Leukotriene-A4 hydrolase

Leukotriene-A4 hydrolase is an enzyme that catalyzes the reaction which converts Leukotriene A4 to Leukotriene B4. It is a bifunctional zinc enzyme (EC 3.3.2.6) with different amino acids attached to it to aid in the catalysis of the reaction. It also acts as an aminopeptidase. Leukotriene-A4 hydrolase is a cytosolic protein and is found in almost all mammalian cells, tissues and organelles that have been examined.

LTA4H
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1GW6, 1H19, 1HS6, 1SQM, 2R59, 2VJ8, 3B7R, 3B7S, 3B7T, 3B7U, 3CHO, 3CHP, 3CHQ, 3CHR, 3CHS, 3FH5, 3FH7, 3FH8, 3FHE, 3FTS, 3FTU, 3FTV, 3FTW, 3FTX, 3FTY, 3FTZ, 3FU0, 3FU3, 3FU5, 3FU6, 3FUD, 3FUE, 3FUF, 3FUH, 3FUI, 3FUJ, 3FUK, 3FUL, 3FUM, 3FUN, 3U9W, 4DPR, 4L2L, 4MKT, 4MS6, 5AEN, 4RVB, 4RSY, 4R7L
Identifiers
Aliases	LTA4H, leukotriene A4 hydrolase
External IDs	OMIM: 151570; MGI: 96836; HomoloGene: 6820; GeneCards: LTA4H; OMA:LTA4H - orthologs
Gene location (Human) Chr. Chromosome 12 (human) Band 12q23.1 Start 96,000,753 bp End 96,043,520 bp
Gene location (Mouse) Chr. Chromosome 10 (mouse) Band 10|10 C2 Start 93,289,273 bp End 93,320,737 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in monocyte granulocyte visceral pleura trabecular bone bone marrow germinal epithelium secondary oocyte lower lobe of lung blood bone marrow cell Top expressed in granulocyte ileum duodenum tibiofemoral joint atrium atrioventricular valve endocardial cushion dermis jejunum thymus More reference expression data BioGPS n/a
Gene ontology Molecular function leukotriene-A4 hydrolase activity peptide binding metal ion binding peptidase activity protein binding aminopeptidase activity hydrolase activity metallopeptidase activity RNA binding epoxide hydrolase activity zinc ion binding metalloaminopeptidase activity Cellular component nucleoplasm extracellular exosome extracellular region nucleus cytoplasm cytosol tertiary granule lumen ficolin-1-rich granule lumen Biological process proteolysis peptide catabolic process leukotriene metabolic process neutrophil degranulation leukotriene biosynthetic process cellular lipid metabolic process long-chain fatty acid biosynthetic process Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 4048 16993 Ensembl ENSG00000111144 ENSMUSG00000015889 UniProt P09960 P24527 RefSeq (mRNA) NM_000895 NM_001256643 NM_001256644 NM_008517 NM_001313897 RefSeq (protein) NP_000886 NP_001243572 NP_001243573 NP_001300826 NP_032543 Location (UCSC) Chr 12: 96 – 96.04 Mb Chr 10: 93.29 – 93.32 Mb PubMed search
Wikidata
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leukotriene-A4 hydrolase
Identifiers
EC no.	3.3.2.6
CAS no.	90119-07-6
Databases
IntEnz	IntEnz view
BRENDA	BRENDA entry
ExPASy	NiceZyme view
KEGG	KEGG entry
MetaCyc	metabolic pathway
PRIAM	profile
PDB structures	RCSB PDB PDBe PDBsum
Gene Ontology	AmiGO / QuickGO
Search PMC articles PubMed articles NCBI proteins

leukotriene A4 hydrolase
Crystallographic structure of LTA4H (rainbow colored N-terminus = blue, C-terminus = red) complexed with the protease inhibitor bestatin (space-filling model, carbon = white, oxygen = red, nitrogen = blue) based on the PDB: 1HS6​ structure.
Identifiers
Symbol	LTA4H
NCBI gene	4048
HGNC	6710
OMIM	151570
PDB	1SQM
RefSeq	NM_000895
UniProt	P09960
Other data
EC number	3.3.2.6
Locus	Chr. 12 q22
Search for Structures Swiss-model Domains InterPro

Function

This enzyme belongs to the family of hydrolases, specifically those acting on ether bonds (ether hydrolases). The systematic name of this enzyme class is (7E,9E,11Z,14Z)-(5S,6S)-5,6-epoxyicosa-7,9,11,14-tetraenoate hydrolase. Other names in common use include LTA4 hydrolase, LTA4H, and leukotriene A4 hydrolase. This enzyme participates in arachidonic acid metabolism.

Catalyzed reaction

The chemical reaction catalyzed by LTA4H.

Leukotriene A4 Hydrolase catalyzes the reaction which converts leukotriene A4 to leukotriene B4. The Leukotriene A4 structure contains an epoxide ring functional group, which are highly reactive due to its ring strain making them extremely electrophilic. This drives the reaction forward, favouring the products Leukotriene B4. Leukotriene A4 hydrolase adds a water molecule across the epoxide ring on Leukotriene A4. The addition of the water molecule opens the epoxide ring and causes the formation of the Hydroxy group at the carbon attached to the oxygen from the epoxide. The second carbon involved in the epoxide ring remains the same resulting in leukotriene B4. The water molecule attacking the double bond also forms into a hydroxy group after work-up. The product of the reaction is Leukotriene B4.

Structure

As of late 2007, 4 structures have been solved for this class of enzymes, with PDB accession codes PDB: 1GW6​, PDB: 1H19​, PDB: 1HS6​, and PDB: 1SQM​.

Further reading

• Evans JF, Dupuis P, Ford-Hutchinson AW (1985). "Purification and characterisation of leukotriene A4 hydrolase from rat neutrophils". Biochimica et Biophysica Acta (BBA) - General Subjects. 840 (1): 43–50. doi:10.1016/0304-4165(85)90160-6. PMID 3995081.
• Shimizu T, Seyama Y, Suzuki K (1987). "Molecular cloning of a cDNA coding for human leukotriene A4 hydrolase. Complete primary structure of an enzyme involved in eicosanoid synthesis". The Journal of Biological Chemistry. 262 (29): 13873–6. doi:10.1016/S0021-9258(18)47872-6. PMID 3654641.
• Haeggstrom J, Meijer J, Radmark O (1986). "Leukotriene A4. Enzymatic conversion into 5,6-dihydroxy-7,9,11,14-eicosatetraenoic acid by mouse liver cytosolic epoxide hydrolase". The Journal of Biological Chemistry. 261 (14): 6332–7. doi:10.1016/S0021-9258(19)84567-2. PMID 3009453.
• Newman JW, Morisseau C, Hammock BD (2005). "Epoxide hydrolases: their roles and interactions with lipid metabolism". Progress in Lipid Research. 44 (1): 1–51. doi:10.1016/j.plipres.2004.10.001. PMID 15748653.
• Fretland AJ, Omiecinski CJ (2000). "Epoxide hydrolases: biochemistry and molecular biology". Chemico-Biological Interactions. 129 (1–2): 41–59. Bibcode:2000CBI...129...41F. doi:10.1016/S0009-2797(00)00197-6. PMID 11154734.
• Orning L, Gierse JK, Fitzpatrick FA (1994). "The bifunctional enzyme leukotriene-A4 hydrolase is an arginine aminopeptidase of high efficiency and specificity". The Journal of Biological Chemistry. 269 (15): 11269–73. doi:10.1016/S0021-9258(19)78120-4. PMID 8157657.
• Ohishi N, Izumi T, Minami M, Kitamura S, Seyama Y, Ohkawa S, et al. (1987). "Leukotriene A4 hydrolase in the human lung. Inactivation of the enzyme with leukotriene A4 isomers". The Journal of Biological Chemistry. 262 (21): 10200–5. doi:10.1016/S0021-9258(18)61098-1. PMID 3038871.

External links

• leukotriene A4 hydrolase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)