Full text data of LTA4H
LTA4H
(LTA4)
[Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Leukotriene A-4 hydrolase; LTA-4 hydrolase; 3.3.2.6 (Leukotriene A(4) hydrolase)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Leukotriene A-4 hydrolase; LTA-4 hydrolase; 3.3.2.6 (Leukotriene A(4) hydrolase)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
hRBCD
IPI00219077
IPI00219077 Leukotriene A4 hydroLase Hydrolyzes an epoxide moiety of leukotriene A4 (LTA-4) to form leukotriene B4 (LTB-4) soluble n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a cytoplasmic n/a found at its expected molecular weight found at molecular weight
IPI00219077 Leukotriene A4 hydroLase Hydrolyzes an epoxide moiety of leukotriene A4 (LTA-4) to form leukotriene B4 (LTB-4) soluble n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a cytoplasmic n/a found at its expected molecular weight found at molecular weight
UniProt
P09960
ID LKHA4_HUMAN Reviewed; 611 AA.
AC P09960; B4DNQ9; F8VV40; Q6IAT6; Q9UCT7;
DT 01-JUL-1989, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 2.
DT 22-JAN-2014, entry version 172.
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 IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [23]
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 [24]
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 [25]
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 [26]
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 [27]
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 [28]
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 [29]
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 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 RefSeq; XP_005268928.1; XM_005268871.1.
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 SMR; P09960; 4-611.
DR IntAct; P09960; 5.
DR MINT; MINT-1388946; -.
DR STRING; 9606.ENSP00000228740; -.
DR BindingDB; P09960; -.
DR ChEMBL; CHEMBL4618; -.
DR GuidetoPHARMACOLOGY; 1395; -.
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.2; 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; EOG7SJD42; -.
DR PhylomeDB; P09960; -.
DR BioCyc; MetaCyc:HS03372-MONOMER; -.
DR BRENDA; 3.3.2.6; 2681.
DR Reactome; REACT_111217; Metabolism.
DR UniPathway; UPA00878; -.
DR ChiTaRS; LTA4H; human.
DR EvolutionaryTrace; P09960; -.
DR GenomeRNAi; 4048; -.
DR NextBio; 15856; -.
DR PRO; PR:P09960; -.
DR ArrayExpress; P09960; -.
DR Bgee; P09960; -.
DR CleanEx; HS_LTA4H; -.
DR Genevestigator; P09960; -.
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; SSF48371; 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
//
ID LKHA4_HUMAN Reviewed; 611 AA.
AC P09960; B4DNQ9; F8VV40; Q6IAT6; Q9UCT7;
DT 01-JUL-1989, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 2.
DT 22-JAN-2014, entry version 172.
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 IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [23]
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 [24]
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 [25]
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 [26]
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 [27]
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 [28]
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 [29]
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.
CC -----------------------------------------------------------------------
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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 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 RefSeq; XP_005268928.1; XM_005268871.1.
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 SMR; P09960; 4-611.
DR IntAct; P09960; 5.
DR MINT; MINT-1388946; -.
DR STRING; 9606.ENSP00000228740; -.
DR BindingDB; P09960; -.
DR ChEMBL; CHEMBL4618; -.
DR GuidetoPHARMACOLOGY; 1395; -.
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.2; 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; EOG7SJD42; -.
DR PhylomeDB; P09960; -.
DR BioCyc; MetaCyc:HS03372-MONOMER; -.
DR BRENDA; 3.3.2.6; 2681.
DR Reactome; REACT_111217; Metabolism.
DR UniPathway; UPA00878; -.
DR ChiTaRS; LTA4H; human.
DR EvolutionaryTrace; P09960; -.
DR GenomeRNAi; 4048; -.
DR NextBio; 15856; -.
DR PRO; PR:P09960; -.
DR ArrayExpress; P09960; -.
DR Bgee; P09960; -.
DR CleanEx; HS_LTA4H; -.
DR Genevestigator; P09960; -.
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; SSF48371; 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
//
MIM
151570
*RECORD*
*FIELD* NO
151570
*FIELD* TI
*151570 LEUKOTRIENE A4 HYDROLASE; LTA4H
*FIELD* TX
CLONING
Leukotrienes are a group of bioactive compounds that play important
read moreroles in immediate hyposensitivity reactions and inflammation. Minami et
al. (1987) reported the full-length cDNA and complete primary structure
of human LTA4 hydrolase. This was the first report of the molecular
cloning of an enzyme involved in the biosynthesis of eicosanoids. Funk
et al. (1987) isolated a cDNA clone corresponding to leukotriene A4
hydrolase from a human lung lambda-gt11 expression library by
immunoscreening with a polyclonal antiserum. Several additional clones
from human lung and placenta cDNA lambda-gt11 libraries were obtained by
plaque hybridization with the (32)P-labeled lung cDNA clone. One of the
clones had an insert of 1,910 basepairs containing a complete
protein-coding region. From the deduced primary structure, leukotriene
A4 hydrolase is a 610-amino acid protein with a calculated molecular
weight of 69,140.
Mancini and Evans (1995) cloned the gene for this enzyme, which is a
bifunctional amino peptidase and epoxide hydrolase, from a placental
lambda phage genomic library. Based on the chromosome localization and
genomic DNA analysis, LTA4 hydrolase was determined to be a single-copy
gene. Primer-extension analysis demonstrated that the transcription
initiation site of the mRNA is 151 nucleotides upstream of the initiator
ATG.
GENE STRUCTURE
Mancini and Evans (1995) determined that the LTA4H gene is greater than
35 kb in length and contains 19 exons ranging in size from 24 to 312 bp.
The introns range in size from 0.26 to 5.7 kb.
MAPPING
By fluorescence in situ hybridization, Mancini and Evans (1995)
localized the LTA4H gene to 12q22.
GENE FUNCTION
Qiu et al. (2006) reported increased mRNA and protein levels of 5-LO
(152390), FLAP (603700), and LTA4H in 72 human carotid atherosclerotic
plaques compared to 6 controls. The proteins colocalized within
macrophages in intimal lesions, presumably facilitating enzyme coupling
and leukotriene B4 (LTB4) synthesis. There was a correlation between
increased levels of 5-LO and LTA4H mRNA and recent or ongoing symptoms
of plaque instability. In contrast, 5-LO mRNA was not increased in mouse
atherosclerotic plaques, and mouse plaques exhibited segregated cellular
expression of 5-LO and LTA4H. These discrepancies indicate important
differences and urge caution in translating mouse models into human
pathology.
Leukotriene A4 hydrolase (LTA4H) is a proinflammatory enzyme that
generates the inflammatory mediator leukotriene B4 (LTB4). LTA4H also
possesses aminopeptidase activity, the physiologic substrate of which
Snelgrove et al. (2010) identified as the neutrophil chemoattractant
proline-glycine-proline (PGP). PGP is a biomarker for chronic
obstructive pulmonary disease (COPD; 606963) and is implicated in
neutrophil persistence in the lung. In acute neutrophil-driven
inflammation, PGP was degraded by LTA4H, which faciliated the resolution
of inflammation. In contrast, cigarette smoke, a major risk factor for
the development of COPD, selectively inhibited LTA4H aminopeptidase
activity, which led to the accumulation of PGP and neutrophils. The
studies of Snelgrove et al. (2010) implied that therapeutic strategies
inhibiting LTA4H to prevent LTB4 generation may not reduce neutrophil
recruitment because of elevated levels of PGP.
MOLECULAR GENETICS
Variants of the gene ALOX5AP (603700), which encodes arachidonate
5-lipoxygenase-activating protein, are associated with risk of
myocardial infarction (see 608557) (Helgadottir et al., 2004).
Helgadottir et al. (2006) showed that a haplotype spanning the LTA4H
gene, which encodes leukotriene A4 hydrolase, a protein in the same
biochemical pathway as ALOX5AP, confers modest risk of myocardial
infarction in an Icelandic cohort. Measurements of leukotriene B4 (LTB4)
production suggested that this risk is mediated through upregulation of
the leukotriene pathway. Three cohorts from the United States also
showed that the haplotype designated HapK confers a modest relative risk
(1.16) in European Americans, but it confers a 3-fold larger risk in
African Americans. About 27% of the European American controls carried
at least one copy of HapK, as compared with only 6% of African American
controls. Helgadottir et al. (2006) found that HapK is very rare in
Africa and that its occurrence in African Americans is due to European
admixture. Interactions with other genetic or environmental risk factors
that are more common in African Americans are likely to account for the
greater relative risk conferred by HapK in this group.
Given the altered balance of pro- and antiinflammatory eicosanoids in
zebrafish with Lta4h mutations (see ANIMAL MODEL), Tobin et al. (2010)
hypothesized that LTA4H polymorphisms may alter the response to human
mycobacterial infections that cause tuberculosis (TB; see 607948) and
leprosy (see 609888). Comparison of 692 Vietnamese HIV-seronegative
pulmonary and meningeal TB patients with 759 healthy controls revealed
fewer heterozygotes at each of 6 LTA4H SNPs (dbSNP rs1978331, dbSNP
rs17677715, dbSNP rs2247570, dbSNP rs2660898, dbSNP rs2660845, and dbSNP
rs2540475) in TB patients. Comparison of frequencies of heterozygotes
versus homozygotes among TB patients and controls yielded odds ratios
(ORs) less than 1 at all 6 SNPs. Adjusting for multiple comparisons,
association of heterozygosity with lower incidence of TB was significant
at dbSNP rs1978331 and dbSNP rs2660898 (P = 0.011 and 0.0003,
respectively, after Bonferroni correction), the 2 SNPs intragenic in
LTA4H with common minor allele frequencies. Among 53 meningeal TB
patients heterozygous at both dbSNP rs1978331 and dbSNP rs2660898, only
4% died within 300 days after diagnosis. In contrast, mortality was 16%
among 156 meningeal TB patients homozygous at these SNPs. Evaluation of
335 paucibacillary leprosy patients, 121 multibacillary (MB) leprosy
patients with erythema nodosum leprosum (ENL), and 443 MB leprosy
patients without ENL from Nepal showed that LTA4H heterozygosity at
dbSNP rs1978331 and dbSNP rs2660898 was significantly associated with a
lower incidence of MB leprosy without ENL (OR = 0.62 and P = 0.001 for
dbSNP rs1978331, and OR = 0.70 and P = 0.021 for dbSNP rs2660898). Tobin
et al. (2010) concluded that LTA4H heterozygosity is associated with
protection from TB infection, lower mortality among patients with severe
TB infection, and protection from development of severe leprosy disease
among exposed individuals. They proposed that LTA4H heterozygosity may
reflect an optimal balance, or rheostat mechanism, of pro- and
antiinflammatory eicosanoids (i.e., LTB4 and LXA4, respectively), and
that modulation of lipoxins, informed by LTA4H genotypes, may result in
better outcomes for patients with TB meningitis.
Behr et al. (2010) reviewed several studies implicating stimulation of
antiinflammatory molecules and inhibition of autophagy by virulent
mycobacteria as a means to evade the host immune system.
ANIMAL MODEL
Using a forward genetic screen with mutagenized zebrafish, Tobin et al.
(2010) identified mutants with differential susceptibility to
Mycobacterium marinum (Mm). Hypersusceptible mutants had a mutation in
Lta4h, but the phenotype was associated not with reduced production of
Ltb4, but with increased production of an antiinflammatory eicosanoid,
lipoxin, and reduced production of Tnf (191160) and decreased neutrophil
migration early after Mm infection. Tobin et al. (2010) concluded that
the reduced inflammation resulting from the Lta4h mutation leads to
increased Mm proliferation.
*FIELD* RF
1. Behr, M.; Schurr, E.; Gros, P.: TB: screening for responses to
a vile visitor. Cell 140: 615-618, 2010.
2. Funk, C. D.; Radmark, O.; Fu, J. Y.; Matsumoto, T.; Jornvall, H.;
Shimizu, T.; Samuelsson, B.: Molecular cloning and amino acid sequence
of leukotriene A(4) hydrolase. Proc. Nat. Acad. Sci. 84: 6677-6681,
1987.
3. Helgadottir, A.; Manolescu, A.; Helgason, A.; Thorleifsson, G.;
Thorsteinsdottir, U.; Gudbjartsson, D. F.; Gretarsdottir, S.; Magnusson,
K. P.; Gudmundsson, G.; Hicks, A.; Jonsson, T.; Grant, S. F. A.; and
19 others: A variant of the gene encoding leukotriene A4 hydrolase
confers ethnicity-specific risk of myocardial infarction. Nature
Genet. 38: 68-74, 2006.
4. Helgadottir, A.; Manolescu, A.; Thorleifsson, G.; Gretarsdottir,
S.; Jonsdottir, H.; Thorsteinsdottir, U.; Samani, N. J.; Gudmundsson,
G.; Grant, S. F. A.; Thorgeirsson, G.; Sveinbjornsdottir, S.; Valdimarsson,
E. M.; and 14 others: The gene encoding 5-lipoxygenase activating
protein confers risk of myocardial infarction and stroke. Nature
Genet. 36: 233-239, 2004.
5. Mancini, J. A.; Evans, J. F.: Cloning and characterization of
the human leukotriene A-4 hydrolase gene. Europ. J. Biochem. 231:
65-71, 1995.
6. Minami, M.; Ohno, S.; Kawasaki, H.; Radmark, O.; Samuelsson, B.;
Jornvall, H.; Shimizu, T.; Seyama, Y.; Suzuki, K.: Molecular cloning
of a cDNA coding for human leukotriene A(4) hydrolase: complete primary
structure of an enzyme involved in eicosanoid synthesis. J. Biol.
Chem. 262: 13873-13876, 1987.
7. Qiu, H.; Gabrielsen, A.; Agardh, H. E.; Wan, M.; Wetterholm, A.;
Wong, C.-H.; Hedin, U.; Swedenborg, J.; Hansson, G. K.; Samuelsson,
B.; Paulsson-Berne, G.; Haeggstrom, J. Z.: Expression of 5-lipoxygenase
and leukotriene A4 hydrolase in human atherosclerotic lesions correlates
with symptoms of plaque instability. Proc. Nat. Acad. Sci. 103:
8161-8166, 2006.
8. Snelgrove, R. J.; Jackson, P. L.; Hardison, M. T.; Noerager, B.
D.; Kinloch, A.; Gagger, A.; Shastry, S.; Rowe, S. M.; Shim, Y. M.;
Hussell, T.; Blalock, J. E.: A critical role for LTA4H in limiting
chronic pulmonary neutrophilic inflammation. Science 330: 90-94,
2010.
9. Tobin, D. M.; Vary, J. C., Jr.; Ray, J. P.; Walsh, G. S.; Dunstan,
S. J.; Bang, N. D.; Hagge, D. A.; Khadge, S.; King, M.-C.; Hawn, T.
R.; Moens, C. B.; Ramakrishnan, L.: The Ita4h locus modulates susceptibility
to Mycobacterial infection in zebrafish and humans. Cell 140: 717-730,
2010.
*FIELD* CN
Ada Hamosh - updated: 11/2/2010
Paul J. Converse - updated: 3/23/2010
Cassandra L. Kniffin - updated: 6/8/2006
*FIELD* CD
Victor A. McKusick: 12/1/1987
*FIELD* ED
alopez: 11/05/2010
terry: 11/2/2010
mgross: 3/25/2010
terry: 3/23/2010
wwang: 6/26/2006
ckniffin: 6/8/2006
alopez: 1/9/2006
alopez: 12/1/2005
terry: 12/1/2005
terry: 6/18/1998
terry: 5/22/1996
mark: 9/27/1995
carol: 1/8/1993
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/27/1989
marie: 3/25/1988
*RECORD*
*FIELD* NO
151570
*FIELD* TI
*151570 LEUKOTRIENE A4 HYDROLASE; LTA4H
*FIELD* TX
CLONING
Leukotrienes are a group of bioactive compounds that play important
read moreroles in immediate hyposensitivity reactions and inflammation. Minami et
al. (1987) reported the full-length cDNA and complete primary structure
of human LTA4 hydrolase. This was the first report of the molecular
cloning of an enzyme involved in the biosynthesis of eicosanoids. Funk
et al. (1987) isolated a cDNA clone corresponding to leukotriene A4
hydrolase from a human lung lambda-gt11 expression library by
immunoscreening with a polyclonal antiserum. Several additional clones
from human lung and placenta cDNA lambda-gt11 libraries were obtained by
plaque hybridization with the (32)P-labeled lung cDNA clone. One of the
clones had an insert of 1,910 basepairs containing a complete
protein-coding region. From the deduced primary structure, leukotriene
A4 hydrolase is a 610-amino acid protein with a calculated molecular
weight of 69,140.
Mancini and Evans (1995) cloned the gene for this enzyme, which is a
bifunctional amino peptidase and epoxide hydrolase, from a placental
lambda phage genomic library. Based on the chromosome localization and
genomic DNA analysis, LTA4 hydrolase was determined to be a single-copy
gene. Primer-extension analysis demonstrated that the transcription
initiation site of the mRNA is 151 nucleotides upstream of the initiator
ATG.
GENE STRUCTURE
Mancini and Evans (1995) determined that the LTA4H gene is greater than
35 kb in length and contains 19 exons ranging in size from 24 to 312 bp.
The introns range in size from 0.26 to 5.7 kb.
MAPPING
By fluorescence in situ hybridization, Mancini and Evans (1995)
localized the LTA4H gene to 12q22.
GENE FUNCTION
Qiu et al. (2006) reported increased mRNA and protein levels of 5-LO
(152390), FLAP (603700), and LTA4H in 72 human carotid atherosclerotic
plaques compared to 6 controls. The proteins colocalized within
macrophages in intimal lesions, presumably facilitating enzyme coupling
and leukotriene B4 (LTB4) synthesis. There was a correlation between
increased levels of 5-LO and LTA4H mRNA and recent or ongoing symptoms
of plaque instability. In contrast, 5-LO mRNA was not increased in mouse
atherosclerotic plaques, and mouse plaques exhibited segregated cellular
expression of 5-LO and LTA4H. These discrepancies indicate important
differences and urge caution in translating mouse models into human
pathology.
Leukotriene A4 hydrolase (LTA4H) is a proinflammatory enzyme that
generates the inflammatory mediator leukotriene B4 (LTB4). LTA4H also
possesses aminopeptidase activity, the physiologic substrate of which
Snelgrove et al. (2010) identified as the neutrophil chemoattractant
proline-glycine-proline (PGP). PGP is a biomarker for chronic
obstructive pulmonary disease (COPD; 606963) and is implicated in
neutrophil persistence in the lung. In acute neutrophil-driven
inflammation, PGP was degraded by LTA4H, which faciliated the resolution
of inflammation. In contrast, cigarette smoke, a major risk factor for
the development of COPD, selectively inhibited LTA4H aminopeptidase
activity, which led to the accumulation of PGP and neutrophils. The
studies of Snelgrove et al. (2010) implied that therapeutic strategies
inhibiting LTA4H to prevent LTB4 generation may not reduce neutrophil
recruitment because of elevated levels of PGP.
MOLECULAR GENETICS
Variants of the gene ALOX5AP (603700), which encodes arachidonate
5-lipoxygenase-activating protein, are associated with risk of
myocardial infarction (see 608557) (Helgadottir et al., 2004).
Helgadottir et al. (2006) showed that a haplotype spanning the LTA4H
gene, which encodes leukotriene A4 hydrolase, a protein in the same
biochemical pathway as ALOX5AP, confers modest risk of myocardial
infarction in an Icelandic cohort. Measurements of leukotriene B4 (LTB4)
production suggested that this risk is mediated through upregulation of
the leukotriene pathway. Three cohorts from the United States also
showed that the haplotype designated HapK confers a modest relative risk
(1.16) in European Americans, but it confers a 3-fold larger risk in
African Americans. About 27% of the European American controls carried
at least one copy of HapK, as compared with only 6% of African American
controls. Helgadottir et al. (2006) found that HapK is very rare in
Africa and that its occurrence in African Americans is due to European
admixture. Interactions with other genetic or environmental risk factors
that are more common in African Americans are likely to account for the
greater relative risk conferred by HapK in this group.
Given the altered balance of pro- and antiinflammatory eicosanoids in
zebrafish with Lta4h mutations (see ANIMAL MODEL), Tobin et al. (2010)
hypothesized that LTA4H polymorphisms may alter the response to human
mycobacterial infections that cause tuberculosis (TB; see 607948) and
leprosy (see 609888). Comparison of 692 Vietnamese HIV-seronegative
pulmonary and meningeal TB patients with 759 healthy controls revealed
fewer heterozygotes at each of 6 LTA4H SNPs (dbSNP rs1978331, dbSNP
rs17677715, dbSNP rs2247570, dbSNP rs2660898, dbSNP rs2660845, and dbSNP
rs2540475) in TB patients. Comparison of frequencies of heterozygotes
versus homozygotes among TB patients and controls yielded odds ratios
(ORs) less than 1 at all 6 SNPs. Adjusting for multiple comparisons,
association of heterozygosity with lower incidence of TB was significant
at dbSNP rs1978331 and dbSNP rs2660898 (P = 0.011 and 0.0003,
respectively, after Bonferroni correction), the 2 SNPs intragenic in
LTA4H with common minor allele frequencies. Among 53 meningeal TB
patients heterozygous at both dbSNP rs1978331 and dbSNP rs2660898, only
4% died within 300 days after diagnosis. In contrast, mortality was 16%
among 156 meningeal TB patients homozygous at these SNPs. Evaluation of
335 paucibacillary leprosy patients, 121 multibacillary (MB) leprosy
patients with erythema nodosum leprosum (ENL), and 443 MB leprosy
patients without ENL from Nepal showed that LTA4H heterozygosity at
dbSNP rs1978331 and dbSNP rs2660898 was significantly associated with a
lower incidence of MB leprosy without ENL (OR = 0.62 and P = 0.001 for
dbSNP rs1978331, and OR = 0.70 and P = 0.021 for dbSNP rs2660898). Tobin
et al. (2010) concluded that LTA4H heterozygosity is associated with
protection from TB infection, lower mortality among patients with severe
TB infection, and protection from development of severe leprosy disease
among exposed individuals. They proposed that LTA4H heterozygosity may
reflect an optimal balance, or rheostat mechanism, of pro- and
antiinflammatory eicosanoids (i.e., LTB4 and LXA4, respectively), and
that modulation of lipoxins, informed by LTA4H genotypes, may result in
better outcomes for patients with TB meningitis.
Behr et al. (2010) reviewed several studies implicating stimulation of
antiinflammatory molecules and inhibition of autophagy by virulent
mycobacteria as a means to evade the host immune system.
ANIMAL MODEL
Using a forward genetic screen with mutagenized zebrafish, Tobin et al.
(2010) identified mutants with differential susceptibility to
Mycobacterium marinum (Mm). Hypersusceptible mutants had a mutation in
Lta4h, but the phenotype was associated not with reduced production of
Ltb4, but with increased production of an antiinflammatory eicosanoid,
lipoxin, and reduced production of Tnf (191160) and decreased neutrophil
migration early after Mm infection. Tobin et al. (2010) concluded that
the reduced inflammation resulting from the Lta4h mutation leads to
increased Mm proliferation.
*FIELD* RF
1. Behr, M.; Schurr, E.; Gros, P.: TB: screening for responses to
a vile visitor. Cell 140: 615-618, 2010.
2. Funk, C. D.; Radmark, O.; Fu, J. Y.; Matsumoto, T.; Jornvall, H.;
Shimizu, T.; Samuelsson, B.: Molecular cloning and amino acid sequence
of leukotriene A(4) hydrolase. Proc. Nat. Acad. Sci. 84: 6677-6681,
1987.
3. Helgadottir, A.; Manolescu, A.; Helgason, A.; Thorleifsson, G.;
Thorsteinsdottir, U.; Gudbjartsson, D. F.; Gretarsdottir, S.; Magnusson,
K. P.; Gudmundsson, G.; Hicks, A.; Jonsson, T.; Grant, S. F. A.; and
19 others: A variant of the gene encoding leukotriene A4 hydrolase
confers ethnicity-specific risk of myocardial infarction. Nature
Genet. 38: 68-74, 2006.
4. Helgadottir, A.; Manolescu, A.; Thorleifsson, G.; Gretarsdottir,
S.; Jonsdottir, H.; Thorsteinsdottir, U.; Samani, N. J.; Gudmundsson,
G.; Grant, S. F. A.; Thorgeirsson, G.; Sveinbjornsdottir, S.; Valdimarsson,
E. M.; and 14 others: The gene encoding 5-lipoxygenase activating
protein confers risk of myocardial infarction and stroke. Nature
Genet. 36: 233-239, 2004.
5. Mancini, J. A.; Evans, J. F.: Cloning and characterization of
the human leukotriene A-4 hydrolase gene. Europ. J. Biochem. 231:
65-71, 1995.
6. Minami, M.; Ohno, S.; Kawasaki, H.; Radmark, O.; Samuelsson, B.;
Jornvall, H.; Shimizu, T.; Seyama, Y.; Suzuki, K.: Molecular cloning
of a cDNA coding for human leukotriene A(4) hydrolase: complete primary
structure of an enzyme involved in eicosanoid synthesis. J. Biol.
Chem. 262: 13873-13876, 1987.
7. Qiu, H.; Gabrielsen, A.; Agardh, H. E.; Wan, M.; Wetterholm, A.;
Wong, C.-H.; Hedin, U.; Swedenborg, J.; Hansson, G. K.; Samuelsson,
B.; Paulsson-Berne, G.; Haeggstrom, J. Z.: Expression of 5-lipoxygenase
and leukotriene A4 hydrolase in human atherosclerotic lesions correlates
with symptoms of plaque instability. Proc. Nat. Acad. Sci. 103:
8161-8166, 2006.
8. Snelgrove, R. J.; Jackson, P. L.; Hardison, M. T.; Noerager, B.
D.; Kinloch, A.; Gagger, A.; Shastry, S.; Rowe, S. M.; Shim, Y. M.;
Hussell, T.; Blalock, J. E.: A critical role for LTA4H in limiting
chronic pulmonary neutrophilic inflammation. Science 330: 90-94,
2010.
9. Tobin, D. M.; Vary, J. C., Jr.; Ray, J. P.; Walsh, G. S.; Dunstan,
S. J.; Bang, N. D.; Hagge, D. A.; Khadge, S.; King, M.-C.; Hawn, T.
R.; Moens, C. B.; Ramakrishnan, L.: The Ita4h locus modulates susceptibility
to Mycobacterial infection in zebrafish and humans. Cell 140: 717-730,
2010.
*FIELD* CN
Ada Hamosh - updated: 11/2/2010
Paul J. Converse - updated: 3/23/2010
Cassandra L. Kniffin - updated: 6/8/2006
*FIELD* CD
Victor A. McKusick: 12/1/1987
*FIELD* ED
alopez: 11/05/2010
terry: 11/2/2010
mgross: 3/25/2010
terry: 3/23/2010
wwang: 6/26/2006
ckniffin: 6/8/2006
alopez: 1/9/2006
alopez: 12/1/2005
terry: 12/1/2005
terry: 6/18/1998
terry: 5/22/1996
mark: 9/27/1995
carol: 1/8/1993
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/27/1989
marie: 3/25/1988