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Information on EC 3.3.2.6 - leukotriene-A4 hydrolase and Organism(s) Cavia porcellus and UniProt Accession P19602
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3.3.2.6 leukotriene-A4 hydrolaseIUBMB 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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Word Map
- 3.3.2.6
-
5-lipoxygenase
-
arachidonic
- epoxide
- medicine
- leukocyte
- asthma
- bestatin
-
chemoattractant
-
eicosanoids
-
metalloenzyme
- flap
-
ionophore
-
alox5ap
-
tuberculous
-
transcellular
-
5-lipoxygenase-activating
- aminopeptidases
- captopril
-
lipoxins
- pro-gly-pro
- montelukast
- proline-glycine-proline
-
5-hete
- zileuton
- diagnostics
- pharmacology
- drug development
The taxonomic range for the selected organisms is: Cavia porcellus
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
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
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
hydrolase, leukotriene A4
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leukotriene A(4) hydrolase
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leukotriene A4 hydrolase
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leukotriene A4 hydrolase/aminopeptidase
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-
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LTA-4 hydrolase
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LTA4 hydrolase
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LTA4H
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
leukotriene A4 + H2O = leukotriene B4
His295, His299, Glu318, Glu271 are amino acids involved in metallic binding and epoxid hydrolase activity, additional Glu296 and Tyr383 are required for the aminopeptidase activity
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leukotriene A4 + H2O = leukotriene B4
mechanistic models, Glu271 is specifically required for the epoxid hydrolase activity and peptidase activity
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leukotriene A4 + H2O = leukotriene B4
bifunctional enzyme acting as an epoxide hydrolase and also as an aminopeptidase
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
hydrolysis of ether bond
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-
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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
90119-07-6
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
leukotriene A4 + H2O
leukotriene B4
biosynthesis of leukotriene B4
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?
leukotriene A4 + H2O
leukotriene B4
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i.e. 5(S)-trans-5,6-oxido-7,9-trans-11,14-cis-eicosatetraenoic acid
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?
leukotriene A4 + H2O
leukotriene B4
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model for the binding of leukotriene A4 to the active site
mutants of Tyr378 are able to generate, not only leukotriene B4, but also (5S,12R)-dihydroxy-6,10-trans-8,14-cis-eicosatetraenoic acid, in a yield of about 20-30%
?
additional information
?
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the aminopeptidase activity accepts a variety of substrates and certain arginyl di- and tri-peptides as well as p-nitroanilide derivates of Ala and Arg
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-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
leukotriene A4 + H2O
leukotriene B4
biosynthesis of leukotriene B4
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?
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Zinc
Zinc
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catalytic zinc site with the signature HEXXH-(X)18-E, three zinc binding ligands: His295, His299 and Glu318
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
pI VALUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
5.4
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chromatofocusing, isoelectric focusing, in absence of SH reducing reagents
5.7
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chromatofocusing, isoelectric focusing, in presence of SH reducing reagents
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
additional information
additional information
mRNA is distributed in liver, brain, lung, heart, kidney, and highly expressed in the intestine and spleen
additional information
-
mRNA is distributed in liver, brain, lung, heart, kidney, and highly expressed in the intestine and spleen
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). LKHA4_CAVPO
611
0
68971
Swiss-Prot
other Location (Reliability: 4)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
pH STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
7.8
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without any organic solvent at 25°C the half-life is less than 10 s, stability increases at higher pH
646978
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
25
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without any organic solvent at pH 7.4 the half-life is less than 10 s, stability increases at lower temperature
ORGANIC SOLVENT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
-
without any organic solvent at pH 7.4 and 25°C the half-life is less than 10 s
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
mRNA is distributed in liver, brain, lung, heart, kidney, and highly expressed in the intestine and spleen
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
the enzyme catalyses the hydrolysis of leukotriene A4 into the proinflammatory substance leukotriene B4
medicine
medicine
-
the product is a classical chemoattractant, triggers adherence and aggregation of leukocytes to the endothelium, modulates immune responses, participates in the host-defence against infections and is a mediator of PAF-induced lethal shock
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Haeggstrm, J.Z.
Cytosolic liver enzymes catalyzing hydrolysis of leukotriene A4 to leukotriene B4 and 5,6-dihydroxyeicosatetraenoic acid
Methods Enzymol.
187
324-334
1990
Cavia porcellus
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
Haeggstrm, J.; Radmark, O.; Fitzpatrick, F.A.
Leukotriene A4-hydrolase activity in guinea pig and human liver
Biochim. Biophys. Acta
835
378-384
1985
Cavia porcellus, Homo sapiens
Minami, M.; Ohishi, N.; Mutho, H.; Izumi, T.; Bito, H.; Wada, H.; Seyama, Y.; Toh, H.; Shimizu, T.
Leukotriene A4 hydrolase is a zinc-containing aminopeptidase
Biochem. Biophys. Res. Commun.
173
620-626
1990
Cavia porcellus, Homo sapiens
Bito, H.; Ohishi, N.; Miki, I.; Minami, M.; Tanabe, T.; Shimizu, T.; Seyama, Y.
Leukotriene A4 hydrolase from guinea pig lung: the presence of two catalytically active forms
J. Biochem.
105
261-264
1989
Cavia porcellus
Haeggstrm, J.; Bergman, T.; Jrnvall, H.; Radmark, O.
Guinea-pig liver leukotriene A4 hydrolase. Purification, characterization and structural properties
Eur. J. Biochem.
174
717-724
1988
Cavia porcellus
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
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