LKHA4_RAT
ID LKHA4_RAT Reviewed; 611 AA.
AC P30349; Q499P2;
DT 01-APR-1993, integrated into UniProtKB/Swiss-Prot.
DT 02-DEC-2020, sequence version 3.
DT 03-AUG-2022, entry version 156.
DE RecName: Full=Leukotriene A-4 hydrolase;
DE Short=LTA-4 hydrolase;
DE EC=3.3.2.6 {ECO:0000269|PubMed:1544505};
DE AltName: Full=Leukotriene A(4) hydrolase;
DE AltName: Full=Tripeptide aminopeptidase LTA4H {ECO:0000305};
DE EC=3.4.11.4 {ECO:0000250|UniProtKB:P09960};
GN Name=Lta4h;
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 [MRNA], CATALYTIC ACTIVITY, FUNCTION, AND ACTIVITY
RP REGULATION.
RX PubMed=1544505; DOI=10.1016/0014-5793(92)80130-9;
RA Makita N., Funk C.D., Imai E., Hoover R.L., Badr K.F.;
RT "Molecular cloning and functional expression of rat leukotriene A4
RT hydrolase using the polymerase chain reaction.";
RL FEBS Lett. 299:273-277(1992).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Prostate;
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 [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Brown Norway;
RX PubMed=15057822; DOI=10.1038/nature02426;
RA Gibbs R.A., Weinstock G.M., Metzker M.L., Muzny D.M., Sodergren E.J.,
RA Scherer S., Scott G., Steffen D., Worley K.C., Burch P.E., Okwuonu G.,
RA Hines S., Lewis L., Deramo C., Delgado O., Dugan-Rocha S., Miner G.,
RA Morgan M., Hawes A., Gill R., Holt R.A., Adams M.D., Amanatides P.G.,
RA Baden-Tillson H., Barnstead M., Chin S., Evans C.A., Ferriera S.,
RA Fosler C., Glodek A., Gu Z., Jennings D., Kraft C.L., Nguyen T.,
RA Pfannkoch C.M., Sitter C., Sutton G.G., Venter J.C., Woodage T., Smith D.,
RA Lee H.-M., Gustafson E., Cahill P., Kana A., Doucette-Stamm L.,
RA Weinstock K., Fechtel K., Weiss R.B., Dunn D.M., Green E.D.,
RA Blakesley R.W., Bouffard G.G., De Jong P.J., Osoegawa K., Zhu B., Marra M.,
RA Schein J., Bosdet I., Fjell C., Jones S., Krzywinski M., Mathewson C.,
RA Siddiqui A., Wye N., McPherson J., Zhao S., Fraser C.M., Shetty J.,
RA Shatsman S., Geer K., Chen Y., Abramzon S., Nierman W.C., Havlak P.H.,
RA Chen R., Durbin K.J., Egan A., Ren Y., Song X.-Z., Li B., Liu Y., Qin X.,
RA Cawley S., Cooney A.J., D'Souza L.M., Martin K., Wu J.Q.,
RA Gonzalez-Garay M.L., Jackson A.R., Kalafus K.J., McLeod M.P.,
RA Milosavljevic A., Virk D., Volkov A., Wheeler D.A., Zhang Z., Bailey J.A.,
RA Eichler E.E., Tuzun E., Birney E., Mongin E., Ureta-Vidal A., Woodwark C.,
RA Zdobnov E., Bork P., Suyama M., Torrents D., Alexandersson M., Trask B.J.,
RA Young J.M., Huang H., Wang H., Xing H., Daniels S., Gietzen D., Schmidt J.,
RA Stevens K., Vitt U., Wingrove J., Camara F., Mar Alba M., Abril J.F.,
RA Guigo R., Smit A., Dubchak I., Rubin E.M., Couronne O., Poliakov A.,
RA Huebner N., Ganten D., Goesele C., Hummel O., Kreitler T., Lee Y.-A.,
RA Monti J., Schulz H., Zimdahl H., Himmelbauer H., Lehrach H., Jacob H.J.,
RA Bromberg S., Gullings-Handley J., Jensen-Seaman M.I., Kwitek A.E.,
RA Lazar J., Pasko D., Tonellato P.J., Twigger S., Ponting C.P., Duarte J.M.,
RA Rice S., Goodstadt L., Beatson S.A., Emes R.D., Winter E.E., Webber C.,
RA Brandt P., Nyakatura G., Adetobi M., Chiaromonte F., Elnitski L.,
RA Eswara P., Hardison R.C., Hou M., Kolbe D., Makova K., Miller W.,
RA Nekrutenko A., Riemer C., Schwartz S., Taylor J., Yang S., Zhang Y.,
RA Lindpaintner K., Andrews T.D., Caccamo M., Clamp M., Clarke L., Curwen V.,
RA Durbin R.M., Eyras E., Searle S.M., Cooper G.M., Batzoglou S., Brudno M.,
RA Sidow A., Stone E.A., Payseur B.A., Bourque G., Lopez-Otin C., Puente X.S.,
RA Chakrabarti K., Chatterji S., Dewey C., Pachter L., Bray N., Yap V.B.,
RA Caspi A., Tesler G., Pevzner P.A., Haussler D., Roskin K.M., Baertsch R.,
RA Clawson H., Furey T.S., Hinrichs A.S., Karolchik D., Kent W.J.,
RA Rosenbloom K.R., Trumbower H., Weirauch M., Cooper D.N., Stenson P.D.,
RA Ma B., Brent M., Arumugam M., Shteynberg D., Copley R.R., Taylor M.S.,
RA Riethman H., Mudunuri U., Peterson J., Guyer M., Felsenfeld A., Old S.,
RA Mockrin S., Collins F.S.;
RT "Genome sequence of the Brown Norway rat yields insights into mammalian
RT evolution.";
RL Nature 428:493-521(2004).
CC -!- FUNCTION: Bifunctional zinc metalloenzyme that comprises both epoxide
CC hydrolase (EH) and aminopeptidase activities (By similarity). Acts as
CC an epoxide hydrolase to catalyze the conversion of LTA4 to the pro-
CC inflammatory mediator leukotriene B4 (LTB4) (PubMed:1544505). Has also
CC aminopeptidase activity, with high affinity for N-terminal arginines of
CC various synthetic tripeptides. In addition to its pro-inflammatory EH
CC activity, may also counteract inflammation by its aminopeptidase
CC activity, which inactivates by cleavage another neutrophil attractant,
CC the tripeptide Pro-Gly-Pro (PGP), a bioactive fragment of collagen
CC generated by the action of matrix metalloproteinase-9 (MMP9) and
CC prolylendopeptidase (PREPL). Involved also in the biosynthesis of
CC resolvin E1 and 18S-resolvin E1 from eicosapentaenoic acid, two lipid
CC mediators that show potent anti-inflammatory and pro-resolving actions
CC (By similarity). {ECO:0000250|UniProtKB:P09960,
CC ECO:0000269|PubMed:1544505}.
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:0000269|PubMed:1544505};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:22325;
CC Evidence={ECO:0000305|PubMed:1544505};
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 (By similarity). Inhibited
CC by captopril (PubMed:1544505). The epoxide hydrolase activity is
CC restrained by suicide inactivation that involves binding of LTA4 to
CC Tyr-379. 4-(4-benzylphenyl)thiazol-2-amine (ARM1) selectively inhibits
CC the epoxide hydrolase activity (By similarity).
CC {ECO:0000250|UniProtKB:P09960, ECO:0000269|PubMed:1544505}.
CC -!- PATHWAY: Lipid metabolism; leukotriene B4 biosynthesis.
CC {ECO:0000269|PubMed:1544505}.
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. {ECO:0000250|UniProtKB:P09960}.
CC -!- SIMILARITY: Belongs to the peptidase M1 family. {ECO:0000305}.
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; S87522; AAB21778.1; -; mRNA.
DR EMBL; AABR07056638; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC099819; AAH99819.1; -; mRNA.
DR PIR; S20444; S20444.
DR RefSeq; NP_001025202.1; NM_001030031.1.
DR AlphaFoldDB; P30349; -.
DR SMR; P30349; -.
DR IntAct; P30349; 2.
DR STRING; 10116.ENSRNOP00000005930; -.
DR ChEMBL; CHEMBL2400; -.
DR MEROPS; M01.004; -.
DR iPTMnet; P30349; -.
DR PhosphoSitePlus; P30349; -.
DR jPOST; P30349; -.
DR PaxDb; P30349; -.
DR PeptideAtlas; P30349; -.
DR PRIDE; P30349; -.
DR Ensembl; ENSRNOT00000005930; ENSRNOP00000005930; ENSRNOG00000004494.
DR GeneID; 299732; -.
DR KEGG; rno:299732; -.
DR UCSC; RGD:1311333; rat.
DR CTD; 4048; -.
DR RGD; 1311333; Lta4h.
DR eggNOG; KOG1047; Eukaryota.
DR GeneTree; ENSGT00940000156375; -.
DR HOGENOM; CLU_014505_0_0_1; -.
DR InParanoid; P30349; -.
DR OMA; YHPICRQ; -.
DR OrthoDB; 775595at2759; -.
DR TreeFam; TF300758; -.
DR BRENDA; 3.3.2.6; 5301.
DR Reactome; R-RNO-2142691; Synthesis of Leukotrienes (LT) and Eoxins (EX).
DR Reactome; R-RNO-6798695; Neutrophil degranulation.
DR Reactome; R-RNO-9018676; Biosynthesis of D-series resolvins.
DR Reactome; R-RNO-9018681; Biosynthesis of protectins.
DR Reactome; R-RNO-9018896; Biosynthesis of E-series 18(S)-resolvins.
DR Reactome; R-RNO-9020265; Biosynthesis of aspirin-triggered D-series resolvins.
DR Reactome; R-RNO-9023661; Biosynthesis of E-series 18(R)-resolvins.
DR UniPathway; UPA00878; -.
DR PRO; PR:P30349; -.
DR Proteomes; UP000002494; Chromosome 7.
DR Bgee; ENSRNOG00000004494; Expressed in jejunum and 20 other tissues.
DR GO; GO:0005737; C:cytoplasm; IDA:RGD.
DR GO; GO:0005829; C:cytosol; IBA:GO_Central.
DR GO; GO:0005654; C:nucleoplasm; IEA:Ensembl.
DR GO; GO:0005634; C:nucleus; IDA:RGD.
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; IDA:RGD.
DR GO; GO:0070006; F:metalloaminopeptidase activity; ISO:RGD.
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:0006691; P:leukotriene metabolic process; IDA:RGD.
DR GO; GO:0043171; P:peptide catabolic process; ISS:UniProtKB.
DR GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW.
DR GO; GO:0043434; P:response to peptide hormone; IEP:RGD.
DR GO; GO:0010043; P:response to zinc ion; IEP:RGD.
DR GO; GO:0060509; P:type I pneumocyte differentiation; IEP:RGD.
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; 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_0000095126"
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"
FT CONFLICT 5
FT /note="A -> E (in Ref. 1; AAB21778)"
FT /evidence="ECO:0000305"
FT CONFLICT 52
FT /note="S -> T (in Ref. 1; AAB21778)"
FT /evidence="ECO:0000305"
FT CONFLICT 136..137
FT /note="CQ -> WE (in Ref. 1; AAB21778)"
FT /evidence="ECO:0000305"
FT CONFLICT 151
FT /note="Missing (in Ref. 1; AAB21778)"
FT /evidence="ECO:0000305"
FT CONFLICT 510
FT /note="K -> R (in Ref. 1; AAB21778)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 611 AA; 69089 MW; 350BDE2683C223C9 CRC64;
MPEVADTCSL ASPASVCRTQ HLHLRCSVDF ARRALTGTAA LTVQSQEDNL RSLTLDTKDL
TIEKVVINGQ EVKYTLGESQ GYKGSPMEIS LPIALSKNQE VVIEISFETS PKSSALQWLT
PEQTSGKQHP YLFSQCQAIH CRAILPCQDT PSVKLTYTAE VSVPKELVAL MSAIRDGEAP
DPEDPSRKIY RFNQRVPIPC YLIALVVGAL ESRQIGPRTL VWSEKEQVEK SAYEFSETES
MLKIAEDLGG PYVWGQYDLL VLPPSFPYGG MENPCLTFVT PTLLAGDKSL SNVIAHEISH
SWTGNLVTNK TWDHFWLNEG HTVYLERHIC GRLFGEKFRH FHALGGWGEL QNTIKTFGES
HPFTKLVVDL KDVDPDVAYS SIPYEKGFAL LFYLEQLLGG PEVFLGFLKA YVEKFSYQSV
TTDDWKSFLY AHFKDKVDLL NQVDWNAWLY APGLPPVKPN YDVTLTNACI ALSQRWVTAK
EEDLNSFSIE DLKDLSSHQL NEFLAQVLQK APLPLGHIKR MQEVYNFNAI NNSEIRFRWL
RLCIQSKWEE AIPLALKMAT EQGRMKFTRP LFKDLAAFDK SHDQAVRTYQ EHKACMHPVT
AMLVGKDLKV D
