ID LKHA4_HUMAN Reviewed; 611 AA.
AC P09960; B4DNQ9; F8VV40; Q6IAT6; Q9UCT7;
DT 01-JUL-1989, integrated into UniProtKB/Swiss-Prot.
DT 23-JAN-2007, sequence version 2.
DT 29-MAY-2013, entry version 165.
DE RecName: Full=Leukotriene A-4 hydrolase;
DE Short=LTA-4 hydrolase;
DE EC=3.3.2.6;
DE AltName: Full=Leukotriene A(4) hydrolase;
GN Name=LTA4H; Synonyms=LTA4;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=3654641;
RA Minami M., Ohno S., Kawasaki H., Raedmark O., Samuelsson B.,
RA Joernvall H., Shimizu T., Seyama Y., Suzuki K.;
RT "Molecular cloning of a cDNA coding for human leukotriene A4
RT hydrolase. Complete primary structure of an enzyme involved in
RT eicosanoid synthesis.";
RL J. Biol. Chem. 262:13873-13876(1987).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND PARTIAL PROTEIN SEQUENCE.
RX PubMed=2821541; DOI=10.1073/pnas.84.19.6677;
RA Funk C.D., Raadmark O., Fu J.Y., Matsumoto T., Joernvall H.,
RA Shimizu T., Samuelsson B.;
RT "Molecular cloning and amino acid sequence of leukotriene A4
RT hydrolase.";
RL Proc. Natl. Acad. Sci. U.S.A. 84:6677-6681(1987).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=7628486; DOI=10.1111/j.1432-1033.1995.tb20671.x;
RA Mancini J.A., Evans J.F.;
RT "Cloning and characterization of the human leukotriene A4 hydrolase
RT gene.";
RL Eur. J. Biochem. 231:65-71(1995).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
RC TISSUE=Lung;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4).
RC TISSUE=Esophageal carcinoma;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16541075; DOI=10.1038/nature04569;
RA Scherer S.E., Muzny D.M., Buhay C.J., Chen R., Cree A., Ding Y.,
RA Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C.,
RA Hernandez J., Hodgson A.V., Hume J., Jackson A., Khan Z.M.,
RA Kovar-Smith C., Lewis L.R., Lozado R.J., Metzker M.L.,
RA Milosavljevic A., Miner G.R., Montgomery K.T., Morgan M.B.,
RA Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D.,
RA Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y., Zhang Z.,
RA Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z.,
RA Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H., Draper H.,
RA Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S., Kelly S.H.,
RA Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V.,
RA Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H., Santibanez J.,
RA Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q., Williams G.A.,
RA Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V., Bailey M.,
RA Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E., Burkett C.E.,
RA Burrell K.L., Calderon E., Cardenas V., Carter K., Casias K.,
RA Cavazos I., Cavazos S.R., Ceasar H., Chacko J., Chan S.N., Chavez D.,
RA Christopoulos C., Chu J., Cockrell R., Cox C.D., Dang M.,
RA Dathorne S.R., David R., Davis C.M., Davy-Carroll L., Deshazo D.R.,
RA Donlin J.E., D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J.,
RA Escotto M., Flagg N., Forbes L.D., Gabisi A.M., Garza M., Hamilton C.,
RA Henderson N., Hernandez O., Hines S., Hogues M.E., Huang M.,
RA Idlebird D.G., Johnson R., Jolivet A., Jones S., Kagan R., King L.M.,
RA Leal B., Lebow H., Lee S., LeVan J.M., Lewis L.C., London P.,
RA Lorensuhewa L.M., Loulseged H., Lovett D.A., Lucier A., Lucier R.L.,
RA Ma J., Madu R.C., Mapua P., Martindale A.D., Martinez E., Massey E.,
RA Mawhiney S., Meador M.G., Mendez S., Mercado C., Mercado I.C.,
RA Merritt C.E., Miner Z.L., Minja E., Mitchell T., Mohabbat F.,
RA Mohabbat K., Montgomery B., Moore N., Morris S., Munidasa M.,
RA Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O., Nwokenkwo S.,
RA Obregon M., Oguh M., Oragunye N., Oviedo R.J., Parish B.J.,
RA Parker D.N., Parrish J., Parks K.L., Paul H.A., Payton B.A., Perez A.,
RA Perrin W., Pickens A., Primus E.L., Pu L.-L., Puazo M., Quiles M.M.,
RA Quiroz J.B., Rabata D., Reeves K., Ruiz S.J., Shao H., Sisson I.,
RA Sonaike T., Sorelle R.P., Sutton A.E., Svatek A.F., Svetz L.A.,
RA Tamerisa K.S., Taylor T.R., Teague B., Thomas N., Thorn R.D.,
RA Trejos Z.Y., Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I.,
RA Vera V.A., Villasana D.M., Wang L., Ward-Moore S., Warren J.T.,
RA Wei X., White F., Williamson A.L., Wleczyk R., Wooden H.S.,
RA Wooden S.H., Yen J., Yoon L., Yoon V., Zorrilla S.E., Nelson D.,
RA Kucherlapati R., Weinstock G., Gibbs R.A.;
RT "The finished DNA sequence of human chromosome 12.";
RL Nature 440:346-351(2006).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Eye;
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
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [10]
RP PROTEIN SEQUENCE OF 2-22, FUNCTION, AND CATALYTIC ACTIVITY.
RC TISSUE=B-cell;
RX PubMed=1897988; DOI=10.1016/0003-9861(91)90402-5;
RA Odlander B., Claesson H.E., Bergman T., Radmark O., Joernvall H.,
RA Haeggstrom J.Z.;
RT "Leukotriene A4 hydrolase in the human B-lymphocytic cell line Raji:
RT indications of catalytically divergent forms of the enzyme.";
RL Arch. Biochem. Biophys. 287:167-174(1991).
RN [11]
RP PROTEIN SEQUENCE OF 2-16.
RX PubMed=6490615;
RA Radmark O., Shimizu T., Joernvall H., Samuelsson B.;
RT "Leukotriene A4 hydrolase in human leukocytes. Purification and
RT properties.";
RL J. Biol. Chem. 259:12339-12345(1984).
RN [12]
RP PROTEIN SEQUENCE OF 366-386, ENZYME REGULATION, COVALENT MODIFICATION
RP AT TYR-379, AND CATALYTIC ACTIVITY.
RX PubMed=7667299; DOI=10.1073/pnas.92.18.8383;
RA Mueller M.J., Wetterholm A., Blomster M., Jornvall H., Samuelsson B.,
RA Haeggstrom J.Z.;
RT "Leukotriene A4 hydrolase: mapping of a henicosapeptide involved in
RT mechanism-based inactivation.";
RL Proc. Natl. Acad. Sci. U.S.A. 92:8383-8387(1995).
RN [13]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 511-611, AND ALTERNATIVE SPLICING
RP (ISOFORMS 1 AND 2).
RX PubMed=8615763;
RA Jendraschak E., Kaminski W.E., Kiefl R., von Schacky C.;
RT "The human leukotriene A4 hydrolase gene is expressed in two
RT alternatively spliced mRNA forms.";
RL Biochem. J. 314:733-737(1996).
RN [14]
RP ZINC-BINDING, FUNCTION AS A PEPTIDASE, AND SIMILARITY TO ZINC
RP PROTEASES.
RX PubMed=1975494; DOI=10.1016/0006-291X(90)91379-7;
RA Toh H., Minami M., Shimizu T.;
RT "Molecular evolution and zinc ion binding motif of leukotriene A4
RT hydrolase.";
RL Biochem. Biophys. Res. Commun. 171:216-221(1990).
RN [15]
RP ZINC-BINDING, AND FUNCTION AS A PEPTIDASE.
RX PubMed=2244921; DOI=10.1016/0006-291X(90)91540-9;
RA Haeggstroem J.Z., Wetterholm A., Shapiro R., Vallee B.L.,
RA Samuelsson B.;
RT "Leukotriene A4 hydrolase: a zinc metalloenzyme.";
RL Biochem. Biophys. Res. Commun. 172:965-970(1990).
RN [16]
RP MUTAGENESIS OF ZINC LIGANDS.
RX PubMed=1881903; DOI=10.1073/pnas.88.17.7620;
RA Medina J.F., Wetterholm A., Raadmark O., Shapiro R., Haeggstroem J.Z.,
RA Vallee B.L., Samuelsson B.;
RT "Leukotriene A4 hydrolase: determination of the three zinc-binding
RT ligands by site-directed mutagenesis and zinc analysis.";
RL Proc. Natl. Acad. Sci. U.S.A. 88:7620-7624(1991).
RN [17]
RP MUTAGENESIS OF GLU-297.
RX PubMed=1516710; DOI=10.1016/0014-5793(92)80806-R;
RA Minami M., Bito H., Ohishi N., Tsuge H., Miyano M., Mori M., Wada H.,
RA Mutoh H., Shimada S., Izumi T., Abe K., Shimuzu T.;
RT "Leukotriene A4 hydrolase, a bifunctional enzyme. Distinction of
RT leukotriene A4 hydrolase and aminopeptidase activities by site-
RT directed mutagenesis at Glu-297.";
RL FEBS Lett. 309:353-357(1992).
RN [18]
RP MUTAGENESIS OF GLU-297.
RX PubMed=1357660; DOI=10.1073/pnas.89.19.9141;
RA Wetterholm A., Medina J.F., Raadmark O., Shapiro R., Haeggstroem J.Z.,
RA Vallee B.L., Samuelsson B.;
RT "Leukotriene A4 hydrolase: abrogation of the peptidase activity by
RT mutation of glutamic acid-296.";
RL Proc. Natl. Acad. Sci. U.S.A. 89:9141-9145(1992).
RN [19]
RP PHOSPHORYLATION AT SER-416.
RX PubMed=9395533; DOI=10.1074/jbc.272.50.31865;
RA Rybina I.V., Liu H., Gor Y., Feinmark S.J.;
RT "Regulation of leukotriene A4 hydrolase activity in endothelial cells
RT by phosphorylation.";
RL J. Biol. Chem. 272:31865-31871(1997).
RN [20]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-73; LYS-337; LYS-414 AND
RP LYS-573, AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [21]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [22]
RP X-RAY CRYSTALLOGRAPHY (1.95 ANGSTROMS).
RX PubMed=11175901; DOI=10.1038/84117;
RA Thunnissen M.M.G.M., Nordlund P., Haeggstroem J.Z.;
RT "Crystal structure of human leukotriene A(4) hydrolase, a bifunctional
RT enzyme in inflammation.";
RL Nat. Struct. Biol. 8:131-135(2001).
RN [23]
RP X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) IN COMPLEX WITH CAPTOPRIL AND
RP ZINC IONS, FUNCTION, COFACTOR, CATALYTIC ACTIVITY, AND ACTIVE SITE.
RX PubMed=12207002; DOI=10.1096/fj.01-1017fje;
RA Thunnissen M.M., Andersson B., Samuelsson B., Wong C.H.,
RA Haeggstrom J.Z.;
RT "Crystal structures of leukotriene A4 hydrolase in complex with
RT captopril and two competitive tight-binding inhibitors.";
RL FASEB J. 16:1648-1650(2002).
RN [24]
RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF MUTANT GLN-272, AND
RP MUTAGENESIS OF GLN-137; GLY-270; MET-271; GLU-272 AND ASN-273.
RX PubMed=11675384; DOI=10.1074/jbc.M106577200;
RA Rudberg P.C., Tholander F., Thunnissen M.M.G.M., Haeggstroem J.Z.;
RT "Leukotriene A4 hydrolase/aminopeptidase. Glutamate 271 is a catalytic
RT residue with specific roles in two distinct enzyme mechanisms.";
RL J. Biol. Chem. 277:1398-1404(2002).
RN [25]
RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF MUTANT ASN-376 IN COMPLEX
RP WITH BESTATIN AND ZINC IONS, FUNCTION, CATALYTIC ACTIVITY, AND
RP MUTAGENESIS OF GLN-135; HIS-140; ASP-372; ASP-374; ASP-376 AND
RP GLU-385.
RX PubMed=11917124; DOI=10.1073/pnas.072090099;
RA Rudberg P.C., Tholander F., Thunnissen M.M., Samuelsson B.,
RA Haeggstrom J.Z.;
RT "Leukotriene A4 hydrolase: selective abrogation of leukotriene B4
RT formation by mutation of aspartic acid 375.";
RL Proc. Natl. Acad. Sci. U.S.A. 99:4215-4220(2002).
RN [26]
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF MUTANT ALA-564 IN COMPLEX
RP WITH ZINC IONS, CATALYTIC ACTIVITY, FUNCTION, COFACTOR, AND
RP MUTAGENESIS OF ARG-564 AND LYS-566.
RX PubMed=15078870; DOI=10.1074/jbc.M401031200;
RA Rudberg P.C., Tholander F., Andberg M., Thunnissen M.M.,
RA Haeggstrom J.Z.;
RT "Leukotriene A4 hydrolase: identification of a common carboxylate
RT recognition site for the epoxide hydrolase and aminopeptidase
RT substrates.";
RL J. Biol. Chem. 279:27376-27382(2004).
RN [27]
RP X-RAY CRYSTALLOGRAPHY (1.47 ANGSTROMS) OF MUTANT GLN-297 IN COMPLEXES
RP WITH SUBSTRATE TRIPEPTIDES AND ZINC IONS, CATALYTIC ACTIVITY,
RP FUNCTION, COFACTOR, AND MUTAGENESIS OF GLU-297 AND ASP-376.
RX PubMed=18804029; DOI=10.1016/j.chembiol.2008.07.018;
RA Tholander F., Muroya A., Roques B.P., Fournie-Zaluski M.C.,
RA Thunnissen M.M., Haeggstrom J.Z.;
RT "Structure-based dissection of the active site chemistry of
RT leukotriene A4 hydrolase: implications for M1 aminopeptidases and
RT inhibitor design.";
RL Chem. Biol. 15:920-929(2008).
RN [28]
RP X-RAY CRYSTALLOGRAPHY (1.58 ANGSTROMS) IN COMPLEXES WITH INHIBITORS
RP AND ZINC IONS.
RX PubMed=19618939; DOI=10.1021/jm900259h;
RA Davies D.R., Mamat B., Magnusson O.T., Christensen J.,
RA Haraldsson M.H., Mishra R., Pease B., Hansen E., Singh J.,
RA Zembower D., Kim H., Kiselyov A.S., Burgin A.B., Gurney M.E.,
RA Stewart L.J.;
RT "Discovery of leukotriene A4 hydrolase inhibitors using metabolomics
RT biased fragment crystallography.";
RL J. Med. Chem. 52:4694-4715(2009).
CC -!- FUNCTION: Epoxide hydrolase that catalyzes the final step in the
CC biosynthesis of the proinflammatory mediator leukotriene B4. Has
CC also aminopeptidase activity.
CC -!- CATALYTIC ACTIVITY: (7E,9E,11Z,14Z)-(5S,6S)-5,6-epoxyicosa-
CC 7,9,11,14-tetraenoate + H(2)O = (6Z,8E,10E,14Z)-(5S,12R)-5,12-
CC dihydroxyicosa-6,8,10,14-tetraenoate.
CC -!- COFACTOR: Binds 1 zinc ion per subunit.
CC -!- ENZYME REGULATION: Inhibited by bestatin. Subject to suicide
CC inhibition by leukotriene A4, due to the formation of a covalent
CC adduct at Tyr-379.
CC -!- PATHWAY: Lipid metabolism; leukotriene B4 biosynthesis.
CC -!- SUBUNIT: Monomer.
CC -!- INTERACTION:
CC P01241:GH1; NbExp=1; IntAct=EBI-721089, EBI-1026046;
CC P23508:MCC; NbExp=1; IntAct=EBI-721089, EBI-307531;
CC -!- SUBCELLULAR LOCATION: Cytoplasm.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=1; Synonyms=L-LTA4;
CC IsoId=P09960-1; Sequence=Displayed;
CC Name=2; Synonyms=S-LTA4;
CC IsoId=P09960-2; Sequence=VSP_041108, VSP_041109;
CC Name=3;
CC IsoId=P09960-3; Sequence=VSP_041107, VSP_041108, VSP_041109;
CC Name=4;
CC IsoId=P09960-4; Sequence=VSP_041107;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Isoform 1 and isoform 2 are expressed in
CC monocytes, lymphocytes, neutrophils, reticulocytes, platelets and
CC fibroblasts.
CC -!- PTM: Phosphorylation at Ser-416 inhibits enzymatic activity.
CC -!- SIMILARITY: Belongs to the peptidase M1 family.
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DR EMBL; J03459; AAA36176.1; -; mRNA.
DR EMBL; J02959; AAA36177.1; -; mRNA.
DR EMBL; U27293; AAA89077.1; -; Genomic_DNA.
DR EMBL; U27275; AAA89077.1; JOINED; Genomic_DNA.
DR EMBL; U27276; AAA89077.1; JOINED; Genomic_DNA.
DR EMBL; U27277; AAA89077.1; JOINED; Genomic_DNA.
DR EMBL; U27278; AAA89077.1; JOINED; Genomic_DNA.
DR EMBL; U27279; AAA89077.1; JOINED; Genomic_DNA.
DR EMBL; U27280; AAA89077.1; JOINED; Genomic_DNA.
DR EMBL; U27281; AAA89077.1; JOINED; Genomic_DNA.
DR EMBL; U27282; AAA89077.1; JOINED; Genomic_DNA.
DR EMBL; U27283; AAA89077.1; JOINED; Genomic_DNA.
DR EMBL; U27284; AAA89077.1; JOINED; Genomic_DNA.
DR EMBL; U27285; AAA89077.1; JOINED; Genomic_DNA.
DR EMBL; U27286; AAA89077.1; JOINED; Genomic_DNA.
DR EMBL; U27287; AAA89077.1; JOINED; Genomic_DNA.
DR EMBL; U27288; AAA89077.1; JOINED; Genomic_DNA.
DR EMBL; U27289; AAA89077.1; JOINED; Genomic_DNA.
DR EMBL; U27290; AAA89077.1; JOINED; Genomic_DNA.
DR EMBL; U27291; AAA89077.1; JOINED; Genomic_DNA.
DR EMBL; U27292; AAA89077.1; JOINED; Genomic_DNA.
DR EMBL; AK298017; BAG60321.1; -; mRNA.
DR EMBL; CR457068; CAG33349.1; -; mRNA.
DR EMBL; BX647158; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; AC007298; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471054; EAW97559.1; -; Genomic_DNA.
DR EMBL; BC032528; AAH32528.1; -; mRNA.
DR EMBL; U43410; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; U43411; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR IPI; IPI00219077; -.
DR IPI; IPI00514090; -.
DR IPI; IPI00790203; -.
DR IPI; IPI00793812; -.
DR PIR; S65947; S65947.
DR RefSeq; NP_000886.1; NM_000895.2.
DR RefSeq; NP_001243572.1; NM_001256643.1.
DR RefSeq; NP_001243573.1; NM_001256644.1.
DR UniGene; Hs.524648; -.
DR PDB; 1GW6; X-ray; 2.20 A; A=2-611.
DR PDB; 1H19; X-ray; 2.10 A; A=1-611.
DR PDB; 1HS6; X-ray; 1.95 A; A=1-611.
DR PDB; 1SQM; X-ray; 2.30 A; A=2-610.
DR PDB; 2R59; X-ray; 1.89 A; A=2-611.
DR PDB; 2VJ8; X-ray; 1.80 A; A=1-611.
DR PDB; 3B7R; X-ray; 1.81 A; L=2-611.
DR PDB; 3B7S; X-ray; 1.47 A; A=2-611.
DR PDB; 3B7T; X-ray; 2.30 A; A=2-611.
DR PDB; 3B7U; X-ray; 1.90 A; X=2-611.
DR PDB; 3CHO; X-ray; 1.80 A; A=2-611.
DR PDB; 3CHP; X-ray; 2.10 A; A=2-611.
DR PDB; 3CHQ; X-ray; 2.09 A; A=2-611.
DR PDB; 3CHR; X-ray; 2.20 A; A=2-611.
DR PDB; 3CHS; X-ray; 2.55 A; A=2-611.
DR PDB; 3FH5; X-ray; 1.63 A; A=1-611.
DR PDB; 3FH7; X-ray; 2.05 A; A=1-611.
DR PDB; 3FH8; X-ray; 1.67 A; A=1-611.
DR PDB; 3FHE; X-ray; 2.16 A; A=1-611.
DR PDB; 3FTS; X-ray; 2.33 A; A=1-611.
DR PDB; 3FTU; X-ray; 1.90 A; A=1-611.
DR PDB; 3FTV; X-ray; 1.70 A; A=1-611.
DR PDB; 3FTW; X-ray; 1.85 A; A=1-611.
DR PDB; 3FTX; X-ray; 1.96 A; A=1-611.
DR PDB; 3FTY; X-ray; 2.15 A; A=1-611.
DR PDB; 3FTZ; X-ray; 2.00 A; A=1-611.
DR PDB; 3FU0; X-ray; 1.80 A; A=1-611.
DR PDB; 3FU3; X-ray; 2.00 A; A=1-611.
DR PDB; 3FU5; X-ray; 2.30 A; A=1-611.
DR PDB; 3FU6; X-ray; 2.05 A; A=1-611.
DR PDB; 3FUD; X-ray; 2.20 A; A=1-611.
DR PDB; 3FUE; X-ray; 2.38 A; A=1-611.
DR PDB; 3FUF; X-ray; 2.60 A; A=1-611.
DR PDB; 3FUH; X-ray; 1.80 A; A=1-611.
DR PDB; 3FUI; X-ray; 2.20 A; A=1-611.
DR PDB; 3FUJ; X-ray; 1.90 A; A=1-611.
DR PDB; 3FUK; X-ray; 1.95 A; A=1-611.
DR PDB; 3FUL; X-ray; 2.39 A; A=1-611.
DR PDB; 3FUM; X-ray; 2.15 A; A=1-611.
DR PDB; 3FUN; X-ray; 1.58 A; A=1-611.
DR PDB; 3U9W; X-ray; 1.25 A; A=4-611.
DR PDB; 4DPR; X-ray; 2.02 A; A=1-611.
DR PDBsum; 1GW6; -.
DR PDBsum; 1H19; -.
DR PDBsum; 1HS6; -.
DR PDBsum; 1SQM; -.
DR PDBsum; 2R59; -.
DR PDBsum; 2VJ8; -.
DR PDBsum; 3B7R; -.
DR PDBsum; 3B7S; -.
DR PDBsum; 3B7T; -.
DR PDBsum; 3B7U; -.
DR PDBsum; 3CHO; -.
DR PDBsum; 3CHP; -.
DR PDBsum; 3CHQ; -.
DR PDBsum; 3CHR; -.
DR PDBsum; 3CHS; -.
DR PDBsum; 3FH5; -.
DR PDBsum; 3FH7; -.
DR PDBsum; 3FH8; -.
DR PDBsum; 3FHE; -.
DR PDBsum; 3FTS; -.
DR PDBsum; 3FTU; -.
DR PDBsum; 3FTV; -.
DR PDBsum; 3FTW; -.
DR PDBsum; 3FTX; -.
DR PDBsum; 3FTY; -.
DR PDBsum; 3FTZ; -.
DR PDBsum; 3FU0; -.
DR PDBsum; 3FU3; -.
DR PDBsum; 3FU5; -.
DR PDBsum; 3FU6; -.
DR PDBsum; 3FUD; -.
DR PDBsum; 3FUE; -.
DR PDBsum; 3FUF; -.
DR PDBsum; 3FUH; -.
DR PDBsum; 3FUI; -.
DR PDBsum; 3FUJ; -.
DR PDBsum; 3FUK; -.
DR PDBsum; 3FUL; -.
DR PDBsum; 3FUM; -.
DR PDBsum; 3FUN; -.
DR PDBsum; 3U9W; -.
DR PDBsum; 4DPR; -.
DR ProteinModelPortal; P09960; -.
DR IntAct; P09960; 5.
DR MINT; MINT-1388946; -.
DR STRING; 9606.ENSP00000228740; -.
DR MEROPS; M01.004; -.
DR PhosphoSite; P09960; -.
DR DMDM; 126353; -.
DR REPRODUCTION-2DPAGE; IPI00219077; -.
DR PaxDb; P09960; -.
DR PRIDE; P09960; -.
DR DNASU; 4048; -.
DR Ensembl; ENST00000228740; ENSP00000228740; ENSG00000111144.
DR Ensembl; ENST00000413268; ENSP00000395051; ENSG00000111144.
DR Ensembl; ENST00000552789; ENSP00000449958; ENSG00000111144.
DR GeneID; 4048; -.
DR KEGG; hsa:4048; -.
DR UCSC; uc001ten.1; human.
DR UCSC; uc010suy.1; human.
DR UCSC; uc010suz.1; human.
DR CTD; 4048; -.
DR GeneCards; GC12M096394; -.
DR HGNC; HGNC:6710; LTA4H.
DR HPA; CAB015221; -.
DR HPA; HPA008399; -.
DR HPA; HPA017017; -.
DR MIM; 151570; gene.
DR neXtProt; NX_P09960; -.
DR PharmGKB; PA24345; -.
DR eggNOG; COG0308; -.
DR HOGENOM; HOG000293296; -.
DR HOVERGEN; HBG001274; -.
DR InParanoid; P09960; -.
DR KO; K01254; -.
DR OMA; QEVKYTL; -.
DR OrthoDB; EOG40GCQC; -.
DR PhylomeDB; P09960; -.
DR BioCyc; MetaCyc:HS03372-MONOMER; -.
DR BRENDA; 3.3.2.6; 2681.
DR Reactome; REACT_111217; Metabolism.
DR UniPathway; UPA00878; -.
DR BindingDB; P09960; -.
DR ChEMBL; CHEMBL4618; -.
DR ChiTaRS; LTA4H; human.
DR EvolutionaryTrace; P09960; -.
DR GenomeRNAi; 4048; -.
DR NextBio; 15856; -.
DR ArrayExpress; P09960; -.
DR Bgee; P09960; -.
DR CleanEx; HS_LTA4H; -.
DR Genevestigator; P09960; -.
DR GermOnline; ENSG00000111144; Homo sapiens.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005634; C:nucleus; IDA:HPA.
DR GO; GO:0004177; F:aminopeptidase activity; IDA:UniProtKB.
DR GO; GO:0004301; F:epoxide hydrolase activity; IDA:UniProtKB.
DR GO; GO:0004463; F:leukotriene-A4 hydrolase activity; IDA:UniProtKB.
DR GO; GO:0008237; F:metallopeptidase activity; IEA:UniProtKB-KW.
DR GO; GO:0008270; F:zinc ion binding; IDA:UniProtKB.
DR GO; GO:0019369; P:arachidonic acid metabolic process; TAS:Reactome.
DR GO; GO:0006954; P:inflammatory response; NAS:ProtInc.
DR GO; GO:0019370; P:leukotriene biosynthetic process; IDA:UniProtKB.
DR GO; GO:0043171; P:peptide catabolic process; IDA:UniProtKB.
DR GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW.
DR InterPro; IPR016024; ARM-type_fold.
DR InterPro; IPR012777; Leukotriene_A4_hydrolase.
DR InterPro; IPR001930; Peptidase_M1.
DR InterPro; IPR015211; Peptidase_M1_C.
DR InterPro; IPR014782; Peptidase_M1_N.
DR PANTHER; PTHR11533; PTHR11533; 1.
DR Pfam; PF09127; Leuk-A4-hydro_C; 1.
DR Pfam; PF01433; Peptidase_M1; 1.
DR PRINTS; PR00756; ALADIPTASE.
DR SUPFAM; SSF48371; ARM-type_fold; 1.
DR TIGRFAMs; TIGR02411; leuko_A4_hydro; 1.
DR PROSITE; PS00142; ZINC_PROTEASE; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Complete proteome;
KW Cytoplasm; Direct protein sequencing; Hydrolase;
KW Leukotriene biosynthesis; Metal-binding; Metalloprotease;
KW Phosphoprotein; Polymorphism; Protease; Reference proteome; Zinc.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 611 Leukotriene A-4 hydrolase.
FT /FTId=PRO_0000095124.
FT REGION 135 137 Substrate binding.
FT REGION 267 272 Substrate binding.
FT REGION 564 566 Substrate binding.
FT ACT_SITE 297 297 Proton acceptor (Probable).
FT ACT_SITE 384 384 Proton donor (Probable).
FT METAL 296 296 Zinc; catalytic.
FT METAL 300 300 Zinc; catalytic.
FT METAL 319 319 Zinc; catalytic.
FT SITE 376 376 Essential for epoxide hydrolase activity,
FT but not for aminopeptidase activity.
FT SITE 379 379 Covalently modified during suicide
FT inhibition by leukotrienes.
FT MOD_RES 73 73 N6-acetyllysine.
FT MOD_RES 337 337 N6-acetyllysine.
FT MOD_RES 414 414 N6-acetyllysine.
FT MOD_RES 416 416 Phosphoserine.
FT MOD_RES 573 573 N6-acetyllysine.
FT VAR_SEQ 1 53 MPEIVDTCSLASPASVCRTKHLHLRCSVDFTRRTLTGTAAL
FT TVQSQEDNLRSL -> MLPQRNLSKRQVPTMHIPVKTRRLL
FT AALK (in isoform 3 and isoform 4).
FT /FTId=VSP_041107.
FT VAR_SEQ 511 532 APLPLGHIKRMQEVYNFNAINN -> MAAALHSIQVGGRNS
FT FGAKDGN (in isoform 2 and isoform 3).
FT /FTId=VSP_041108.
FT VAR_SEQ 533 611 Missing (in isoform 2 and isoform 3).
FT /FTId=VSP_041109.
FT VARIANT 131 131 Y -> H (in dbSNP:rs45630737).
FT /FTId=VAR_051570.
FT MUTAGEN 135 135 Q->A,L: Srongly increased epoxide
FT hydrolase activity.
FT MUTAGEN 135 135 Q->A: Strongly reduced aminopeptidase
FT activity. Strongly decreased affinity for
FT leukotriene. Abolishes epoxide hydrolase
FT activity.
FT MUTAGEN 137 137 Q->A: No loss of activity.
FT MUTAGEN 137 137 Q->L: Aminopeptidase activity strongly
FT impaired, but keeps LTA4 activity.
FT MUTAGEN 137 137 Q->N: Aminopeptidase activity almost
FT absent, but keeps LTA4 activity.
FT MUTAGEN 140 140 H->Q: Aminopeptidase activity almost
FT absent, but keeps LTA4 activity.
FT MUTAGEN 269 269 G->A: No loss of activity.
FT MUTAGEN 270 270 G->A: No loss of activity.
FT MUTAGEN 271 271 M->L: No loss of activity.
FT MUTAGEN 272 272 E->A,D: Complete loss of activity.
FT MUTAGEN 272 272 E->Q: Loss of LTA4 activity, and
FT aminopeptidase activity strongly
FT impaired.
FT MUTAGEN 273 273 N->A: No loss of activity.
FT MUTAGEN 296 296 H->Y: Complete loss of activity.
FT MUTAGEN 297 297 E->A: Loss of both activities.
FT MUTAGEN 297 297 E->K: Loss of both activities.
FT MUTAGEN 297 297 E->Q: Loss of aminopeptidase activity,
FT but keeps LTA4 activity.
FT MUTAGEN 300 300 H->L: Complete loss of activity.
FT MUTAGEN 319 319 E->A: Complete loss of activity.
FT MUTAGEN 372 372 D->N: No loss of activity.
FT MUTAGEN 374 374 D->N: No loss of activity.
FT MUTAGEN 376 376 D->A: Strongly reduced hydrolysis of
FT peptides starting with Arg. Small effect
FT on hydrolysis of peptides starting with
FT Ala. Strongly reduced epoxide hydrolase
FT activity.
FT MUTAGEN 376 376 D->E: Strongly reduced aminopeptidase
FT activity. Abolishes epoxide hydrolase
FT activity.
FT MUTAGEN 376 376 D->N: Abolishes aminopeptidase and
FT epoxide hydrolase activity.
FT MUTAGEN 385 385 E->Q: Reduced aminopeptidase activity.
FT Minor effect on epoxide hydrolase
FT activity.
FT MUTAGEN 564 564 R->A,K,M: Abolishes epoxide hydrolase
FT activity. Reduced aminopeptidase
FT activity.
FT MUTAGEN 566 566 K->A,M: Strongly reduced affinity for
FT peptide substrates. Reduced epoxide
FT hydrolase and aminopeptidase activity.
FT MUTAGEN 566 566 K->R: No effect on epoxide hydrolase and
FT aminopeptidase activity.
FT CONFLICT 115 115 A -> T (in Ref. 6; BX647158).
FT CONFLICT 123 123 Q -> R (in Ref. 6; BX647158).
FT CONFLICT 297 297 E -> G (in Ref. 4; BAG60321).
FT CONFLICT 309 309 N -> S (in Ref. 6; BX647158).
FT CONFLICT 378 378 A -> V (in Ref. 6; BX647158).
FT TURN 14 16
FT STRAND 17 29
FT TURN 30 33
FT STRAND 34 45
FT STRAND 50 59
FT STRAND 61 67
FT STRAND 74 76
FT HELIX 81 83
FT STRAND 85 95
FT STRAND 100 108
FT STRAND 116 119
FT HELIX 121 123
FT STRAND 124 129
FT STRAND 131 134
FT TURN 137 140
FT HELIX 141 143
FT STRAND 155 164
FT STRAND 167 180
FT STRAND 182 184
FT STRAND 187 198
FT HELIX 200 202
FT STRAND 205 209
FT STRAND 211 216
FT STRAND 219 223
FT HELIX 225 227
FT HELIX 228 234
FT TURN 235 237
FT HELIX 238 249
FT STRAND 258 261
FT STRAND 267 271
FT STRAND 276 279
FT HELIX 281 283
FT STRAND 286 288
FT TURN 289 291
FT HELIX 292 299
FT TURN 300 302
FT TURN 304 306
FT STRAND 307 311
FT HELIX 312 314
FT HELIX 315 334
FT HELIX 336 357
FT HELIX 362 364
FT STRAND 365 367
FT HELIX 375 378
FT HELIX 382 398
FT HELIX 401 415
FT STRAND 418 420
FT HELIX 422 432
FT HELIX 434 436
FT HELIX 437 441
FT HELIX 445 450
FT TURN 464 466
FT HELIX 467 478
FT HELIX 481 486
FT HELIX 489 492
FT HELIX 497 508
FT HELIX 515 525
FT HELIX 527 529
FT HELIX 533 545
FT HELIX 551 561
FT HELIX 565 577
FT HELIX 579 592
FT HELIX 593 595
FT HELIX 598 608
SQ SEQUENCE 611 AA; 69285 MW; 329BF6D04D4A06E1 CRC64;
MPEIVDTCSL ASPASVCRTK HLHLRCSVDF TRRTLTGTAA LTVQSQEDNL RSLVLDTKDL
TIEKVVINGQ EVKYALGERQ SYKGSPMEIS LPIALSKNQE IVIEISFETS PKSSALQWLT
PEQTSGKEHP YLFSQCQAIH CRAILPCQDT PSVKLTYTAE VSVPKELVAL MSAIRDGETP
DPEDPSRKIY KFIQKVPIPC YLIALVVGAL ESRQIGPRTL VWSEKEQVEK SAYEFSETES
MLKIAEDLGG PYVWGQYDLL VLPPSFPYGG MENPCLTFVT PTLLAGDKSL SNVIAHEISH
SWTGNLVTNK TWDHFWLNEG HTVYLERHIC GRLFGEKFRH FNALGGWGEL QNSVKTFGET
HPFTKLVVDL TDIDPDVAYS SVPYEKGFAL LFYLEQLLGG PEIFLGFLKA YVEKFSYKSI
TTDDWKDFLY SYFKDKVDVL NQVDWNAWLY SPGLPPIKPN YDMTLTNACI ALSQRWITAK
EDDLNSFNAT DLKDLSSHQL NEFLAQTLQR APLPLGHIKR MQEVYNFNAI NNSEIRFRWL
RLCIQSKWED AIPLALKMAT EQGRMKFTRP LFKDLAAFDK SHDQAVRTYQ EHKASMHPVT
AMLVGKDLKV D
//
