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Information on EC 3.3.2.6 - leukotriene-A4 hydrolase and Organism(s) Mus musculus and UniProt Accession P24527
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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: Mus musculus
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
-
-
-
-
leukotriene A(4) hydrolase
-
-
-
-
leukotriene A4 hydrolase
leukotriene A4 hydrolase/aminopeptidase
-
-
-
-
LTA-4 hydrolase
-
-
-
-
LTA4 hydrolase
LTA4H
leukotriene A4 hydrolase
-
-
-
-
LTA4 hydrolase
-
-
-
-
LTA4H
-
-
-
-
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
-
leukotriene A4 + H2O = leukotriene B4
mechanistic models, Glu271 is specifically required for the epoxid hydrolase activity and peptidase activity
-
leukotriene A4 + H2O = leukotriene B4
bifunctional enzyme acting as an epoxide hydrolase and also as an aminopeptidase
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
hydrolysis of ether bond
hydrolysis of ether bond
-
-
-
-
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
-
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
(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
-
-
-
-
?
L-Ala-4-nitroanilide + H2O
L-Ala + 4-nitroaniline
-
aminopeptidase activity
-
-
?
leukotriene A4 + H2O
leukotriene B4
-
-
LTB4 is an endogenous itch mediator in the skin and is involved in the pruritus response in allergic reactions
-
?
leukotriene A4 + H2O
leukotriene B4
-
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
?
-
the aminopeptidase binding site shares a similar structure to LTA4H at its ligand binding sites
-
-
?
additional information
?
-
-
the aminopeptidase binding site shares a similar structure to LTA4H at its ligand binding sites
-
-
?
additional information
?
-
-
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
-
-
?
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
(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
-
-
-
-
?
leukotriene A4 + H2O
leukotriene B4
-
-
LTB4 is an endogenous itch mediator in the skin and is involved in the pruritus response in allergic reactions
-
?
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Zn2+
zinc metalloenzyme, enzyme LTA4H folds into three domains and creates a deep cleft harboring the catalytic Zn2+ site, forming the active site with an L-shaped hydrophobic pocket deep into the protein
Co2+
-
apoenzyme is inactive and can be reactivated by addition of stoichiometric amounts of zinc and cobalt
Zinc
Zinc
-
apoenzyme is inactive and can be reactivated by addition of stoichiometric amounts of zinc and cobalt
Zinc
-
catalytic zinc site with the signature HEXXH-(X)18-E, three zinc binding ligands: His295, His299 and Glu318
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
(S)-2-((2S,3R)-3-amino-2-hydroxy-4-phenylbutanamido)-4-methylpentanoic acid
-
4-(dimethylamino)-N-[7-(hydroxyamino)-7-oxoheptyl]benzamide
markedly diminishes early neutrophilic inflammation in mouse models of ALI and IPF under a clinical safety dose, enzyme binding structure, overview
bestatin
significantly inhibit LTB4 production, bestatin effectively inhibits LTB4 synthesis and tumorigenesis in the ApcMin/+ and CRC patient-derived xenograft mouse model
JNJ-26993135
shows selective inhibition of LTB4 biosynthesis in a murine model, suggesting a potent compound targeting LTA4H
suberanilohydroxamic acid
markedly diminishes early neutrophilic inflammation in mouse models of ALI and IPF under a clinical safety dose, enzyme binding structure, overview
-
(2S)-2-amino-3-[4-(benzyloxy)phenyl]propane-1-thiol
-
it are about 50 derivates and related structures synthesized and assayed their inhibition of enzyme catalyzes hxdrolysis of L-alanine-4-nitroanilide
1-(1-[2-[4-(1,3-benzothiazol-2-yloxy)phenoxy]ethyl]piperidin-4-yl)pyrrolidin-2-one
-
-
1-(1-[[6-(1,3-benzothiazol-2-yloxy)-1-benzofuran-3-yl]methyl]piperidin-4-yl)pyrrolidin-2-one
-
-
1-(1-[[6-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)-1-benzofuran-3-yl]methyl]piperidin-4-yl)pyrrolidin-2-one
-
-
1-(5-[[5-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)-1-benzofuran-3-yl]methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl)ethanone
-
-
1-(5-[[5-([1,3]thiazolo[4,5-c]pyridin-2-yloxy)-1-benzofuran-3-yl]methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl)ethanone
-
-
1-(5-[[5-([1,3]thiazolo[5,4-b]pyridin-2-yloxy)-1-benzofuran-3-yl]methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl)ethanone
-
-
1-(5-[[6-(1,3-benzothiazol-2-yloxy)-1-benzofuran-3-yl]methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl)ethanone
-
-
1-(5-[[6-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)-1-benzofuran-3-yl]methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl)ethanone
-
-
1-(5-[[6-([1,3]thiazolo[4,5-c]pyridin-2-yloxy)-1-benzofuran-3-yl]methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl)ethanone
-
-
1-(5-[[6-([1,3]thiazolo[5,4-b]pyridin-2-yloxy)-1-benzofuran-3-yl]methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl)ethanone
-
-
1-[[6-(1,3-benzothiazol-2-yloxy)-1-benzofuran-3-yl]methyl]piperidine-4-carboxylic acid
-
-
1-[[6-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)-1-benzofuran-3-yl]methyl]piperidine-4-carboxylic acid
-
-
2-[[2-(piperidin-1-ylmethyl)-1-benzofuran-5-yl]oxy][1,3]thiazolo[4,5-b]pyridine
-
-
2-[[2-(piperidin-1-ylmethyl)-1-benzofuran-6-yl]oxy][1,3]thiazolo[4,5-b]pyridine
-
-
2-[[3-(morpholin-4-ylmethyl)-1-benzofuran-6-yl]oxy][1,3]thiazolo[4,5-b]pyridine
-
-
2-[[3-(piperidin-1-ylmethyl)-1-benzofuran-6-yl]oxy][1,3]thiazolo[4,5-b]pyridine
-
-
JNJ 26993135
-
a selective LTA4H inhibitor, leads to reduction of TH2 cytokines and mucin levels, and blocks mast cell production of LTB4 and suppresses airway hyperresponsiveness
N-(1-[[6-(1,3-benzothiazol-2-yloxy)-1-benzofuran-3-yl]methyl]piperidin-4-yl)acetamide
-
-
N-(1-[[6-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)-1-benzofuran-3-yl]methyl]piperidin-4-yl)acetamide
-
-
N-[(3-endo)-8-[[6-(1,3-benzothiazol-2-yloxy)-1-benzofuran-3-yl]methyl]-8-azabicyclo[3.2.1]oct-3-yl]acetamide
-
-
N-[(3-endo)-8-[[6-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)-1-benzofuran-3-yl]methyl]-8-azabicyclo[3.2.1]oct-3-yl]acetamide
-
-
S-[4-(dimethylamino)benzyl]-N-[(2S)-2-methyl-3-sulfanylpropanoyl]-L-cysteine
-
i.e. SA6541, a specific inhibiter of LTA4 hydrolase, that attenuates 5-lipoxygenase metabolite-induced scratching behavior, but does not affect the increase in vascular permeability caused by 5-hydroperoxyeicosatetraenoic acid, 5-HPETE, overview
[6]-gingerol
-
from ginger, [6]-gingerol suppresses anchorage-independent cancer cell growth by inhibiting LTA4H activity in mice, overview. [6]-Gingerol specifically binds with LTA4H in vitro and ex vivo
2-oxo-3-amino carboxylic esters
-
comparison of inhibition of mutant and wild-type enzymes
-
additional information
drug repurposing of histone deacetylase (HDAC) inhibitors that alleviate neutrophilic inflammation in acute lung injury and idiopathic pulmonary fibrosis via inhibiting leukotriene A4 hydrolase and blocking LTB4 biosynthesis, overview. Analysis of potential inhibitors of LTA4H across a panel of 18 HDAC inhibitors, using enzymatic assay, thermofluor assay, and X-ray crystallographic investigation. Detailed mechanisms of down-regulation of proinflammatory cytokines by SAHA or M344 are determined in vivo. Cotreatment of N-(6-(2-aminophenylamino)-6-oxyhexyl)-4-methylbenzamide and (S)-2-((2S,3R)-3-amino-2-hydroxy-4-phenylbutanamido)-4-methylpentanoic acid synergistically represses the migration of neutrophil and LTB4-induced neutrophil migration is not affected by these treatments. Molecular modeling of HDAC inhibitors against LTA4H hydrolase and aminopeptidase
-
additional information
-
drug repurposing of histone deacetylase (HDAC) inhibitors that alleviate neutrophilic inflammation in acute lung injury and idiopathic pulmonary fibrosis via inhibiting leukotriene A4 hydrolase and blocking LTB4 biosynthesis, overview. Analysis of potential inhibitors of LTA4H across a panel of 18 HDAC inhibitors, using enzymatic assay, thermofluor assay, and X-ray crystallographic investigation. Detailed mechanisms of down-regulation of proinflammatory cytokines by SAHA or M344 are determined in vivo. Cotreatment of N-(6-(2-aminophenylamino)-6-oxyhexyl)-4-methylbenzamide and (S)-2-((2S,3R)-3-amino-2-hydroxy-4-phenylbutanamido)-4-methylpentanoic acid synergistically represses the migration of neutrophil and LTB4-induced neutrophil migration is not affected by these treatments. Molecular modeling of HDAC inhibitors against LTA4H hydrolase and aminopeptidase
-
additional information
treatment with bestatin does not inhibit cell proliferation of NIH/3T3 normal mouse embryo fibroblast cells
-
additional information
-
cigarette smoke exposure acidifies the airspaces and induced localization of the LTA4H protein into the nuclei of the epithelial cells. This results in accumulation of proline-glycine-proline in the airspaces by suppressing the LTA4H aminopeptidase activity
-
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
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.00068
4-(dimethylamino)-N-[7-(hydroxyamino)-7-oxoheptyl]benzamide
Mus musculus
pH and temperature not specified in the publication
0.01
abexinostat
Mus musculus
above, pH and temperature not specified in the publication
0.01
belinostat
Mus musculus
above, pH and temperature not specified in the publication
0.01
entinostat
Mus musculus
above, pH and temperature not specified in the publication
0.01
givinostat
Mus musculus
above, pH and temperature not specified in the publication
0.01
JNJ-26481585
Mus musculus
above, pH and temperature not specified in the publication
0.01
mocetinostat
Mus musculus
above, pH and temperature not specified in the publication
0.01
N-(6-(2-aminophenylamino)-6-oxyhexyl)-4-methylbenzamide
Mus musculus
above, pH and temperature not specified in the publication
0.01
panobinostat
Mus musculus
above, pH and temperature not specified in the publication
0.01
pracinostat
Mus musculus
above, pH and temperature not specified in the publication
0.01
resminostat
Mus musculus
above, pH and temperature not specified in the publication
0.01
rocilinostat
Mus musculus
above, pH and temperature not specified in the publication
0.01
scriptaid
Mus musculus
above, pH and temperature not specified in the publication
0.00765
suberanilohydroxamic acid
Mus musculus
pH and temperature not specified in the publication
-
0.01
trichostatin A
Mus musculus
above, pH and temperature not specified in the publication
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
pI VALUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
LTA4H shows increased expression along with increased LTB4 in an azoxymethane-induced colorectal cancer (CRC) mouse model
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
physiological function
malfunction
metabolism
physiological function
additional information
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 epoxide hydrolase activity. LTA4H also has putative roles in cancer development. Enzyme LTA4H precisely controls EH activity toward LTB4 and AP activity toward PGP
physiological function
in the eicosanoid metabolic processes, leukotriene A4 hydrolase (LTA4H) is an epoxide hydrolase that catalyzes conversion of the unstable allelic epoxide leukotriene A4 (LTA4) to leukotriene B4 (LTB4), which is known to have classical biological functions including chemotaxis, endothelial adherence, and activation of leukocytes. It exerts its actions through a transmembrane protein receptor, LTB4 receptor type 1 (BLT1). The leukotriene A4 hydrolase (LTA4H) pathway plays a role in colorectal cancer (CRC). High expression of LTA4H and leukotriene B4 receptor type 1 (BLT1) are also associated with CRC survival probability
physiological function
leukotriene A4 hydrolase (LTA4H) is a key enzyme in the biosynthesis of leukotriene B4 (LTB4)
malfunction
-
enzyme inhibition blocks lung inflammation, antigen uptake by lung dendritic cells and subsequent trafficking of dendritic cells to draining lymph nodes and the lung are decreased upon enzyme inhibition
malfunction
-
the enzyme is linked to inflammation diseases, especially asthma and rheumatoid arthritis , mouse model, overview
malfunction
-
cigarette smoke exposure promotes the development of cigarette smoke-induced emphysema by suppressing the enzymatic activities of the LTA4H aminopeptidase in lung tissues
metabolism
-
LTA4H in reactive oxygen species detoxification pathways and eicosanoid biosynthetic pathways, overview
metabolism
-
the enzyme is involved in the leukotriene metabolism. In the leukotriene biosynthesis, cells expressing 5-lipoxygenase form LTA4 and transfer it to cells expressing LTA4 hydrolase or LTC4 synthase to produce LTB4 or LTC4
physiological function
-
leukotriene A4 hydrolase is involved in recruitment of both CD4+ and CD8+ T cells to inflammation sites, as well as trafficking of dendritic cells to draining lymph nodes
physiological function
-
the enzyme is involved in the leukotriene metabolism, leukotrienes are lipid mediators of inflammation formed by enzymatic oxidation of arachidonic acid
additional information
LTA4H folds into three domains and creates a deep cleft harboring the catalytic Zn2+ site, forming the active site with an L-shaped hydrophobic pocket deep into the protein
additional information
-
LTA4H folds into three domains and creates a deep cleft harboring the catalytic Zn2+ site, forming the active site with an L-shaped hydrophobic pocket deep into the protein
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_MOUSE
611
0
69051
Swiss-Prot
other Location (Reliability: 4)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
LTA4H folds into three domains and creates a deep cleft harboring the catalytic Zn2+ site, forming the active site with an L-shaped hydrophobic pocket deep into the protein
additional information
-
LTA4H folds into three domains and creates a deep cleft harboring the catalytic Zn2+ site, forming the active site with an L-shaped hydrophobic pocket deep into the protein
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
enzyme in complex with inhibitors SAHA or M344, X-ray diffraction structure determination and analysis
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
E296D
-
decrease of inhibitor potency of bestatin in comparison to wild-type enzyme, but the inhibitor potencies of alpha-oxo-beta-amino carboxylic ester, a thioamine and amino hydroxamic acid is identical for mutant and wild-type enzyme
E296N
-
decrease of inhibitor potency of bestatin in comparison to wild-type enzyme, but the inhibitor potencies of alpha-oxo-beta-amino carboxylic ester, a thioamine and amino hydroxamic acid is identical for mutant and wild-type enzyme
E296Q
-
decrease of inhibitor potency of bestatin in comparison to wild-type enzyme, but the inhibitor potencies of alpha-oxo-beta-amino carboxylic ester, a thioamine and amino hydroxamic acid is identical for mutant and wild-type enzyme
additional information
-
bone marrow cells from LTA4H-/- mice injected into 5LO-/- mice, defective for 5-lipoxygenase, restores the ability to synthesize LTB4, overview
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant enzyme, expression in Escherichia coli as a fusion protein with ten additional amino acids at the amino terminus
-
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expression in Escherichia coli as a fusion protein with ten additional amino acids at the amino terminus
-
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
LTA4H shows increased expression along with increased LTB4 in an azoxymethane-induced colorectal cancer (CRC) mouse model
the enzyme expression is upregulated in keratinocytes by 2-chloroethyl ethyl sulfide via p38MAP kinase signaling pathway, inhibition of p38 MAP kinase suppresses CEES-induced expression of LTA4 hydrolase, overview
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
drug development
Drug repurposing of histone deacetylase inhibitors that alleviate neutrophilic inflammation in acute lung injury and idiopathic pulmonary fibrosis via inhibiting leukotriene A4 hydrolase and blocking LTB4 biosynthesis
medicine
pharmacology
-
inhibition of LTA4H is a potential therapeutic strategy that can modulate key aspects of asthma
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
medicine
-
the enzyme catalyses the hydrolysis of leukotriene A4 into the proinflammatory substance leukotriene B4
medicine
-
LTA4H appears to be a promising target for development of drugs for prevention and treatment of atherosclerosis and its associated thrombotic complications
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Wetterholm, A.; Medina, J.F.; Radmark, O.; Shapiro, R.; Haeggstrm, J.Z.; Vallee, B.L.; Samuelsson, B.
Recombinant mouse leukotriene A4 hydrolase: a zinc metalloenzyme with dual enzymatic activities
Biochim. Biophys. Acta
1080
96-102
1991
Mus musculus
Ollmann, I.R.; Hogg, J.H.; Munoz, B.; Haeggstrom, J.Z.; Samuelsson, B.; Wong, C.H.
Investigation of the inhibition of leukotriene A4 hydrolase
Bioorg. Med. Chem.
3
969-995
1995
Mus musculus
Andberg, M.; Wetterholm, A.; Medina, J.F.; Haeggstrom, J.Z.
Leukotriene A4 hydrolase: a critical role of glutamic acid-296 for the binding of bestatin
Biochem. J.
345
621-625
2000
Mus musculus
-
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
Chiba, Y.; Shimada, A.; Satoh, M.; Saitoh, Y.; Kawamura, N.; Hanai, A.; Keino, H.; Ide, Y.; Shimizu, T.; Hosokawa, M.
Sensory system-predominant distribution of leukotriene A4 hydrolase and its colocalization with calretinin in the mouse nervous system
Neuroscience
141
917-927
2006
Mus musculus
Qiu, H.; Gabrielsen, A.; Agardh, H.E.; Wan, M.; Wetterholm, A.; Wong, C.H.; Hedin, U.; Swedenborg, J.; Hansson, G.K.; Samuelsson, B.; Paulsson-Berne, G.; Haeggstroem, J.Z.
Expression of 5-lipoxygenase and leukotriene A4 hydrolase in human atherosclerotic lesions correlates with symptoms of plaque instability
Proc. Natl. Acad. Sci. USA
103
8161-8166
2006
Homo sapiens, Mus musculus
Rao, N.L.; Riley, J.P.; Banie, H.; Xue, X.; Sun, B.; Crawford, S.; Lundeen, K.A.; Yu, F.; Karlsson, L.; Fourie, A.M.; Dunford, P.J.
Leukotriene A4 hydrolase inhibition attenuates allergic airway inflammation and hyperresponsiveness
Am. J. Respir. Crit. Care Med.
181
899-907
2010
Mus musculus, Mus musculus BALB/c
Tsuji, F.; Aono, H.; Tsuboi, T.; Murakami, T.; Enomoto, H.; Mizutani, K.; Inagaki, N.
Role of leukotriene B4 in 5-lipoxygenase metabolite- and allergy-induced itch-associated responses in mice
Biol. Pharm. Bull.
33
1050-1053
2010
Mus musculus
Jeong, C.H.; Bode, A.M.; Pugliese, A.; Cho, Y.Y.; Kim, H.G.; Shim, J.H.; Jeon, Y.J.; Li, H.; Jiang, H.; Dong, Z.
[6]-Gingerol suppresses colon cancer growth by targeting leukotriene A4 hydrolase
Cancer Res.
69
5584-5591
2009
Mus musculus, Homo sapiens (P09960)
Fourie, A.M.
Modulation of inflammatory disease by inhibitors of leukotriene A4 hydrolase
Curr. Opin. Investig. Drugs
10
1173-1182
2009
Homo sapiens, Mus musculus, Mus musculus C57BL/6
Zarini, S.; Gijon, M.A.; Ransome, A.E.; Murphy, R.C.; Sala, A.
Transcellular biosynthesis of cysteinyl leukotrienes in vivo during mouse peritoneal inflammation
Proc. Natl. Acad. Sci. USA
106
8296-8301
2009
Mus musculus
Black, A.T.; Joseph, L.B.; Casillas, R.P.; Heck, D.E.; Gerecke, D.R.; Sinko, P.J.; Laskin, D.L.; Laskin, J.D.
Role of MAP kinases in regulating expression of antioxidants and inflammatory mediators in mouse keratinocytes following exposure to the half mustard, 2-chloroethyl ethyl sulfide
Toxicol. Appl. Pharmacol.
245
352-360
2010
Mus musculus
Eccles, W.; Blevitt, J.M.; Booker, J.N.; Chrovian, C.C.; Crawford, S.; de Leon, A.R.; Deng, X.; Fourie, A.M.; Grice, C.A.; Herman, K.; Karlsson, L.; Kearney, A.M.; Lee-Dutra, A.; Liang, J.; Luna, R.; Pippel, D.; Rao, N.; Riley, J.P.; Santillan, A.; Savall, B.; Tanis, V.M.; Xue, X.; Young, A.L.
Identification of benzofuran central cores for the inhibition of leukotriene A4 hydrolase
Bioorg. Med. Chem. Lett.
23
811-815
2013
Homo sapiens, Mus musculus
Paige, M.; Wang, K.; Burdick, M.; Park, S.; Cha, J.; Jeffery, E.; Sherman, N.; Shim, Y.M.
Role of leukotriene A4 hydrolase aminopeptidase in the pathogenesis of emphysema
J. Immunol.
192
5059-5068
2014
Mus musculus
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)
Zhao, S.; Yao, K.; Li, D.; Liu, K.; Jin, G.; Yan, M.; Wu, Q.; Chen, H.; Shin, S.H.; Bai, R.; Wang, G.; Bode, A.M.; Dong, Z.; Guo, Z.; Dong, Z.
Inhibition of LTA4H by bestatin in human and mouse colorectal cancer
EBioMedicine
44
361-374
2019
Homo sapiens (P09960), Homo sapiens, Mus musculus (P24527), Mus musculus, Mus musculus C57BL/6J (P24527)
Lu, W.; Yao, X.; Ouyang, P.; Dong, N.; Wu, D.; Jiang, X.; Wu, Z.; Zhang, C.; Xu, Z.; Tang, Y.; Zou, S.; Liu, M.; Li, J.; Zeng, M.; Lin, P.; Cheng, F.; Huang, J.
Drug repurposing of histone deacetylase inhibitors that alleviate neutrophilic inflammation in acute lung injury and idiopathic pulmonary fibrosis via inhibiting leukotriene A4 hydrolase and blocking LTB4 biosynthesis
J. Med. Chem.
60
1817-1828
2017
Homo sapiens (P09960), Homo sapiens, Mus musculus (P24527), Mus musculus
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