3.3.2.6: leukotriene-A4 hydrolase
This is an abbreviated version!
For detailed information about leukotriene-A4 hydrolase, go to the full flat file.
Word Map on EC 3.3.2.6
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3.3.2.6
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5-lipoxygenase
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arachidonic
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epoxide
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medicine
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leukocyte
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asthma
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bestatin
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chemoattractant
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eicosanoids
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metalloenzyme
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flap
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ionophore
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alox5ap
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tuberculous
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transcellular
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5-lipoxygenase-activating
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aminopeptidases
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captopril
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lipoxins
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pro-gly-pro
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montelukast
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proline-glycine-proline
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5-hete
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zileuton
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diagnostics
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pharmacology
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drug development
- 3.3.2.6
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5-lipoxygenase
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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
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5-hete
- zileuton
- diagnostics
- pharmacology
- drug development
Reaction
Synonyms
EH, epoxide hydrolase, hydrolase, leukotriene A4, leukotriene A(4) hydrolase, leukotriene A4 hydrolase, leukotriene A4 hydrolase/aminopeptidase, leukotriene hydrolase A4, leukotriene-A4 hydrolase, leukotriene-A4-hydrolase, LT A4 hydrolase, LTA-4 hydrolase, LTA4 hydrolase, LTA4-h, LTA4H, More
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General Information
General Information on EC 3.3.2.6 - leukotriene-A4 hydrolase
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malfunction
metabolism
physiological function
additional information
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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
increase of leukotriene synthesis in spinal microglia produced via p38 MAPK plays a role in the generation of neuropathic pain
malfunction
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the enzyme is linked to inflammation diseases, especially asthma and also rheumatoid arthritis, significant role for LTB4 production in the pathogenesis of asthma, overview. LTB4 and BLT1 may be involved in the steroid resistance experienced by some patients with asthma
malfunction
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the enzyme is linked to inflammation diseases, especially asthma and rheumatoid arthritis , mouse model, overview
malfunction
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cigarette smoke exposure promotes the development of cigarette smoke-induced emphysema by suppressing the enzymatic activities of the LTA4H aminopeptidase in lung tissues
malfunction
leukotriene A4 hydrolase (LTA4H) regulates the balance between the anti-inflammatory lipoxins and pro-inflammatory leukotriene B4, with direct implications in tuberculosis-driven inflammation. In humans, a single nucleotide polymorphism in the LTA4H promoter which regulates its transcriptional activity (rs17525495) is identified and described to impact clinical severity of tuberculosis presentation and response to corticosteroid therapy. A higher incidence of severe tuberculosis-associated immune reconstitution inflammatorysyndrome among patients with mutant LTA4H genotypes is observed compared to the wild type, despite similar incidence of tuberculosis-associated immune reconstitution inflammatory syndrome and similar immune restoration in both groups. Steroids are effective in alleviating IRIS in all the genotypes
malfunction
imbalances in leukotriene B4 synthesis are related to several pathologic conditions
malfunction
inhibition of the LTB4 conversion ameliorates inflammation and leads to accumulation of pro-resolving Lipoxin A4 (LXA4) while inhibition of PGP degradation potentiates neutrophilic inflammation
malfunction
knocking out LTA4H significantly reduces skin cancer development in the 7,12-dimethylbenz(a)anthracene (DMBA)-initiated/12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted two-stage skin cancer mouse model. LTA4H depletion dramatically decreases anchorage-dependent and -independent skin cancer cell growth by inducing cell cycle arrest at the G0/G1 phase. Depletion of LTA4H enhances p27 protein stability, which is associated with decreased phosphorylation of CDK2 at Thr160 and inhibition of the CDK2/cyclin E complex, resulting in down-regulated p27 ubiquitination. Cell phenotypes, overview
malfunction
LTB4 levels are persistently elevated in bronchoalveolar lavage fluid (BALF) of lipopolysaccharide (LPS)-induced ALI, and the leukotriene levels in pulmonary edema fluid are significantly higher in ALI patients compared to control patients with hydrostatic pulmonary edema. In addition, LTB4 level is increased in lung homogenates, and BALF of patients with IPF and the level of LTB4 correlate with the extent of fibrosis in histological sections
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
malfunction
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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
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malfunction
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the enzyme is linked to inflammation diseases, especially asthma and rheumatoid arthritis , mouse model, overview
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leukotriene A4 hydrolase catalyzes the final step in the synthesis of leukotriene B4, LTB4, a potent chemoattractant and proinflammatory eicosanoid
metabolism
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leukotriene A4 hydrolase catalyzes the final step in the synthesis of leukotriene B4, LTB4, a potent chemoattractant and proinflammatory eicosanoid
metabolism
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leukotriene A4 hydrolase is a key enzyme in the leukotriene pathway, which hydrolyzes leukotriene A4 to leukotriene B4, a proinflammatory mediator
metabolism
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LTA4H catalyzes the last step in the synthesis of the pro-inflammatory molecule leukotriene B4
metabolism
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LTA4H catalyzes the last step in the synthesis of the pro-inflammatory molecule leukotriene B4
metabolism
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LTA4H catalyzes the last step in the synthesis of the pro-inflammatory molecule leukotriene B4
metabolism
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LTA4H in reactive oxygen species detoxification pathways and eicosanoid biosynthetic pathways, overview
metabolism
LTA4H is a key enzyme in the leukotriene pathway, which catalyzes the final and rate-determining step in the synthesis of LTB4
metabolism
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no difference in LTA4 hydrolase expression in patients with naturally occurring allergic rhinitis compared to controls, suggesting that LTB4 is less important chronically or that LTA4 hydrolase is not the rate-limiting step in its synthesis
metabolism
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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
metabolism
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the enzyme takes part in the pathway for the conversion of arachidonic acid to eicosanoids, overview
metabolism
leukotriene A4 hydrolase participates in the metabolism of lipid mediators and peptides
metabolism
the enzyme catalyzes the final rate-limiting step in the biosynthesis of leukotriene B4
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
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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
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leukotrienes are involved in antiinflammation via eicosanoids, lipid mediators derived from arachidonic acid including the proinflammatory leukotrienes as well as the anti-inflammatory lipoxins, complex interplay between proinflammatory leukotrienes and antiinflammatory lipoxins. The enzyme is important in the balance between proinflammatory and anti-inflammatory responses in tuberculosis
physiological function
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the enzyme is involved in the leukotriene metabolism, leukotrienes are lipid mediators of inflammation formed by enzymatic oxidation of arachidonic acid
physiological function
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the correlations between leukotriene B4 and the enzyme have significance on resistance and development of arthritis
physiological function
leukotriene A4 hydrolase (LTA4H) regulates the balance between the anti-inflammatory lipoxins and pro-inflammatory leukotriene B4, with direct implications in tuberculosis-driven inflammation. In humans, a single nucleotide polymorphism in the LTA4H promoter which regulates its transcriptional activity (rs17525495) is identified and described to impact clinical severity of tuberculosis presentation and response to corticosteroid therapy. A higher incidence of severe tuberculosis-associated immune reconstitution inflammatorysyndrome among patients with mutant LTA4H genotypes is observed compared to the wild type, despite similar incidence of tuberculosis-associated immune reconstitution inflammatory syndrome and similar immune restoration in both groups. Steroids are effective in alleviating IRIS in all the genotypes
physiological function
ELR1 CXC chemokines (e.g. interleukin-8) bind to CXCR1 and CXCR2 receptors expressed on neutrophils, and attract them to sites of inflammation. Ensuing degradation of collagen by neutrophil-derived proteases generates many tripeptide proline-glycine-proline (PGP) peptides that mimic key sequences found in ELR1 CXC chemokines, and act as a potent neutrophil chemoattractant. Extracellular leukotriene (LT) A4 hydrolase (LTA4H) degrades PGP and resolves neutrophilic inflammation, whereas intracellular epoxide hydrolase function (EC 3.3.2.10) of the same enzyme converts LTA4 to LTB4. LTB4 is a proinflammatory lipid mediator capable of recruiting and activating an array of cells, including neutrophils. The intracellular activity of LTA4H within leukocytes can generate the lipid mediator LTB4 that can also promote neutrophil recruitment by binding to LTB4 receptor (BLT1).Thus, LTA4H exhibits opposing pro- and anti-inflammatory roles that govern neutrophil recruitment. Cigarette smoke disrupts leukotriene (LT) A4 hydrolase (LTA4H)-mediated resolution of pulmonary neutrophilic inflammation. In response to infection or injury, resident cells within the lung will release chemoattractants that will promote neutrophil recruitment from the vasculature and into the tissue. Epithelial cells and alveolar macrophages, for example, may release IL-8 that will bind to CXCR1/2 on the surface of the neutrophil and promote recruitment. Cigarette smoke chemically acetylates PGP, enhancing its chemotactic activity and protecting it from degradation by LTA4H. Second, biochemical and preliminary murine studies suggest that cigarette smoke can selectively abrogate the peptidase activity of LTA4H, with minimal effect on the hydrolase activity. Thus, cigarette smoke pushes LTA4H toward a uniquely proinflammatory phenotype, whereby LTB4 and PGP together induce increased pulmonary neutrophilic inflammation. Acrolein in cigarette smoke in part inhibits LTA4H peptidase activity. Acrolein, derived from cigarette smoke or physiologically during inflammation (lipid peroxidation, metabolism of threonine or spermine), can inhibit LTA4H-mediated degradation of PGP, allowing the peptide to accumulate and maintain neutrophilic inflammation. LTA4H enzyme inhibitors may fail to distinguish between the opposing activities of the enzyme, and could inadvertently lead to persistent neutrophilia
physiological function
enzyme leukotriene A4 hydrolase (LTA4H) is a bifunctional enzyme with epoxide hydrolase (EH) and aminopeptidase (AP) activities
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
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
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
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. High expression of LTA4H and BLT1 negatively correlate with CRC patient survival probability
physiological function
leukotriene A4 hydrolase (LTA4H) is a bifunctional enzyme that exhibits LTA4H and aminopeptidase activities, it is a key enzyme in the biosynthesis of leukotriene B4 (LTB4). LTA4H is well-known to regulate chemotactic activity of human neutrophils. LTB4 is secreted by neutrophils at inflammation sites in response to formyl peptides, playing an important role in neutrophil activation and migration to formyl peptides
physiological function
leukotriene A4 hydrolase (LTA4H) is a bifunctional zinc metalloenzyme overexpressed in several human cancers. LTA4H regulates cell cycle and skin carcinogenesis. LTA4H is a key modulator of cell cycle through its negative effect on p27 expression. LTA4H mediates the G0/G1 cell cycle phase through p27 proteasome degradation and is is implicated in cell growth, cell cycle distribution. LTA4H mediates p27 stability through LTB4/BLT1 pathway. LTA4H and BLT1 influence the formation of the CDK2/cyclin E complex and the phosphorylation of CDK2 at Thr160
physiological function
leukotriene A4 hydrolase (LTA4H) is a key enzyme in the biosynthesis of leukotriene B4 (LTB4)
physiological function
leukotriene A4 hydrolase is a soluble enzyme with epoxide hydrolase and aminopeptidase activities catalysing the conversion of leukotriene A4 to leukotriene B4 and the hydrolysis of the peptide proline-glycine-proline. Bifunctional LTA4H shows two catalytic activities, aminopeptidase activity hydrolysing the tripeptide proline-glycine-proline (PGP), and epoxide hydrolase activity on leukotriene A4 (LTA4) generating leukotriene B4 (LTB4), a potent inducer of macrophage, T-lymphocyte and neutrophil chemotaxis
physiological function
the human leukotriene A4 hydrolase (LTA4H) is a 69 kDa protein involved in the arachidonic acid cascade. LTA4H converts leukotriene A4 (LTA4) into leukotriene B4 (LTB4).1 LTB4 triggers the adhesion and aggregation of leukocytes in the endothelium2 and acts as an attractant for different leukocytes (monocytes, neutrophils, macrophages, and dendritic cells). The overproduction of LTB4 has been associated with different pathological conditions and diseases. The leukotriene A4 hydrolase (LTA4H) is a bifunctional enzyme, containing a peptidase and a hydrolase activity both activities having opposing functions regulating inflammatory response. The hydrolase activity is responsible for the conversion of leukotriene A4 to pro-inflammatory leukotriene B4
physiological function
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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
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physiological function
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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
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HIV-1 transforms the monocyte plasma membrane proteome including also cytosolic LTA4H, the process is linked to cell viability, overview
additional information
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protection from both tuberculosis and multibacillary leprosy is associated with heterozygosity for LTA4H polymorphisms
additional information
binding pocket of the apo LTA4H protein (PDB entry 5FWQ) with bound Zn2+, overview
additional information
enzyme residues E271, D375, Arg563, and Lys555 are involved in enzyme-substrate interactions
additional information
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enzyme residues E271, D375, Arg563, and Lys555 are involved in enzyme-substrate interactions
additional information
eosinophils express LTA4 hydrolase and release LTB4. In addition to neutrophils, epithelial cells, and certain phagocytes, eosinophils are classified as contributors to the generation of the inflammatory mediator LTB4. Leukotriene B4 (LTB4) is a potent neutrophil chemoattractant, and this mediator might be an alternative to the Th17 axis as a potential mechanism leading to airway neutrophils. The enzyme might play a role in asthma
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
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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
additional information
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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
the enzyme has two catalytic pockets, a hydrophobic domain that recognizes the lipophilic hydrocarbon chain of LTA4 and a hydrophilic domain that recognizes the N-terminal region of PGP. Both domains converge in a common catalytic zone where the carboxylate group of each substrate interacts with alkaline amino acids in the protein. Thus, different catalytic pockets for separate activities share a carboxylate group recognition zone