; GO:0005654; C:nucleoplasm; IEA:Ensembl.
DR GO; GO:0005634; C:nucleus; IBA:GO_Central.
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:0070006; F:metalloaminopeptidase activity; IEA:Ensembl.
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 2: Evidence at transcript level;
KW Acetylation; Cytoplasm; Hydrolase; Leukotriene biosynthesis; Metal-binding;
KW Metalloprotease; Phosphoprotein; Protease; Reference proteome; Zinc.
FT CHAIN 1..611
FT /note="Leukotriene A-4 hydrolase"
FT /id="PRO_0000244880"
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; 69306 MW; E0FB709BE629ED7D CRC64;
MPEVVDTCSL ASPASVCQTK HLHLRCSIDF TRRVLSGTAA LTIQSQEDNL RSLILDTKDL
TIEKVVINGQ EVKYTLGERQ SYKGSPIEIS LPIALCKNQE IVIEISFETS PKSSALQWLT
PEQTSGKEHP YLFSQCQAIH CRAILPCQDT PSVKLTYSAE VSVPKELVAL MSAIRDGEAP
DPEDPNRKIY RFSQKVPIPC YLIALVVGAL ESRQIGPRTL VWSEKEQVEK SAYEFSETES
MLKIAEDLGG PYIWGQYDLL VLPPSFPYGG MENPCLTFVT PTLLAGDKSL SNVIAHEISH
SWTGNLVTNK TWDHFWLNEG HTVYLERHIC GRLFGEKFRH FHALGGWGEL QNSIKTFGET
HPFTKLVVDL TNTDPDVAYS SVPYEKGFAL LFYLEQLLGG PEVFLGFLKA YVEKFSYKSI
TTDNWKDFLY SHFKDKVDIL NQVDWNTWLY SPGLPPVKPN YDMTLTNACI SLSQRWITAK
DDDLNSFSSA DLKDFSSHQV NEFLAQMLQN APLPLGHIKR MQEVYNFNAI NNSEIRFRWL
RLCIQSKWEE AIPLALKMAT EQGRMKFTRP LFKDLAAFDK SHDQAIRTYK EHKASMHPVT
AMLVGKDLKV D
