P09960 (LKHA4_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Leukotriene A-4 hydrolase
Short name=LTA-4 hydrolase
EC=3.3.2.6

Alternative name(s):
Leukotriene A(4) hydrolase

Gene names

Name:	LTA4H
Synonyms:	LTA4

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	611 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Epoxide hydrolase that catalyzes the final step in the biosynthesis of the proinflammatory mediator leukotriene B4. Has also aminopeptidase activity. Ref.10 Ref.14 Ref.15 Ref.23 Ref.25 Ref.26 Ref.27
Catalytic activity	(7E,9E,11Z,14Z)-(5S,6S)-5,6-epoxyicosa-7,9,11,14-tetraenoate + H2O = (6Z,8E,10E,14Z)-(5S,12R)-5,12-dihydroxyicosa-6,8,10,14-tetraenoate. Ref.10 Ref.12 Ref.23 Ref.25 Ref.26 Ref.27
Cofactor	Binds 1 zinc ion per subunit. Ref.23 Ref.26 Ref.27
Enzyme regulation	Inhibited by bestatin. Subject to suicide inhibition by leukotriene A4, due to the formation of a covalent adduct at Tyr-379. Ref.12
Pathway	Lipid metabolism; leukotriene B4 biosynthesis.
Subunit structure	Monomer.
Subcellular location	Cytoplasm.
Tissue specificity	Isoform 1 and isoform 2 are expressed in monocytes, lymphocytes, neutrophils, reticulocytes, platelets and fibroblasts.
Post-translational modification	Phosphorylation at Ser-416 inhibits enzymatic activity.
Sequence similarities	Belongs to the peptidase M1 family.

Ontologies

Keywords
Biological process	Leukotriene biosynthesis
Cellular component	Cytoplasm
Coding sequence diversity	Alternative splicing Polymorphism
Ligand	Metal-binding Zinc
Molecular function	Hydrolase Metalloprotease Protease
PTM	Acetylation Phosphoprotein
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	arachidonic acid metabolic process Traceable author statement. Source: Reactome inflammatory response Non-traceable author statement Ref.22. Source: ProtInc leukotriene biosynthetic process Inferred from direct assay Ref.26. Source: UniProtKB peptide catabolic process Inferred from direct assay Ref.26Ref.27. Source: UniProtKB proteolysis Inferred from electronic annotation. Source: UniProtKB-KW
Cellular_component	cytosol Traceable author statement. Source: Reactome nucleus Inferred from direct assay. Source: HPA
Molecular_function	aminopeptidase activity Inferred from direct assay Ref.26Ref.27. Source: UniProtKB epoxide hydrolase activity Inferred from direct assay Ref.26. Source: UniProtKB leukotriene-A4 hydrolase activity Inferred from direct assay Ref.26. Source: UniProtKB metallopeptidase activity Inferred from electronic annotation. Source: UniProtKB-KW zinc ion binding Inferred from direct assay Ref.26Ref.27. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
GH1	P01241	1	EBI-721089,EBI-1026046
MCC	P23508	1	EBI-721089,EBI-307531

Alternative products

This entry describes 4 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: P09960-1)

Also known as: L-LTA4;

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: P09960-2)

Also known as: S-LTA4;

The sequence of this isoform differs from the canonical sequence as follows:
     511-532: APLPLGHIKRMQEVYNFNAINN → MAAALHSIQVGGRNSFGAKDGN
     533-611: Missing.

Isoform 3 (identifier: P09960-3)

The sequence of this isoform differs from the canonical sequence as follows:
     1-53: MPEIVDTCSL...QSQEDNLRSL → MLPQRNLSKRQVPTMHIPVKTRRLLAALK
     511-532: APLPLGHIKRMQEVYNFNAINN → MAAALHSIQVGGRNSFGAKDGN
     533-611: Missing.

Isoform 4 (identifier: P09960-4)

The sequence of this isoform differs from the canonical sequence as follows:
     1-53: MPEIVDTCSL...QSQEDNLRSL → MLPQRNLSKRQVPTMHIPVKTRRLLAALK

Note: No experimental confirmation available.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Initiator methionine

1

1

Removed Ref.10 Ref.11

Chain

2 – 611

610

Leukotriene A-4 hydrolase

PRO_0000095124

Regions

Region

135 – 137

3

Substrate binding

Region

267 – 272

6

Substrate binding

Region

564 – 566

3

Substrate binding

Sites

Active site

297

1

Proton acceptor Probable

Active site

384

1

Proton donor Probable

Metal binding

296

1

Zinc; catalytic

Metal binding

300

1

Zinc; catalytic

Metal binding

319

1

Zinc; catalytic

Site

376

1

Essential for epoxide hydrolase activity, but not for aminopeptidase activity

Site

379

1

Covalently modified during suicide inhibition by leukotrienes

Amino acid modifications

Modified residue

73

1

N6-acetyllysine Ref.20

Modified residue

337

1

N6-acetyllysine Ref.20

Modified residue

414

1

N6-acetyllysine Ref.20

Modified residue

416

1

Phosphoserine Ref.19

Modified residue

573

1

N6-acetyllysine Ref.20

Natural variations

Alternative sequence

1 – 53

53

MPEIV…NLRSL → MLPQRNLSKRQVPTMHIPVK TRRLLAALK in isoform 3 and isoform 4.

VSP_041107

Alternative sequence

511 – 532

22

APLPL…NAINN → MAAALHSIQVGGRNSFGAKD GN in isoform 2 and isoform 3.

VSP_041108

Alternative sequence

533 – 611

79

Missing in isoform 2 and isoform 3.

VSP_041109

Natural variant

131

1

Y → H.
Corresponds to variant rs45630737 [ dbSNP | Ensembl ].

VAR_051570

Experimental info

Mutagenesis

135

1

Q → A or L: Srongly increased epoxide hydrolase activity. Ref.16 Ref.25

Mutagenesis

135

1

Q → A: Strongly reduced aminopeptidase activity. Strongly decreased affinity for leukotriene. Abolishes epoxide hydrolase activity. Ref.16 Ref.25

Mutagenesis

137

1

Q → A: No loss of activity. Ref.16 Ref.24

Mutagenesis

137

1

Q → L: Aminopeptidase activity strongly impaired, but keeps LTA4 activity. Ref.16 Ref.24

Mutagenesis

137

1

Q → N: Aminopeptidase activity almost absent, but keeps LTA4 activity. Ref.16 Ref.24

Mutagenesis

140

1

H → Q: Aminopeptidase activity almost absent, but keeps LTA4 activity. Ref.16 Ref.25

Mutagenesis

269

1

G → A: No loss of activity. Ref.16

Mutagenesis

270

1

G → A: No loss of activity. Ref.16 Ref.24

Mutagenesis

271

1

M → L: No loss of activity. Ref.16 Ref.24

Mutagenesis

272

1

E → A or D: Complete loss of activity. Ref.16 Ref.24

Mutagenesis

272

1

E → Q: Loss of LTA4 activity, and aminopeptidase activity strongly impaired. Ref.16 Ref.24

Mutagenesis

273

1

N → A: No loss of activity. Ref.16 Ref.24

Mutagenesis

296

1

H → Y: Complete loss of activity. Ref.16

Mutagenesis

297

1

E → A: Loss of both activities. Ref.16 Ref.17 Ref.18 Ref.27

Mutagenesis

297

1

E → K: Loss of both activities. Ref.16 Ref.17 Ref.18 Ref.27

Mutagenesis

297

1

E → Q: Loss of aminopeptidase activity, but keeps LTA4 activity. Ref.16 Ref.17 Ref.18 Ref.27

Mutagenesis

300

1

H → L: Complete loss of activity. Ref.16

Mutagenesis

319

1

E → A: Complete loss of activity. Ref.16

Mutagenesis

372

1

D → N: No loss of activity. Ref.16 Ref.25

Mutagenesis

374

1

D → N: No loss of activity. Ref.16 Ref.25

Mutagenesis

376

1

D → A: Strongly reduced hydrolysis of peptides starting with Arg. Small effect on hydrolysis of peptides starting with Ala. Strongly reduced epoxide hydrolase activity. Ref.16 Ref.25 Ref.27

Mutagenesis

376

1

D → E: Strongly reduced aminopeptidase activity. Abolishes epoxide hydrolase activity. Ref.16 Ref.25 Ref.27

Mutagenesis

376

1

D → N: Abolishes aminopeptidase and epoxide hydrolase activity. Ref.16 Ref.25 Ref.27

Mutagenesis

385

1

E → Q: Reduced aminopeptidase activity. Minor effect on epoxide hydrolase activity. Ref.16 Ref.25

Mutagenesis

564

1

R → A, K or M: Abolishes epoxide hydrolase activity. Reduced aminopeptidase activity. Ref.16 Ref.26

Mutagenesis

566

1

K → A or M: Strongly reduced affinity for peptide substrates. Reduced epoxide hydrolase and aminopeptidase activity. Ref.16 Ref.26

Mutagenesis

566

1

K → R: No effect on epoxide hydrolase and aminopeptidase activity. Ref.16 Ref.26

Sequence conflict

115

1

A → T in BX647158. Ref.6

Sequence conflict

123

1

Q → R in BX647158. Ref.6

Sequence conflict

297

1

E → G in BAG60321. Ref.4

Sequence conflict

309

1

N → S in BX647158. Ref.6

Sequence conflict

378

1

A → V in BX647158. Ref.6

Secondary structure

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611

Helix Strand Turn

Details...

Turn

14 – 16

3

Beta strand

17 – 29

13

Turn

30 – 33

4

Beta strand

34 – 45

12

Beta strand

50 – 59

10

Beta strand

61 – 67

7

Beta strand

74 – 76

3

Helix

81 – 83

3

Beta strand

85 – 95

11

Beta strand

100 – 108

9

Beta strand

116 – 119

4

Helix

121 – 123

3

Beta strand

124 – 129

6

Beta strand

131 – 134

4

Turn

137 – 140

4

Helix

141 – 143

3

Beta strand

155 – 164

10

Beta strand

167 – 180

14

Beta strand

182 – 184

3

Beta strand

187 – 198

12

Helix

200 – 202

3

Beta strand

205 – 209

5

Beta strand

211 – 216

6

Beta strand

219 – 223

5

Helix

225 – 227

3

Helix

228 – 234

7

Turn

235 – 237

3

Helix

238 – 249

12

Beta strand

258 – 261

4

Beta strand

267 – 271

5

Beta strand

276 – 279

4

Helix

281 – 283

3

Beta strand

286 – 288

3

Turn

289 – 291

3

Helix

292 – 299

8

Turn

300 – 302

3

Turn

304 – 306

3

Beta strand

307 – 311

5

Helix

312 – 314

3

Helix

315 – 334

20

Helix

336 – 357

22

Helix

362 – 364

3

Beta strand

365 – 367

3

Helix

375 – 378

4

Helix

382 – 398

17

Helix

401 – 415

15

Beta strand

418 – 420

3

Helix

422 – 432

11

Helix

434 – 436

3

Helix

437 – 441

5

Helix

445 – 450

6

Turn

464 – 466

3

Helix

467 – 478

12

Helix

481 – 486

6

Helix

489 – 492

4

Helix

497 – 508

12

Helix

515 – 525

11

Helix

527 – 529

3

Helix

533 – 545

13

Helix

551 – 561

11

Helix

565 – 577

13

Helix

579 – 592

14

Helix

593 – 595

3

Helix

598 – 608

11

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 (L-LTA4) [UniParc]. Last modified January 23, 2007. Version 2. Checksum: 329BF6D04D4A06E1	FASTA	611	69,285
	10 20 30 40 50 60 MPEIVDTCSL ASPASVCRTK HLHLRCSVDF TRRTLTGTAA LTVQSQEDNL RSLVLDTKDL 70 80 90 100 110 120 TIEKVVINGQ EVKYALGERQ SYKGSPMEIS LPIALSKNQE IVIEISFETS PKSSALQWLT 130 140 150 160 170 180 PEQTSGKEHP YLFSQCQAIH CRAILPCQDT PSVKLTYTAE VSVPKELVAL MSAIRDGETP 190 200 210 220 230 240 DPEDPSRKIY KFIQKVPIPC YLIALVVGAL ESRQIGPRTL VWSEKEQVEK SAYEFSETES 250 260 270 280 290 300 MLKIAEDLGG PYVWGQYDLL VLPPSFPYGG MENPCLTFVT PTLLAGDKSL SNVIAHEISH 310 320 330 340 350 360 SWTGNLVTNK TWDHFWLNEG HTVYLERHIC GRLFGEKFRH FNALGGWGEL QNSVKTFGET 370 380 390 400 410 420 HPFTKLVVDL TDIDPDVAYS SVPYEKGFAL LFYLEQLLGG PEIFLGFLKA YVEKFSYKSI 430 440 450 460 470 480 TTDDWKDFLY SYFKDKVDVL NQVDWNAWLY SPGLPPIKPN YDMTLTNACI ALSQRWITAK 490 500 510 520 530 540 EDDLNSFNAT DLKDLSSHQL NEFLAQTLQR APLPLGHIKR MQEVYNFNAI NNSEIRFRWL 550 560 570 580 590 600 RLCIQSKWED AIPLALKMAT EQGRMKFTRP LFKDLAAFDK SHDQAVRTYQ EHKASMHPVT 610 AMLVGKDLKV D
	Isoform 2 (S-LTA4) [UniParc]. Checksum: 474891F08B0215A8	FASTA	532	59,733
	10 20 30 40 50 60 MPEIVDTCSL ASPASVCRTK HLHLRCSVDF TRRTLTGTAA LTVQSQEDNL RSLVLDTKDL 70 80 90 100 110 120 TIEKVVINGQ EVKYALGERQ SYKGSPMEIS LPIALSKNQE IVIEISFETS PKSSALQWLT 130 140 150 160 170 180 PEQTSGKEHP YLFSQCQAIH CRAILPCQDT PSVKLTYTAE VSVPKELVAL MSAIRDGETP 190 200 210 220 230 240 DPEDPSRKIY KFIQKVPIPC YLIALVVGAL ESRQIGPRTL VWSEKEQVEK SAYEFSETES 250 260 270 280 290 300 MLKIAEDLGG PYVWGQYDLL VLPPSFPYGG MENPCLTFVT PTLLAGDKSL SNVIAHEISH 310 320 330 340 350 360 SWTGNLVTNK TWDHFWLNEG HTVYLERHIC GRLFGEKFRH FNALGGWGEL QNSVKTFGET 370 380 390 400 410 420 HPFTKLVVDL TDIDPDVAYS SVPYEKGFAL LFYLEQLLGG PEIFLGFLKA YVEKFSYKSI 430 440 450 460 470 480 TTDDWKDFLY SYFKDKVDVL NQVDWNAWLY SPGLPPIKPN YDMTLTNACI ALSQRWITAK 490 500 510 520 530 EDDLNSFNAT DLKDLSSHQL NEFLAQTLQR MAAALHSIQV GGRNSFGAKD GN
	Isoform 3 [UniParc]. Checksum: A1CDA72AF83A875C	FASTA	508	57,300
	10 20 30 40 50 60 MLPQRNLSKR QVPTMHIPVK TRRLLAALKV LDTKDLTIEK VVINGQEVKY ALGERQSYKG 70 80 90 100 110 120 SPMEISLPIA LSKNQEIVIE ISFETSPKSS ALQWLTPEQT SGKEHPYLFS QCQAIHCRAI 130 140 150 160 170 180 LPCQDTPSVK LTYTAEVSVP KELVALMSAI RDGETPDPED PSRKIYKFIQ KVPIPCYLIA 190 200 210 220 230 240 LVVGALESRQ IGPRTLVWSE KEQVEKSAYE FSETESMLKI AEDLGGPYVW GQYDLLVLPP 250 260 270 280 290 300 SFPYGGMENP CLTFVTPTLL AGDKSLSNVI AHEISHSWTG NLVTNKTWDH FWLNEGHTVY 310 320 330 340 350 360 LERHICGRLF GEKFRHFNAL GGWGELQNSV KTFGETHPFT KLVVDLTDID PDVAYSSVPY 370 380 390 400 410 420 EKGFALLFYL EQLLGGPEIF LGFLKAYVEK FSYKSITTDD WKDFLYSYFK DKVDVLNQVD 430 440 450 460 470 480 WNAWLYSPGL PPIKPNYDMT LTNACIALSQ RWITAKEDDL NSFNATDLKD LSSHQLNEFL 490 500 AQTLQRMAAA LHSIQVGGRN SFGAKDGN
	Isoform 4 [UniParc]. Checksum: A70BF2792A0427C7	FASTA	587	66,852
	10 20 30 40 50 60 MLPQRNLSKR QVPTMHIPVK TRRLLAALKV LDTKDLTIEK VVINGQEVKY ALGERQSYKG 70 80 90 100 110 120 SPMEISLPIA LSKNQEIVIE ISFETSPKSS ALQWLTPEQT SGKEHPYLFS QCQAIHCRAI 130 140 150 160 170 180 LPCQDTPSVK LTYTAEVSVP KELVALMSAI RDGETPDPED PSRKIYKFIQ KVPIPCYLIA 190 200 210 220 230 240 LVVGALESRQ IGPRTLVWSE KEQVEKSAYE FSETESMLKI AEDLGGPYVW GQYDLLVLPP 250 260 270 280 290 300 SFPYGGMENP CLTFVTPTLL AGDKSLSNVI AHEISHSWTG NLVTNKTWDH FWLNEGHTVY 310 320 330 340 350 360 LERHICGRLF GEKFRHFNAL GGWGELQNSV KTFGETHPFT KLVVDLTDID PDVAYSSVPY 370 380 390 400 410 420 EKGFALLFYL EQLLGGPEIF LGFLKAYVEK FSYKSITTDD WKDFLYSYFK DKVDVLNQVD 430 440 450 460 470 480 WNAWLYSPGL PPIKPNYDMT LTNACIALSQ RWITAKEDDL NSFNATDLKD LSSHQLNEFL 490 500 510 520 530 540 AQTLQRAPLP LGHIKRMQEV YNFNAINNSE IRFRWLRLCI QSKWEDAIPL ALKMATEQGR 550 560 570 580 MKFTRPLFKD LAAFDKSHDQ AVRTYQEHKA SMHPVTAMLV GKDLKVD

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Molecular cloning of a cDNA coding for human leukotriene A4 hydrolase. Complete primary structure of an enzyme involved in eicosanoid synthesis." Minami M., Ohno S., Kawasaki H., Raedmark O., Samuelsson B., Joernvall H., Shimizu T., Seyama Y., Suzuki K. J. Biol. Chem. 262:13873-13876(1987) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[2]	"Molecular cloning and amino acid sequence of leukotriene A4 hydrolase." Funk C.D., Raadmark O., Fu J.Y., Matsumoto T., Joernvall H., Shimizu T., Samuelsson B. Proc. Natl. Acad. Sci. U.S.A. 84:6677-6681(1987) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), PARTIAL PROTEIN SEQUENCE.
[3]	"Cloning and characterization of the human leukotriene A4 hydrolase gene." Mancini J.A., Evans J.F. Eur. J. Biochem. 231:65-71(1995) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[4]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3). Tissue: Lung.
[5]	"Cloning of human full open reading frames in Gateway(TM) system entry vector (pDONR201)." Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B. Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
[6]	"The full-ORF clone resource of the German cDNA consortium." Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., Wiemann S., Schupp I. BMC Genomics 8:399-399(2007) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4). Tissue: Esophageal carcinoma.
[7]	"The finished DNA sequence of human chromosome 12." Scherer S.E., Muzny D.M., Buhay C.J., Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V., Hume J., Jackson A., Khan Z.M., Kovar-Smith C., Lewis L.R. , Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R., Montgomery K.T., Morgan M.B., Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D., Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y., Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z., Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H., Draper H., Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S., Kelly S.H., Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H., Santibanez J., Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q., Williams G.A., Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V., Bailey M., Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E., Burkett C.E., Burrell K.L., Calderon E., Cardenas V., Carter K., Casias K., Cavazos I., Cavazos S.R., Ceasar H., Chacko J., Chan S.N., Chavez D., Christopoulos C., Chu J., Cockrell R., Cox C.D., Dang M., Dathorne S.R., David R., Davis C.M., Davy-Carroll L., Deshazo D.R., Donlin J.E., D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J., Escotto M., Flagg N., Forbes L.D., Gabisi A.M., Garza M., Hamilton C., Henderson N., Hernandez O., Hines S., Hogues M.E., Huang M., Idlebird D.G., Johnson R., Jolivet A., Jones S., Kagan R., King L.M., Leal B., Lebow H., Lee S., LeVan J.M., Lewis L.C., London P., Lorensuhewa L.M., Loulseged H., Lovett D.A., Lucier A., Lucier R.L., Ma J., Madu R.C., Mapua P., Martindale A.D., Martinez E., Massey E., Mawhiney S., Meador M.G., Mendez S., Mercado C., Mercado I.C., Merritt C.E., Miner Z.L., Minja E., Mitchell T., Mohabbat F., Mohabbat K., Montgomery B., Moore N., Morris S., Munidasa M., Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O., Nwokenkwo S., Obregon M., Oguh M., Oragunye N., Oviedo R.J., Parish B.J., Parker D.N., Parrish J., Parks K.L., Paul H.A., Payton B.A., Perez A., Perrin W., Pickens A., Primus E.L., Pu L.-L., Puazo M., Quiles M.M., Quiroz J.B., Rabata D., Reeves K., Ruiz S.J., Shao H., Sisson I., Sonaike T., Sorelle R.P., Sutton A.E., Svatek A.F., Svetz L.A., Tamerisa K.S., Taylor T.R., Teague B., Thomas N., Thorn R.D., Trejos Z.Y., Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I., Vera V.A., Villasana D.M., Wang L., Ward-Moore S., Warren J.T., Wei X., White F., Williamson A.L., Wleczyk R., Wooden H.S., Wooden S.H., Yen J., Yoon L., Yoon V., Zorrilla S.E., Nelson D., Kucherlapati R., Weinstock G., Gibbs R.A. Nature 440:346-351(2006) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[8]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[9]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). Tissue: Eye.
[10]	"Leukotriene A4 hydrolase in the human B-lymphocytic cell line Raji: indications of catalytically divergent forms of the enzyme." Odlander B., Claesson H.E., Bergman T., Radmark O., Joernvall H., Haeggstrom J.Z. Arch. Biochem. Biophys. 287:167-174(1991) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 2-22, FUNCTION, CATALYTIC ACTIVITY. Tissue: B-cell.
[11]	"Leukotriene A4 hydrolase in human leukocytes. Purification and properties." Radmark O., Shimizu T., Joernvall H., Samuelsson B. J. Biol. Chem. 259:12339-12345(1984) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 2-16.
[12]	"Leukotriene A4 hydrolase: mapping of a henicosapeptide involved in mechanism-based inactivation." Mueller M.J., Wetterholm A., Blomster M., Jornvall H., Samuelsson B., Haeggstrom J.Z. Proc. Natl. Acad. Sci. U.S.A. 92:8383-8387(1995) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 366-386, ENZYME REGULATION, COVALENT MODIFICATION AT TYR-379, CATALYTIC ACTIVITY.
[13]	"The human leukotriene A4 hydrolase gene is expressed in two alternatively spliced mRNA forms." Jendraschak E., Kaminski W.E., Kiefl R., von Schacky C. Biochem. J. 314:733-737(1996) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 511-611, ALTERNATIVE SPLICING (ISOFORMS 1 AND 2).
[14]	"Molecular evolution and zinc ion binding motif of leukotriene A4 hydrolase." Toh H., Minami M., Shimizu T. Biochem. Biophys. Res. Commun. 171:216-221(1990) [PubMed] [Europe PMC] [Abstract] Cited for: ZINC-BINDING, FUNCTION AS A PEPTIDASE, SIMILARITY TO ZINC PROTEASES.
[15]	"Leukotriene A4 hydrolase: a zinc metalloenzyme." Haeggstroem J.Z., Wetterholm A., Shapiro R., Vallee B.L., Samuelsson B. Biochem. Biophys. Res. Commun. 172:965-970(1990) [PubMed] [Europe PMC] [Abstract] Cited for: ZINC-BINDING, FUNCTION AS A PEPTIDASE.
[16]	"Leukotriene A4 hydrolase: determination of the three zinc-binding ligands by site-directed mutagenesis and zinc analysis." Medina J.F., Wetterholm A., Raadmark O., Shapiro R., Haeggstroem J.Z., Vallee B.L., Samuelsson B. Proc. Natl. Acad. Sci. U.S.A. 88:7620-7624(1991) [PubMed] [Europe PMC] [Abstract] Cited for: MUTAGENESIS OF ZINC LIGANDS.
[17]	"Leukotriene A4 hydrolase, a bifunctional enzyme. Distinction of leukotriene A4 hydrolase and aminopeptidase activities by site-directed mutagenesis at Glu-297." Minami M., Bito H., Ohishi N., Tsuge H., Miyano M., Mori M., Wada H., Mutoh H., Shimada S., Izumi T., Abe K., Shimuzu T. FEBS Lett. 309:353-357(1992) [PubMed] [Europe PMC] [Abstract] Cited for: MUTAGENESIS OF GLU-297.
[18]	"Leukotriene A4 hydrolase: abrogation of the peptidase activity by mutation of glutamic acid-296." Wetterholm A., Medina J.F., Raadmark O., Shapiro R., Haeggstroem J.Z., Vallee B.L., Samuelsson B. Proc. Natl. Acad. Sci. U.S.A. 89:9141-9145(1992) [PubMed] [Europe PMC] [Abstract] Cited for: MUTAGENESIS OF GLU-297.
[19]	"Regulation of leukotriene A4 hydrolase activity in endothelial cells by phosphorylation." Rybina I.V., Liu H., Gor Y., Feinmark S.J. J. Biol. Chem. 272:31865-31871(1997) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION AT SER-416.
[20]	"Lysine acetylation targets protein complexes and co-regulates major cellular functions." Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C., Olsen J.V., Mann M. Science 325:834-840(2009) [PubMed] [Europe PMC] [Abstract] Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-73; LYS-337; LYS-414 AND LYS-573, MASS SPECTROMETRY.
[21]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[22]	"Crystal structure of human leukotriene A(4) hydrolase, a bifunctional enzyme in inflammation." Thunnissen M.M.G.M., Nordlund P., Haeggstroem J.Z. Nat. Struct. Biol. 8:131-135(2001) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.95 ANGSTROMS).
[23]	"Crystal structures of leukotriene A4 hydrolase in complex with captopril and two competitive tight-binding inhibitors." Thunnissen M.M., Andersson B., Samuelsson B., Wong C.H., Haeggstrom J.Z. FASEB J. 16:1648-1650(2002) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) IN COMPLEX WITH CAPTOPRIL AND ZINC IONS, FUNCTION, COFACTOR, CATALYTIC ACTIVITY, ACTIVE SITE.
[24]	"Leukotriene A4 hydrolase/aminopeptidase. Glutamate 271 is a catalytic residue with specific roles in two distinct enzyme mechanisms." Rudberg P.C., Tholander F., Thunnissen M.M.G.M., Haeggstroem J.Z. J. Biol. Chem. 277:1398-1404(2002) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF MUTANT GLN-272, MUTAGENESIS OF GLN-137; GLY-270; MET-271; GLU-272 AND ASN-273.
[25]	"Leukotriene A4 hydrolase: selective abrogation of leukotriene B4 formation by mutation of aspartic acid 375." Rudberg P.C., Tholander F., Thunnissen M.M., Samuelsson B., Haeggstrom J.Z. Proc. Natl. Acad. Sci. U.S.A. 99:4215-4220(2002) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF MUTANT ASN-376 IN COMPLEX WITH BESTATIN AND ZINC IONS, FUNCTION, CATALYTIC ACTIVITY, MUTAGENESIS OF GLN-135; HIS-140; ASP-372; ASP-374; ASP-376 AND GLU-385.
[26]	"Leukotriene A4 hydrolase: identification of a common carboxylate recognition site for the epoxide hydrolase and aminopeptidase substrates." Rudberg P.C., Tholander F., Andberg M., Thunnissen M.M., Haeggstrom J.Z. J. Biol. Chem. 279:27376-27382(2004) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF MUTANT ALA-564 IN COMPLEX WITH ZINC IONS, CATALYTIC ACTIVITY, FUNCTION, COFACTOR, MUTAGENESIS OF ARG-564 AND LYS-566.
[27]	"Structure-based dissection of the active site chemistry of leukotriene A4 hydrolase: implications for M1 aminopeptidases and inhibitor design." Tholander F., Muroya A., Roques B.P., Fournie-Zaluski M.C., Thunnissen M.M., Haeggstrom J.Z. Chem. Biol. 15:920-929(2008) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.47 ANGSTROMS) OF MUTANT GLN-297 IN COMPLEXES WITH SUBSTRATE TRIPEPTIDES AND ZINC IONS, CATALYTIC ACTIVITY, FUNCTION, COFACTOR, MUTAGENESIS OF GLU-297 AND ASP-376.
[28]	"Discovery of leukotriene A4 hydrolase inhibitors using metabolomics biased fragment crystallography." Davies D.R., Mamat B., Magnusson O.T., Christensen J., Haraldsson M.H., Mishra R., Pease B., Hansen E., Singh J., Zembower D., Kim H., Kiselyov A.S., Burgin A.B., Gurney M.E., Stewart L.J. J. Med. Chem. 52:4694-4715(2009) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.58 ANGSTROMS) IN COMPLEXES WITH INHIBITORS AND ZINC IONS.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

J03459 mRNA. Translation: AAA36176.1.
J02959 mRNA. Translation: AAA36177.1.
U27293 , U27275, U27276, U27277, U27278, U27279, U27280, U27281, U27282, U27283, U27284, U27285, U27286, U27287, U27288, U27289, U27290, U27291, U27292 Genomic DNA. Translation: AAA89077.1.
AK298017 mRNA. Translation: BAG60321.1.
CR457068 mRNA. Translation: CAG33349.1.
BX647158 mRNA. No translation available.
AC007298 Genomic DNA. No translation available.
CH471054 Genomic DNA. Translation: EAW97559.1.
BC032528 mRNA. Translation: AAH32528.1.
U43410 Genomic DNA. No translation available.
U43411 Genomic DNA. No translation available.

IPI

IPI00219077.
IPI00514090.
IPI00790203.
IPI00793812.

PIR

S65947.

RefSeq

NP_000886.1. NM_000895.2.
NP_001243572.1. NM_001256643.1.
NP_001243573.1. NM_001256644.1.

UniGene

Hs.524648.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1GW6	X-ray	2.20	A	2-611	[»]
1H19	X-ray	2.10	A	1-611	[»]
1HS6	X-ray	1.95	A	1-611	[»]
1SQM	X-ray	2.30	A	2-610	[»]
2R59	X-ray	1.89	A	2-611	[»]
2VJ8	X-ray	1.80	A	1-611	[»]
3B7R	X-ray	1.81	L	2-611	[»]
3B7S	X-ray	1.47	A	2-611	[»]
3B7T	X-ray	2.30	A	2-611	[»]
3B7U	X-ray	1.90	X	2-611	[»]
3CHO	X-ray	1.80	A	2-611	[»]
3CHP	X-ray	2.10	A	2-611	[»]
3CHQ	X-ray	2.09	A	2-611	[»]
3CHR	X-ray	2.20	A	2-611	[»]
3CHS	X-ray	2.55	A	2-611	[»]
3FH5	X-ray	1.63	A	1-611	[»]
3FH7	X-ray	2.05	A	1-611	[»]
3FH8	X-ray	1.67	A	1-611	[»]
3FHE	X-ray	2.16	A	1-611	[»]
3FTS	X-ray	2.33	A	1-611	[»]
3FTU	X-ray	1.90	A	1-611	[»]
3FTV	X-ray	1.70	A	1-611	[»]
3FTW	X-ray	1.85	A	1-611	[»]
3FTX	X-ray	1.96	A	1-611	[»]
3FTY	X-ray	2.15	A	1-611	[»]
3FTZ	X-ray	2.00	A	1-611	[»]
3FU0	X-ray	1.80	A	1-611	[»]
3FU3	X-ray	2.00	A	1-611	[»]
3FU5	X-ray	2.30	A	1-611	[»]
3FU6	X-ray	2.05	A	1-611	[»]
3FUD	X-ray	2.20	A	1-611	[»]
3FUE	X-ray	2.38	A	1-611	[»]
3FUF	X-ray	2.60	A	1-611	[»]
3FUH	X-ray	1.80	A	1-611	[»]
3FUI	X-ray	2.20	A	1-611	[»]
3FUJ	X-ray	1.90	A	1-611	[»]
3FUK	X-ray	1.95	A	1-611	[»]
3FUL	X-ray	2.39	A	1-611	[»]
3FUM	X-ray	2.15	A	1-611	[»]
3FUN	X-ray	1.58	A	1-611	[»]
3U9W	X-ray	1.25	A	4-611	[»]
4DPR	X-ray	2.02	A	1-611	[»]

ProteinModelPortal

P09960.

ModBase

Search...

Protein-protein interaction databases

IntAct

P09960. 5 interactions.

MINT

MINT-1388946.

STRING

9606.ENSP00000228740.

Protein family/group databases

MEROPS

M01.004.

PTM databases

PhosphoSite

P09960.

Polymorphism databases

DMDM

126353.

2D gel databases

REPRODUCTION-2DPAGE

IPI00219077.

Proteomic databases

PaxDb

P09960.

PRIDE

P09960.

Protocols and materials databases

DNASU

4048.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000228740; ENSP00000228740; ENSG00000111144.
ENST00000413268; ENSP00000395051; ENSG00000111144.
ENST00000552789; ENSP00000449958; ENSG00000111144.

GeneID

4048.

KEGG

hsa:4048.

UCSC

uc001ten.1. human.
uc010suy.1. human.
uc010suz.1. human.

Organism-specific databases

CTD

4048.

GeneCards

GC12M096394.

HGNC

HGNC:6710. LTA4H.

HPA

CAB015221.
HPA008399.
HPA017017.

MIM

151570. gene.

neXtProt

NX_P09960.

PharmGKB

PA24345.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG0308.

HOGENOM

HOG000293296.

HOVERGEN

HBG001274.

InParanoid

P09960.

KO

K01254.

OMA

QEVKYTL.

OrthoDB

EOG40GCQC.

PhylomeDB

P09960.

Enzyme and pathway databases

BioCyc

MetaCyc:HS03372-MONOMER.

BRENDA

3.3.2.6. 2681.

Reactome

REACT_111217. Metabolism.

UniPathway

UPA00878.

Gene expression databases

ArrayExpress

P09960.

Bgee

P09960.

CleanEx

HS_LTA4H.

Genevestigator

P09960.

GermOnline

ENSG00000111144. Homo sapiens.

Family and domain databases

InterPro

IPR016024. ARM-type_fold.
IPR012777. Leukotriene_A4_hydrolase.
IPR001930. Peptidase_M1.
IPR015211. Peptidase_M1_C.
IPR014782. Peptidase_M1_N.
[Graphical view]

PANTHER

PTHR11533. PTHR11533. 1 hit.

Pfam

PF09127. Leuk-A4-hydro_C. 1 hit.
PF01433. Peptidase_M1. 1 hit.
[Graphical view]

PRINTS

PR00756. ALADIPTASE.

SUPFAM

SSF48371. ARM-type_fold. 1 hit.

TIGRFAMs

TIGR02411. leuko_A4_hydro. 1 hit.

PROSITE

PS00142. ZINC_PROTEASE. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

P09960.

ChEMBL

CHEMBL4618.

ChiTaRS

LTA4H. human.

EvolutionaryTrace

P09960.

GenomeRNAi

4048.

NextBio

15856.

SOURCE

Search...

Entry information

Entry name

LKHA4_HUMAN

Accession

Primary (citable) accession number: P09960
Secondary accession number(s): B4DNQ9 , F8VV40, Q6IAT6, Q9UCT7

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 1, 1989
Last sequence update:	January 23, 2007
Last modified:	May 29, 2013
This is version 165 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.