1.13.11.34: arachidonate 5-lipoxygenase
This is an abbreviated version!
For detailed information about arachidonate 5-lipoxygenase, go to the full flat file.
Word Map on EC 1.13.11.34
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1.13.11.34
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cyclooxygenase
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prostaglandin
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leukocyte
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neutrophil
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eicosanoids
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cox-2
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asthma
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indomethacin
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ionophore
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phospholipase
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zileuton
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polymorphonuclear
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thromboxane
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flap
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airway
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peritoneal
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5-hete
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platelet
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eosinophil
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mast
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cysteinyl
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allergic
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edema
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12-lipoxygenase
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histamine
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lta4
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nordihydroguaiaretic
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lipoxygenases
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paf
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ndga
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bronchoconstriction
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5-hydroxyeicosatetraenoic
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asthmatic
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basophil
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platelet-activating
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anaphylaxis
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zymosan
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antigen-induced
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lipoxins
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montelukast
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hetes
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mpges-1
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carrageenan-induced
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a23187-stimulated
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paf-induced
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pro-resolving
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synthesis
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bronchospasm
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medicine
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drug development
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14carachidonic
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pharmacology
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bronchoconstrictors
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ulcerogenic
- 1.13.11.34
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cyclooxygenase
- prostaglandin
- leukocyte
- neutrophil
-
eicosanoids
- cox-2
- asthma
- indomethacin
-
ionophore
- phospholipase
- zileuton
-
polymorphonuclear
-
thromboxane
- flap
- airway
- peritoneal
-
5-hete
- platelet
-
eosinophil
-
mast
-
cysteinyl
-
allergic
- edema
-
12-lipoxygenase
- histamine
- lta4
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nordihydroguaiaretic
- lipoxygenases
- paf
- ndga
-
bronchoconstriction
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5-hydroxyeicosatetraenoic
-
asthmatic
-
basophil
-
platelet-activating
- anaphylaxis
- zymosan
-
antigen-induced
-
lipoxins
- montelukast
-
hetes
- mpges-1
-
carrageenan-induced
-
a23187-stimulated
-
paf-induced
-
pro-resolving
- synthesis
- bronchospasm
- medicine
- drug development
-
14carachidonic
- pharmacology
-
bronchoconstrictors
-
ulcerogenic
Reaction
Synonyms
5-lipoxygenase, 5-LO, 5-LO1, 5-LOX, 5DELTA-lipoxygenase, 5LO, 5LOX-1, ALOX5, arachidonate 5-LO, arachidonate:oxygen oxidoreductase, arachidonic 5-lipoxygenase, arachidonic acid 5-lipoxygenase, C-5-lipoxygenase, DELTA5-lipoxygenase, H5-LO, leukotriene A4 synthase, leukotriene-A4 synthase, lipoxygenase 15, lipoxygenase 5, lipoxygenase-1, LO-1, LOX-15, LOX-5, LTA synthase, LTA4 synthase, oxygenase, arachidonate, 5-lip-, PMNL 5-lipoxygenase
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General Information
General Information on EC 1.13.11.34 - arachidonate 5-lipoxygenase
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malfunction
metabolism
physiological function
additional information
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5-LO-/- infected with Trypanosoma cruzi, are more susceptible than C57BL/6 and wild-type 129Sv, showing higher parasitemia and mortality
malfunction
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blockade of 5-LOX signaling results in downregulation of cyclin D1, matrix metalloproteinase (MMP-7, -9), urokinase plasminogen activator and its receptor, and pro-apoptotic proteins
malfunction
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Trypanosoma cruzi infection in mice deficient in 5-lipoxygenase (5-LO) results in transiently increased parasitemia, and improved survival rate compared with wild type mice. Myocardia from 5-LO-deficient mice exhibit reduced inflammation, collagen deposition, and migration of CD4+, CD8+, and interferon-gamma-producer cells compared with wild type littermates. Moreover, decreased amounts of tumor necrosis factor-alpha, interferon-gamma, and nitric oxide synthase are found in the hearts of 5-LO-deficient mice
malfunction
a protein isoform of human 5-LO that lacks exon 4, termed 5-LODELTA4, lacks canonical enzymatic activity as it misses the non-heme iron but it still retains ATP-binding affinity. The enzyme mutant 5-LODELTA4 stimulates wild-type 5-LO activity and product formation at low protein concentrations
malfunction
catalytically inactive mutant 5-LODELTA13, lacking exon 13, inhibits 5-LO product biosynthesis when co-expressed with active wild-type 5-LO1. Mutant 5-LODELTA13 inhibits leukotriene but not 5-hydroxyeicosatetraenoic acid (5-HETE) biosynthesis. This inhibition is independent of 5-LODELTA13-FLAP interactions since it occurs in cells expressing FLAP or not. Mutant 5-LODELTA13 is hyperphosphorylated on S523 and S273 compared to wild-type 5-LO1
malfunction
in 5-LO/FLAP-transfected HeLa cells, treatment with the thiol-oxidizing agent diamide which promotes glutathionylation at surface Cys residues leads to a decreased leukotriene synthesis by wild-type 5-LO
malfunction
the naturally occuring mutant 5-LO catalytically inactive isoforms 5-LODELTA13, 5-LODELTA4 and 5-LOp12, lacking the exons 13, 4 or a part of exon 12, respectively, are identified in B and T cell lines as well as in primary B and T cells and monocytes. Wild-type 5-LO is localized in the nucleus whereas all natural mutant isoforms are located in the cytosol. Coexpression of the truncated natural isoforms inhibits or stimulates 5-LO wild-type expression in transiently and stably transfected HEK-293T cells suggesting that the isoforms have other functions than canonical leukotriene biosynthesis. Detection of alternatively spliced 5-LO transcripts in primary monocytes of patients with rheumatoid arthritis and sepsis
metabolism
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5-lipoxygenase is involved in the production of matrix metalloproteinase-9
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5-lipoxygenase products may not only play a major role in controlling heart tissue parasitism, i.e., host resistance to acute infection with Trypanosoma cruzi in vivo, but in the event of an infection also play an important part in erythrocyte oxidative stress, an NO-dependent effect. 5-lipoxygenase metabolites increase lipid peroxidation levels in erythrocytes during the early phase of murine Trypanosoma cruzi infection, but do not participate in the development of anemia, thrombocytopenia or leukopenia in Trypanosoma cruzi-infected mice
physiological function
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5-lipoxygenase-derived lipid hydroperoxide is responsible for endogenous DNA-adduct formation. 5-lipoxygenase is responsible for the generation of the heptanone-etheno-2'-deoxyguanosine DNA-adduct in CESS cells
physiological function
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5-lipoxygenase/5-lipoxygenase activating protein interaction, which may serve as a feed-back control point for leukotriene C4 biosynthesis
physiological function
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catalyzes two steps in biosynthesis of leukotrienes, a group of lipid mediators of inflammation derived from arachidonic acid, which are used as antagonists in treatment of asthma. A potential role also in atherosclerosis
physiological function
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role of the 5-lipoxygenase pathway in B cells before the cells finally differentiate to plasma cells
physiological function
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5-lipoxygenase is a key determinant of acute myocardial inflammation and mortality during Trypanosoma cruzi infection
physiological function
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5-lipoxygenase plays a pivotal role in atherogenesis and is involved in plaque stability
physiological function
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5-LO products significantly contribute to tumour cell proliferation
physiological function
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activation of 5-LOX modulates the G1/S phase transition regulatory proteins and causes cell proliferation
physiological function
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several arachidonic acid metabolites formed via the 5-LO pathway (5-HETE, 5-oxo-ETE, leukotriene B4, leukotriene D4) can promote proliferationof cancer cells
physiological function
5-lipoxygenase (5-LOX) is the key player of pro-inflammatory leukotriene biosynthesis. Its regulatory or socalled PLAT (polycystin-1, lipoxygenase, alpha-toxin) domain binds allosteric modulators like calcium, membranes, coactosin-like protein and Dicer, thereby influencing 5-LOX activity at the nuclearmembrane by mediating translocation. The PLAT domain may also regulate cytosolic 5-LOX activity and possibly influence microRNA metabolism
physiological function
5-lipoxygenase enzyme catalyzes the initial steps in the biosynthesis of pro-inflammatory leukotrienes
physiological function
5-lipoxygenase is implicated in the pathogenesis of inflammatory and immune diseases
physiological function
being a mobile enzyme, 5-LO migrates from the cytosol to the nuclear envelope where it is believed to interact with 5-lipoxygenase-activating protein (FLAP) and receives the substrate arachidonic acid. Enzyme 5-LO is prone to redox regulation in the cell, e.g. 5-LO inhibition by glutathione peroxidase (GPX) 1 and 4
physiological function
changes in 5-LOX activator ATP concentration in the cell can affect the production of 5-LOX products, such as leukotrienes and lipoxins, and thus have wide implications for the regulation of cellular inflammation. The enzyme is involved in the synthesis of leukotrienes B4 and A4, important metabolites of the regulation of inflammation. 5-LOX catalytic activity is regulated through several mechanisms by the cell. 5-LOX is recruited to the nuclear membrane upon cellular Ca2+ influx. Calcium binds to allosteric sites in the 5-LOX N-terminal polycystin-1/lipoxygenase/alpha-toxin (PLAT) domain, promoting attachment to the membrane via conserved tryptophan residues that embed into the lipid bilayer
physiological function
human 5-lipoxygenase (5-LOX) is responsible for the formation of leukotriene (LT)A4, a pivotal intermediate in the biosynthesis of the leukotrienes, a family of proinflammatory lipid mediator. Role of active site residues F421, Q363 and L368 in regulating the donor-acceptor distances, thus affecting H-transfer as well as regiospecificity of the enzyme reaction, the H-abstraction is the rate limiting step for 5-LOX and the observed KIE of 5-LOX is masked by a change in regioselectivity
physiological function
leukotrienes are inflammatory mediators that play a pivotal role in many diseases like asthma bronchiale, atherosclerosis and in various types of cancer. The key enzyme for generation of leukotrienes is the 5-lipoxygenase, 5-LO, that catalyzes the initial steps in the conversion of arachidonate to the instable epoxide leukotriene A4 (LTA4) via the intermediate 5(S)-hydroperoxy-6,8,11,14-(E,Z,Z,Z)-eicosatetraenoic acid (5-HpETE). LTA4 can then be metabolized by the LTA4 hydrolase to the potent chemoattractant and leukocyte activator LTB4 or conjugated with glutathione to the cysteinyl leukotriene LTC4 by LTC4 synthase
physiological function
leukotrienes biosynthesis is initiated by the action of 5-LOX at the level of nuclear membrane and the mechanism of enzyme-membrane interaction is thought to involve structural flexibility and conformational changes at the level of the protein tertiary structure. The conformational change between the apo- and holo-5-LOX might contribute in vivo to the 5-LOX trafficking among different compartments of the cell, thus leading to a modulation of its signaling
physiological function
the 5-LO-derived leukotriene A4, LTA4, can be converted by the action of platelet 12-lipoxygenase (12-LO) to lipoxin A4 (LXA4), which exerts potent anti-inflammatory activities and vascular bed-dependent vasodilatory actions. Dietary plant sterols, beta-sitosterol, campesterol, and stigmasterol, in the combination used, can alleviate lipid peroxidation and inflammatory events in vivo. These effects are possibly exerted via the modulation of myeloperoxidase, 5-lipoxygenase, and 12-lipoxygenase activities
physiological function
the enzyme initiates the synthesis of pro-inflammatory leukotrienes and catalyze the peroxidation of polyunsaturated fatty acids
modeling of the active conformation of human 5-LOX, overview
additional information
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modeling of the active conformation of human 5-LOX, overview
additional information
molecular dynamics simulations the conformational changes induced by iron removal in 5-LOX, overview. The degree of enzyme flexibility is related to the presence of iron into the active site that is able to stabilize the protein increasing its rigidity, structure modeling based on the crystal structure at 2.4 A resolution, overview
additional information
structure-function analysis, overview. 5-LOX reveals a fully encapsulated active site, amino acid residue Phe177 plays a critical role in providing a fully functional active site, it shields the active site in the absence of substrate serving as the active site portal. Role for His600, deep in the elongated cavity, in positioning the substrate for catalysis
additional information
the ability of the isolated PLAT domain to bind Dicer C-terminus whereas the interaction with coactosin-like protein requires the interplay of the catalytic and the PLAT domain
additional information
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the ability of the isolated PLAT domain to bind Dicer C-terminus whereas the interaction with coactosin-like protein requires the interplay of the catalytic and the PLAT domain
additional information
the active site of 5-LOX contains a nonheme Fe2+ ion coordinated by three polar histidines H372, H550, and H367, the carbonyl group of N554, the carboxylic group of the C-terminal I673, and a water molecule, modeling of the active site of 5-LOX. A hydrophobic cleft formed by nonpolar amino acids L414, I415, L368, L607, L420, F421, F177, A424, A410, A603, V604, and P569 can also play an important role in orientation of ligands in the active site of 5-LOX