ID LKHA4_MOUSE Reviewed; 611 AA.
AC P24527; Q3UY71; Q8VDR8;
DT 01-MAR-1992, integrated into UniProtKB/Swiss-Prot.
DT 27-JUL-2011, sequence version 4.
DT 01-MAY-2013, entry version 128.
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;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Sciurognathi;
OC Muroidea; Muridae; Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Spleen;
RX PubMed=1710117; DOI=10.1016/0006-291X(91)90459-K;
RA Medina J.F., Raadmark O., Funk C.D., Haeggstroem J.Z.;
RT "Molecular cloning and expression of mouse leukotriene A4 hydrolase
RT cDNA.";
RL Biochem. Biophys. Res. Commun. 176:1516-1524(1991).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Olfactory bulb;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M.,
RA Davis M.J., Wilming L.G., Aidinis V., Allen J.E.,
RA Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L.,
RA Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M.,
RA Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R.,
RA Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G.,
RA di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G.,
RA Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M.,
RA Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N.,
RA Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T.,
RA Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H.,
RA Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K.,
RA Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J.,
RA Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L.,
RA Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K.,
RA Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P.,
RA Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O.,
RA Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G.,
RA Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M.,
RA Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B.,
RA Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K.,
RA Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A.,
RA Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K.,
RA Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C.,
RA Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J.,
RA Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y.,
RA Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T.,
RA Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N.,
RA Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N.,
RA Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S.,
RA Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J.,
RA Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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 [4]
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 [5]
RP MUTAGENESIS OF TYR-384, CATALYTIC ACTIVITY, FUNCTION,
RP BIOPHYSICOCHEMICAL PROPERTIES, AND ENZYME REGULATION.
RX PubMed=9287304; DOI=10.1074/jbc.272.37.23057;
RA Andberg M.B., Hamberg M., Haeggstrom J.Z.;
RT "Mutation of tyrosine 383 in leukotriene A4 hydrolase allows
RT conversion of leukotriene A4 into 5S,6S-dihydroxy-7,9-trans-11,14-cis-
RT eicosatetraenoic acid. Implications for the epoxide hydrolase
RT mechanism.";
RL J. Biol. Chem. 272:23057-23063(1997).
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.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=5 uM for leukotriene A4;
CC Vmax=1030 nmol/min/mg enzyme for leukotriene A4;
CC -!- PATHWAY: Lipid metabolism; leukotriene B4 biosynthesis.
CC -!- SUBCELLULAR LOCATION: Cytoplasm.
CC -!- PTM: Phosphorylation at Ser-416 inhibits enzymatic activity (By
CC similarity).
CC -!- SIMILARITY: Belongs to the peptidase M1 family.
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DR EMBL; M63848; AAB59675.1; -; mRNA.
DR EMBL; AK134931; BAE22342.1; -; mRNA.
DR EMBL; BC021417; AAH21417.1; -; mRNA.
DR IPI; IPI00229527; -.
DR PIR; JN0066; JN0066.
DR RefSeq; NP_032543.2; NM_008517.2.
DR UniGene; Mm.271071; -.
DR ProteinModelPortal; P24527; -.
DR SMR; P24527; 6-610.
DR STRING; 10090.ENSMUSP00000016033; -.
DR MEROPS; M01.004; -.
DR PhosphoSite; P24527; -.
DR PaxDb; P24527; -.
DR PRIDE; P24527; -.
DR Ensembl; ENSMUST00000016033; ENSMUSP00000016033; ENSMUSG00000015889.
DR GeneID; 16993; -.
DR KEGG; mmu:16993; -.
DR CTD; 4048; -.
DR MGI; MGI:96836; Lta4h.
DR eggNOG; COG0308; -.
DR GeneTree; ENSGT00530000063003; -.
DR HOGENOM; HOG000293296; -.
DR HOVERGEN; HBG001274; -.
DR InParanoid; Q3UY71; -.
DR KO; K01254; -.
DR OMA; QEVKYTL; -.
DR OrthoDB; EOG40GCQC; -.
DR UniPathway; UPA00878; -.
DR ChEMBL; CHEMBL3738; -.
DR NextBio; 291088; -.
DR Bgee; P24527; -.
DR CleanEx; MM_LTA4H; -.
DR Genevestigator; P24527; -.
DR GermOnline; ENSMUSG00000015889; Mus musculus.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0005634; C:nucleus; IEA:Compara.
DR GO; GO:0004177; F:aminopeptidase activity; ISS:UniProtKB.
DR GO; GO:0004301; F:epoxide hydrolase activity; ISS:UniProtKB.
DR GO; GO:0004463; F:leukotriene-A4 hydrolase activity; ISS:UniProtKB.
DR GO; GO:0008237; F:metallopeptidase activity; IEA:UniProtKB-KW.
DR GO; GO:0008270; F:zinc ion binding; ISS:UniProtKB.
DR GO; GO:0019370; P:leukotriene biosynthetic process; ISS:UniProtKB.
DR GO; GO:0043171; P:peptide catabolic process; ISS:UniProtKB.
DR GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW.
DR 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 Acetylation; Complete proteome; Cytoplasm; Hydrolase;
KW Leukotriene biosynthesis; Metal-binding; Metalloprotease;
KW Phosphoprotein; Protease; Reference proteome; Zinc.
FT INIT_MET 1 1 Removed (By similarity).
FT CHAIN 2 611 Leukotriene A-4 hydrolase.
FT /FTId=PRO_0000095125.
FT REGION 135 137 Substrate binding (By similarity).
FT REGION 267 272 Substrate binding (By similarity).
FT REGION 564 566 Substrate binding (By similarity).
FT ACT_SITE 297 297 Proton acceptor (By similarity).
FT ACT_SITE 384 384 Proton donor (By similarity).
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 (By
FT similarity).
FT SITE 379 379 Covalently modified during suicide
FT inhibition by leukotrienes (By
FT similarity).
FT MOD_RES 73 73 N6-acetyllysine (By similarity).
FT MOD_RES 337 337 N6-acetyllysine (By similarity).
FT MOD_RES 414 414 N6-acetyllysine (By similarity).
FT MOD_RES 416 416 Phosphoserine (By similarity).
FT MOD_RES 573 573 N6-acetyllysine (By similarity).
FT MUTAGEN 296 296 H->Y: Complete loss of activity.
FT MUTAGEN 300 300 H->Y: Complete loss of activity.
FT MUTAGEN 319 319 E->Q: Complete loss of activity.
FT MUTAGEN 384 384 Y->F,H,Q: Alters leukotriene hydrolase
FT activity, strongly enhancing the
FT formation of a metabolite that is
FT normally produced in trace amounts.
FT CONFLICT 447 447 T -> A (in Ref. 1; AAB59675 and 3;
FT AAH21417).
SQ SEQUENCE 611 AA; 69051 MW; CCF8D30F6FA9721E CRC64;
MPEVADTCSL ASPASVCRTQ HLHLRCSVDF ARRTLTGTAA LTVQSQEENL RSLTLDTKDL
TIEKVVINGQ EVKYTLGESQ GYKGSPMEIS LPIALSKNQE IVIEISFETS PKSSALQWLT
PEQTSGKQHP YLFSQCQAIH CRAILPCQDT PSVKLTYTAE VSVPKELVAL MSAIRDGEAP
DPEDPSRKIY RFNQRVPIPC YLIALVVGAL ESRQIGPRTL VWSEKEQVEK SANEFSETES
MLKIAEDLGG PYVWGQYDLL VLPPSFPYGG MENPCLTFVT PTLLAGDKSL SNVIAHEISH
SWTGNLVTNK TWDHFWLNEG HTVYLERHIC GRLFGEKFRH FHALGGWGEL QNTIKTFGES
HPFTKLVVDL KDVDPDVAYS SIPYEKGFAL LFYLEQLLGG PEVFLGFLKA YVKKFSYQSV
TTDDWKSFLY SHFKDKVDLL NQVDWNTWLY APGLPPVKPN YDVTLTNACI ALSQRWVTAK
EEDLSSFSIA DLKDLSSHQL NEFLAQVLQK APLPLGHIKR MQEVYNFNAI NNSEIRFRWL
RLCIQSKWEE AIPLALKMAT EQGRMKFTRP LFKDLAAFDK SHDQAVHTYQ EHKASMHPVT
AMLVGRDLKV D
//
