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Literature summary for 3.3.2.6 extracted from
- Leukotriene A4 hydrolase an emerging target of natural products for cancer chemoprevention and chemotherapy (2018), Ann. N. Y. Acad. Sci., 1431, 3-13 .
Application
| Application | Comment | Organism |
|---|---|---|
| drug development | development of LTA4H inhibitors in cancer prevention and therapy | Homo sapiens |
Crystallization (Commentary)
| Crystallization (Comment) | Organism |
|---|---|
| crystal structure determination | Homo sapiens |
Protein Variants
| Protein Variants | Comment | Organism |
|---|---|---|
| additional information | mutations of residues Glu271 and Glu296, as well as Asp375 are critical for LTA4H enzymatic activity | Homo sapiens |
Inhibitors
| Inhibitors | Comment | Organism | Structure |
|---|---|---|---|
| 1-([4-[(1,3-benzothiazol-2-yl)oxy]phenyl]methyl)piperidine-4-carboxylic acid | i.e. JNJ-26993135 | Homo sapiens |  |
| 4'-O-prenyl-[6]-gingerol | - |
Homo sapiens | |
| 4-(4-benzylphenyl)-1,3-thiazol-2-amine | i.e. ARM1 | Homo sapiens | |
| 4-[(2R)-2-[[4-(4-chlorophenoxy)phenoxy]methyl]pyrrolidin-1-yl]butanoic acid | i.e. DG051 | Homo sapiens | |
| bestatin | isolated from Streptomyces olivoreticuli, a general AP inhibitor, inhibits LTB4 biosynthesis. Treatment with bestatin inhibits cell proliferation of lung carcinoma A549 cells by significantly reducing LTA4H activity | Homo sapiens | |
| bestatin | isolated from Streptomyces olivoreticuli, a general AP inhibitor, inhibits LTB4 biosynthesis. Following a short-term intraperitoneal treatment with 10 mg/kg bestatin, LTB4 biosynthesis in the esophagoduodenal junction is significantly suppressed in rats treated with EGDA compared to that in the untreated group, in an esophagogastroduodenal anastomosis (EGDA) surgical model. Bestatin inhibits LTA4H/LTB4 activation and reduces tumorigenesis in EGDA rats | Rattus norvegicus | |
| diacetyl-[6]-gingerol | - |
Homo sapiens | |
| JNJ-26993135 | shows selective inhibition of LTB4 biosynthesis in a murine model, suggesting a potent compound targeting LTA4H | Mus musculus | |
| methyl shogoal | a [6]-gingerol derivative | Homo sapiens | |
| additional information | tosedostat, or CHR-2797 shows inhibition of the aminopeptidase activity. [6]-Gingerol and derivatives show chemopreventive effects and selective cytotoxicity toward HCT-116 cells but not toward healthy cells | Homo sapiens | |
| additional information | treatment with bestatin does not inhibit cell proliferation of NIH/3T3 normal mouse embryo fibroblast cells | Mus musculus | |
| N-[3-(4-benzylphenoxy)propyl]-N-methyl-beta-alanine | i.e. SC-57461A | Homo sapiens | |
| resveratrol | binds directly to LTA4H and inhibits its activity. The antiproliferative effect of resveratrol is decreased in LTA4H mRNA knockdown cells, LTA4H is a direct target of resveratrol | Homo sapiens | |
| SA6541 | inhibits LTA4H activation | Homo sapiens | |
| sulindac sulfide | reduces LTA4H activity in HT29 CRC cells, thus lowering LTB4 levels and decreasing HT29 cell viability | Homo sapiens | |
| [10]-gingerol | - |
Homo sapiens | |
| [6]-gingerol | - |
Homo sapiens | |
Localization
| Localization | Comment | Organism | GeneOntology No. | Textmining |
|---|---|---|---|---|
| cytosol | - |
Rattus norvegicus | 5829 | - |
| cytosol | - |
Homo sapiens | 5829 | - |
Natural Substrates/ Products (Substrates)
| Natural Substrates | Organism | Comment (Nat. Sub.) | Natural Products | Comment (Nat. Pro.) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| leukotriene A4 + H2O | Rattus norvegicus | - |
leukotriene B4 | - |
? | |
| leukotriene A4 + H2O | Homo sapiens | - |
leukotriene B4 | - |
? | |
| leukotriene A4 + H2O | Mus musculus | - |
leukotriene B4 | - |
? | |
Organism
| Organism | UniProt | Comment | Textmining |
|---|---|---|---|
| Homo sapiens | P09960 | - |
- |
| Mus musculus | P24527 | - |
- |
| Rattus norvegicus | P30349 | - |
- |
Purification (Commentary)
| Purification (Comment) | Organism |
|---|---|
| enzyme monomer from leukocytes | Homo sapiens |
Source Tissue
| Source Tissue | Comment | Organism | Textmining |
|---|---|---|---|
| A-549 cell | - |
Homo sapiens | - |
| adenocarcinoma cell | human esophageal adenocarcinoma cell (EAC) and adjacent nontumor esophageal tissues reveal overexpression of LTA4H in EAC tissues compared to that in nontumor samples | Homo sapiens | - |
| colorectal cancer cell | - |
Homo sapiens | - |
| colorectal cancer cell | LTA4H shows increased expression along with increased LTB4 in an azoxymethane-induced colorectal cancer (CRC) mouse model | Mus musculus | - |
| duodenum | - |
Rattus norvegicus | - |
| embryonic fibroblast | - |
Mus musculus | - |
| endothelial cell | - |
Homo sapiens | - |
| erythrocyte | - |
Homo sapiens | - |
| esophageal adenocarcinoma cell | - |
Rattus norvegicus | - |
| fibroblast | - |
Mus musculus | - |
| glioma cell | - |
Homo sapiens | - |
| HCT-116 cell | - |
Homo sapiens | - |
| HT-29 cell | - |
Homo sapiens | - |
| leukocyte | - |
Homo sapiens | - |
| additional information | 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 | Rattus norvegicus | - |
| additional information | LTA4H is overexpressed in several other human cancers, particularly lung adenocarcinoma, adenosquamous carcinoma, bronchioalveolar carcinoma, large cell carcinoma, thyroid adenocarcinoma, and gall bladder adenocarcinoma | Homo sapiens | - |
| neuroblastoma cell | - |
Homo sapiens | - |
| neutrophil | - |
Homo sapiens | - |
| neutrophil | - |
Mus musculus | - |
| non-Hodgkin lymphoma cell | upregulation of LTA4H expression in primary effusion lymphoma, which is a rare HIV-associated non-Hodgkin B cell lymphoma | Homo sapiens | - |
Substrates and Products (Substrate)
| Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| leukotriene A4 + H2O | - |
Rattus norvegicus | leukotriene B4 | - |
? | |
| leukotriene A4 + H2O | - |
Homo sapiens | leukotriene B4 | - |
? | |
| leukotriene A4 + H2O | - |
Mus musculus | leukotriene B4 | - |
? | |
| additional information | proline-glycine-proline (PGP) is a substrate for the enzyme's aminopeptidase (AP) activity | Rattus norvegicus | ? | - |
? | |
| additional information | proline-glycine-proline (PGP) is a substrate for the enzyme's aminopeptidase (AP) activity | Homo sapiens | ? | - |
? | |
Subunits
| Subunits | Comment | Organism |
|---|---|---|
| monomer | - |
Homo sapiens |
Synonyms
| Synonyms | Comment | Organism |
|---|---|---|
| EH | - |
Rattus norvegicus |
| EH | - |
Homo sapiens |
| EH | - |
Mus musculus |
| epoxide hydrolase | - |
Rattus norvegicus |
| epoxide hydrolase | - |
Homo sapiens |
| epoxide hydrolase | - |
Mus musculus |
| leukotriene A4 hydrolase | - |
Rattus norvegicus |
| leukotriene A4 hydrolase | - |
Homo sapiens |
| leukotriene A4 hydrolase | - |
Mus musculus |
| LTA4H | - |
Rattus norvegicus |
| LTA4H | - |
Homo sapiens |
| LTA4H | - |
Mus musculus |
IC50 Value
| IC50 Value | IC50 Value Maximum | Comment | Organism | Inhibitor | Structure |
|---|---|---|---|---|---|
| 0.000011 | - |
pH and temperature not specified in the publication | Homo sapiens | 1-([4-[(1,3-benzothiazol-2-yl)oxy]phenyl]methyl)piperidine-4-carboxylic acid | |
| 0.000025 | - |
pH and temperature not specified in the publication | Homo sapiens | N-[3-(4-benzylphenoxy)propyl]-N-methyl-beta-alanine | |
| 0.000047 | - |
pH and temperature not specified in the publication | Homo sapiens | 4-[(2R)-2-[[4-(4-chlorophenoxy)phenoxy]methyl]pyrrolidin-1-yl]butanoic acid | |
| 0.0005 | - |
pH and temperature not specified in the publication | Homo sapiens | 4-(4-benzylphenyl)-1,3-thiazol-2-amine | |
Expression
| Organism | Comment | Expression |
|---|---|---|
| Homo sapiens | human esophageal adenocarcinoma cell (EAC) and adjacent nontumor esophageal tissues reveal overexpression of LTA4H in EAC tissues compared to that in nontumor samples. LTA4H is overexpressed in several other human cancers, particularly lung adenocarcinoma, adenosquamous carcinoma, bronchioalveolar carcinoma, large cell carcinoma, thyroid adenocarcinoma, and gall bladder adenocarcinoma. Upregulation of LTA4H expression in primary effusion lymphoma, which is a rare HIV-associated non-Hodgkin B cell lymphoma | up |
| Rattus norvegicus | 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 | up |
| Mus musculus | LTA4H shows increased expression along with increased LTB4 in an azoxymethane-induced colorectal cancer (CRC) mouse model | up |
General Information
| General Information | Comment | Organism |
|---|---|---|
| malfunction | silencing of LTA4H translation by shRNA in HCT116 human colorectal carcinoma cells suppresses cell growth, stimulation of the aminopeptidase (AP) activity of LTA4H enhanced colony formation in HCT116 cells, indicating that LTA4H activity is associated with the malignant potential of CRC cells | Homo sapiens |
| metabolism | the enzyme is involved in the LTA4H/LTB4 biosynthesis pathway, overview. 5-Lipoxygenase catalyzes the conversion of to (5S)-hydroperoxy-6-trans-8,11,14-cis-eicosatetraenoic (5-HpETE) to LTA4 in the presence of 5-lipoxygenase-activating protein (FLAP). LTA4 is unstable and hydrolyzes to LTB4 by LTA4H. LTB4 then activates the G protein-coupled receptors BLT1 and BLT2. Biosynthesis of LTB4 typically occurs in a cell that expresses both 5-LOX and LTA4H. LTA4H is expressed in cells and tissues without 5-LOX activity, indicating that they cannot produce the substrate for LTA4H, such as in erythrocytes and endothelial cells. LTB4 biosynthesis pathway and cancer development, overview | Homo sapiens |
| 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 | Rattus norvegicus |
| 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. An increased level of leukotriene B4 (LTB4), which is biosynthesized by leukotriene A4 hydrolase (LTA4H), is implicated in several types of cancer, including colon and prostate cancer. LTB4 is formed from an unstable intermediate, leukotriene A4 (LTA4). The aminopeptidase activity substrate proline-glycine-proline (PGP) generated from collagen acts as a proinflammatory factor by neutrophilic chemotaxis. Enzyme LTA4H precisely controls EH activity toward LTB4 and AP activity toward PGP | Homo sapiens |
| 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 | Mus musculus |
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