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Information on EC 3.3.2.6 - leukotriene-A4 hydrolase and Organism(s) Rattus norvegicus and UniProt Accession P30349

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EC Tree
     3 Hydrolases
         3.3 Acting on ether bonds
             3.3.2 Ether hydrolases
                3.3.2.6 leukotriene-A4 hydrolase
IUBMB Comments
This is a bifunctional zinc metalloprotease that displays both epoxide hydrolase and aminopeptidase activities [4,6]. It preferentially cleaves tripeptides at an arginyl bond, with dipeptides and tetrapeptides being poorer substrates (see EC 3.4.11.6, aminopeptidase B). It also converts leukotriene A4 into leukotriene B4, unlike EC 3.3.2.10, soluble epoxide hydrolase, which converts leukotriene A4 into 5,6-dihydroxy-7,9,11,14-icosatetraenoic acid [3,4]. In vertebrates, five epoxide-hydrolase enzymes have been identified to date: EC 3.3.2.6 (leukotriene A4 hydrolase), EC 3.3.2.7 (hepoxilin-epoxide hydrolase), EC 3.3.2.9 (microsomal epoxide hydrolase), EC 3.3.2.10 (soluble epoxide hydrolase) and EC 3.3.2.11 (cholesterol-5,6-oxide hydrolase) .
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Rattus norvegicus
UNIPROT: P30349
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Word Map
The taxonomic range for the selected organisms is: Rattus norvegicus
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
Synonyms
lta4h, lta4 hydrolase, leukotriene a4 hydrolase, leukotriene a(4) hydrolase, leukotriene-a4 hydrolase, leukotriene a4 hydrolase/aminopeptidase, lta4-h, leukotriene-a4-hydrolase, more
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
epoxide hydrolase
-
leukotriene A4 hydrolase
-
LTA4 hydrolase
-
hydrolase, leukotriene A4
-
-
-
-
leukotriene A(4) hydrolase
-
-
-
-
leukotriene A4 hydrolase
leukotriene A4 hydrolase/aminopeptidase
-
-
-
-
leukotriene-A4-hydrolase
-
-
LTA-4 hydrolase
-
-
-
-
LTA4 hydrolase
LTA4H
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
leukotriene A4 + H2O = leukotriene B4
show the reaction diagram
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
hydrolysis of ether bond
-
-
-
-
PATHWAY SOURCE
PATHWAYS
-
-, -, -, -
SYSTEMATIC NAME
IUBMB Comments
(7E,9E,11Z,14Z)-(5S,6S)-5,6-epoxyicosa-7,9,11,14-tetraenoate hydrolase
This is a bifunctional zinc metalloprotease that displays both epoxide hydrolase and aminopeptidase activities [4,6]. It preferentially cleaves tripeptides at an arginyl bond, with dipeptides and tetrapeptides being poorer substrates [6] (see EC 3.4.11.6, aminopeptidase B). It also converts leukotriene A4 into leukotriene B4, unlike EC 3.3.2.10, soluble epoxide hydrolase, which converts leukotriene A4 into 5,6-dihydroxy-7,9,11,14-icosatetraenoic acid [3,4]. In vertebrates, five epoxide-hydrolase enzymes have been identified to date: EC 3.3.2.6 (leukotriene A4 hydrolase), EC 3.3.2.7 (hepoxilin-epoxide hydrolase), EC 3.3.2.9 (microsomal epoxide hydrolase), EC 3.3.2.10 (soluble epoxide hydrolase) and EC 3.3.2.11 (cholesterol-5,6-oxide hydrolase) [5].
CAS REGISTRY NUMBER
COMMENTARY hide
90119-07-6
-
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
leukotriene A4 + H2O
leukotriene B4
show the reaction diagram
leukotriene A4 + H2O
leukotriene B4
show the reaction diagram
leukotriene A5 + H2O
?
show the reaction diagram
-
i.e. 5(S)-trans-5,6-oxido-7,9-trans-11,14,17-cis-eicosatetraenoic acid
-
-
?
additional information
?
-
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
leukotriene A4 + H2O
leukotriene B4
show the reaction diagram
leukotriene A4 + H2O
leukotriene B4
show the reaction diagram
additional information
?
-
-
LTA4H is a zinc metalloprotease
-
-
?
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Zinc
-
catalytic zinc site with the signature HEXXH-(X)18-E, three zinc binding ligands: His295, His299 and Glu318
Zn2+
-
LTA4H is a zinc metalloprotease
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
bestatin
2-oxo-3-amino carboxylic esters
-
-
-
4-[(2R)-2-[[4-(4-chlorophenoxy)phenoxy]methyl]pyrrolidin-1-yl]butanoic acid
-
i.e. DG-051, a phase II clinical candidate
4-[(2S)-2-[[4-(4-chloro-2-hydroxyphenoxy)phenoxy]methyl]pyrrolidin-1-yl]butanoic acid
-
i.e. DG-051 M1-A, a derivative derived from DG-051
4-[(2S)-2-[[4-(4-chloro-3-hydroxyphenoxy)phenoxy]methyl]pyrrolidin-1-yl]butanoic acid
-
i.e. DG-051 M1-B, a derivative derived from DG-051
4-[(2S)-2-[[4-(4-chlorophenoxy)phenoxy]methyl]-1-oxidopyrrolidin-1-yl]butanoic acid
-
i.e. DG-051 M2, an N-oxide derivative derived from DG-051
bestatin
-
-
captopril
-
-
Kelatorphan
-
-
leukotriene A4
-
-
Leukotriene A5
-
-
thioamine
-
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
albumin
-
stimulates aminopeptidase activity
-
Br-
-
stimulates aminopeptidase activity
Cl-
-
stimulates aminopeptidase activity
SCN-
-
stimulates aminopeptidase activity
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.02 - 0.03
leukotriene A4
-
pH 7.7-7.8, 37°C
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
additional information
-
-
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
esophageal and duodenal
Manually annotated by BRENDA team
peripheral
Manually annotated by BRENDA team
enzyme expression analysis, LTA4h mRNA is expressed in both spinal neurons and microglia, overview
Manually annotated by BRENDA team
-
alveolar macrophage
Manually annotated by BRENDA team
additional information
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
additional information
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
malfunction
increase of leukotriene synthesis in spinal microglia produced via p38 MAPK plays a role in the generation of neuropathic pain
physiological function
enzyme leukotriene A4 hydrolase (LTA4H) is characterized as a bifunctional enzyme with epoxide hydrolase (EH) and aminopeptidase (AP) activities. LTA4H plays a critical role in modulating inflammation by producing LTB4 via its EH activity. LTA4H also has putative roles in cancer development
metabolism
-
LTA4H catalyzes the last step in the synthesis of the pro-inflammatory molecule leukotriene B4
physiological function
-
the correlations between leukotriene B4 and the enzyme have significance on resistance and development of arthritis
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION?
LKHA4_RAT
611
0
69089
Swiss-Prot
other Location (Reliability: 4)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
50000
-
gel filtration
68000
-
1 * 68000, SDS-PAGE
69000
-
calculated from DNA sequence
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
monomer
-
1 * 68000, SDS-PAGE
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
-20°C, 30% glycerol, stable for at least 2 months
-
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
semiquantitative LTA4H expression analysis in peripheral nerves and spinal cord, overview
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
LTA4H is overexpressed in all rat esophageal adenocarcinoma (EAC) samples compared to that in the normal duodenal tissues in an esophagogastroduodenal anastomosis (EGDA) surgical model
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
medicine
medicine
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Evans, J.F.; Dupuis, P.; Ford-Hutchinson, A.W.
Purification and characterisation of leukotriene A4 hydrolase from rat neutrophils
Biochim. Biophys. Acta
840
43-50
1985
Rattus norvegicus
Manually annotated by BRENDA team
Samuelsson, B.; Funk, C.D.
Enzymes involved in the biosynthesis of leukotriene B4
J. Biol. Chem.
264
19469-19472
1989
Cavia porcellus, Homo sapiens, Rattus norvegicus
Manually annotated by BRENDA team
Nathaniel, D.J.; Evans, J.F.; Leblanc, Y.; Leveille, C.; Fitzsimmons, B.J.; Ford-Hutchinson, A.W.
Leukotriene A5 is a substrate and an inhibitor of rat and human neutrophil LTA4 hydrolase
Biochem. Biophys. Res. Commun.
131
827-835
1985
Homo sapiens, Rattus norvegicus
Manually annotated by BRENDA team
Makita, N.; Funk, C.D.; Imai, E.; Hoover, R.L.; Badr, K.F.
Molecular cloning and functional expression of rat leukotriene A4 hydrolase using the polymerase chain reaction
FEBS Lett.
299
273-277
1992
Rattus norvegicus
Manually annotated by BRENDA team
Haeggstrom, J.Z.; Kull, F.; Rudberg, P.C.; Tholander, F.; Thunnissen, M.M.
Leukotriene A4 hydrolase
Prostaglandins
68-69
495-510
2002
Saccharomyces cerevisiae, Cavia porcellus, Homo sapiens, Mus musculus, Rattus norvegicus, Xenopus laevis
Manually annotated by BRENDA team
Chen, X.; Li, N.; Wang, S.; Wu, N.; Hong, J.; Jiao, X.; Krasna, M.J.; Beer, D.G.; Yang, C.S.
Leukotriene A4 hydrolase in rat and human esophageal adenocarcinomas and inhibitory effects of bestatin
J. Natl. Cancer Inst.
95
1053-1061
2003
Homo sapiens, Rattus norvegicus (P30349)
Manually annotated by BRENDA team
Brock, T.G.; Maydanski, E.; McNish, R.W.; Peters-Golden, M.
Co-localization of leukotriene A4 hydrolase with 5-lipoxygenase in nuclei of alveolar macrophages and rat basophilic leukemia cells but not neutrophils
J. Biol. Chem.
276
35071-35077
2001
Rattus norvegicus
Manually annotated by BRENDA team
Enache, L.A.; Zhang, J.; Sullins, D.W.; Kennedy, I.; Onua, E.; Zembower, D.E.; Muellner, F.W.; Singh, J.; Kiselyov, A.S.
Synthesis and structural assignment of two major metabolites of the LTA4H inhibitor DG-051
Bioorg. Med. Chem. Lett.
19
6275-6279
2009
Canis lupus familiaris, Homo sapiens, Rattus norvegicus
Manually annotated by BRENDA team
Okubo, M.; Yamanaka, H.; Kobayashi, K.; Noguchi, K.
Leukotriene synthases and the receptors induced by peripheral nerve injury in the spinal cord contribute to the generation of neuropathic pain
Glia
58
599-610
2010
Rattus norvegicus (P30349)
Manually annotated by BRENDA team
Mendes, M.T.; Silveira, P.F.
The interrelationship between leukotriene B4 and leukotriene-A4-hydrolase in collagen/adjuvant-induced arthritis in rats
BioMed Res. Int.
2014
730421
2014
Rattus norvegicus
Manually annotated by BRENDA team
Vo, T.T.L.; Jang, W.J.; Jeong, C.H.
Leukotriene A4 hydrolase an emerging target of natural products for cancer chemoprevention and chemotherapy
Ann. N. Y. Acad. Sci.
1431
3-13
2018
Homo sapiens (P09960), Mus musculus (P24527), Rattus norvegicus (P30349)
Manually annotated by BRENDA team