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evolution
gene ALOX15 encodes for human 15-LOX type 1 and murine 12/15-LOX. Although the encoded enzymes display slightly different specificities (15- versus 12-lipoxygenating activity), these proteins represent evolutionary and functionally closely-related enzymes that share a high degree of sequence similarity. Of note, these 12/15LOXs that are encoded by the ALOX15 genes have separated from other LOXs early during evolution, although they share close biochemical properties with other LOXs such as ALOX12 or ALOX15B
evolution
gene ALOX15 encodes for human 15-LOX type 1 and murine 12/15-LOX. Although the encoded enzymes display slightly different specificities (15- versus 12-lipoxygenating activity), these proteins represent evolutionary and functionally closely-related enzymes that share a high degree of sequence similarity. Of note, these 12/15LOXs that are encoded by the ALOX15 genes have separated from other LOXs early during evolution, although they share close biochemical properties with other LOXs such as ALOX12 or ALOX15B
evolution
LOX isozymes and classification systems, overview
evolution
LOX isozymes and classification systems, overview
evolution
LOX isozymes and classification systems, overview
evolution
LOX isozymes and classification systems, overview
evolution
mammals (mice, rats, pigs) express 12-lipoxygenating ALOX15 orthologues. 15-lipoxygenating isoforms are found in primates (orangutans, humans), suggesting an evolution of ALOX15 specificity. Other primates (baboons, rhesus monkeys) express 12-lipoxygenating enzymes. Gibbons, which are flanked in evolution by rhesus monkeys (12-lipoxygenating ALOX15) and orangutans (15-lipoxygenating ALOX15), express an ALOX15 ortholog with pronounced dual specificity, an evolution of ALOX15 specificity, which is aimed at optimizing the biosynthetic capacity for antiinflammatory and proresolving lipoxins. Phylogenetic analysis
evolution
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mammals (mice, rats, pigs) express 12-lipoxygenating ALOX15 orthologues. 15-lipoxygenating isoforms are found in primates (orangutans, humans), suggesting an evolution of ALOX15 specificity. Other primates (baboons, rhesus monkeys) express 12-lipoxygenating enzymes. Gibbons, which are flanked in evolution by rhesus monkeys (12-lipoxygenating ALOX15) and orangutans (15-lipoxygenating ALOX15), express an ALOX15 ortholog with pronounced dual specificity, an evolution of ALOX15 specificity, which is aimed at optimizing the biosynthetic capacity for antiinflammatory and proresolving lipoxins. Phylogenetic analysis
evolution
mammals (mice, rats, pigs) express 12-lipoxygenating ALOX15 orthologues. 15-lipoxygenating isoforms are found in primates (orangutans, humans), suggesting an evolution of ALOX15 specificity. Other primates (baboons, rhesus monkeys) express 12-lipoxygenating enzymes. Gibbons, which are flanked in evolution by rhesus monkeys (12-lipoxygenating ALOX15) and orangutans (15-lipoxygenating ALOX15), express an ALOX15 ortholog with pronounced dual specificity, an evolution of ALOX15 specificity, which is aimed at optimizing the biosynthetic capacity for antiinflammatory and proresolving lipoxins. Phylogenetic analysis
evolution
mammals (mice, rats, pigs) express 12-lipoxygenating ALOX15 orthologues. 15-lipoxygenating isoforms are found in primates (orangutans, humans), suggesting an evolution of ALOX15 specificity. Other primates (baboons, rhesus monkeys) express 12-lipoxygenating enzymes. Gibbons, which are flanked in evolution by rhesus monkeys (12-lipoxygenating ALOX15) and orangutans (15-lipoxygenating ALOX15), express an ALOX15 ortholog with pronounced dual specificity, an evolution of ALOX15 specificity, which is aimed at optimizing the biosynthetic capacity for antiinflammatory and proresolving lipoxins. Phylogenetic analysis
evolution
H2QBX9
mammals (mice, rats, pigs) express 12-lipoxygenating ALOX15 orthologues. 15-lipoxygenating isoforms are found in primates (orangutans, humans), suggesting an evolution of ALOX15 specificity. Other primates (baboons, rhesus monkeys) express 12-lipoxygenating enzymes. Gibbons, which are flanked in evolution by rhesus monkeys (12-lipoxygenating ALOX15) and orangutans (15-lipoxygenating ALOX15), express an ALOX15 ortholog with pronounced dual specificity, an evolution of ALOX15 specificity, which is aimed at optimizing the biosynthetic capacity for antiinflammatory and proresolving lipoxins. Phylogenetic analysis
evolution
mammals (mice, rats, pigs) express 12-lipoxygenating ALOX15 orthologues. 15-lipoxygenating isoforms are found in primates (orangutans, humans), suggesting an evolution of ALOX15 specificity. Other primates (baboons, rhesus monkeys) express 12-lipoxygenating enzymes. Gibbons, which are flanked in evolution by rhesus monkeys (12-lipoxygenating ALOX15) and orangutans (15-lipoxygenating ALOX15), express an ALOX15 ortholog with pronounced dual specificity, an evolution of ALOX15 specificity, which is aimed at optimizing the biosynthetic capacity for antiinflammatory and proresolving lipoxins. Phylogenetic analysis
evolution
mammals (mice, rats, pigs) express 12-lipoxygenating ALOX15 orthologues. 15-lipoxygenating isoforms are found in primates (orangutans, humans), suggesting an evolution of ALOX15 specificity. Other primates (baboons, rhesus monkeys) express 12-lipoxygenating enzymes. Gibbons, which are flanked in evolution by rhesus monkeys (12-lipoxygenating ALOX15) and orangutans (15-lipoxygenating ALOX15), express an ALOX15 ortholog with pronounced dual specificity, an evolution of ALOX15 specificity, which is aimed at optimizing the biosynthetic capacity for antiinflammatory and proresolving lipoxins. Phylogenetic analysis
evolution
mammals (mice, rats, pigs) express 12-lipoxygenating ALOX15 orthologues. 15-lipoxygenating isoforms are found in primates (orangutans, humans), suggesting an evolution of ALOX15 specificity. Other primates (baboons, rhesus monkeys) express 12-lipoxygenating enzymes. Gibbons, which are flanked in evolution by rhesus monkeys (12-lipoxygenating ALOX15) and orangutans (15-lipoxygenating ALOX15), express an ALOX15 ortholog with pronounced dual specificity, an evolution of ALOX15 specificity, which is aimed at optimizing the biosynthetic capacity for antiinflammatory and proresolving lipoxins. Phylogenetic analysis
evolution
mammals (mice, rats, pigs) express 12-lipoxygenating ALOX15 orthologues. 15-lipoxygenating isoforms are found in primates (orangutans, humans), suggesting an evolution of ALOX15 specificity. Other primates (baboons, rhesus monkeys) express 12-lipoxygenating enzymes. Gibbons, which are flanked in evolution by rhesus monkeys (12-lipoxygenating ALOX15) and orangutans (15-lipoxygenating ALOX15), express an ALOX15 ortholog with pronounced dual specificity, an evolution of ALOX15 specificity, which is aimed at optimizing the biosynthetic capacity for antiinflammatory and proresolving lipoxins. Phylogenetic analysis
evolution
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mammals (mice, rats, pigs) express 12-lipoxygenating ALOX15 orthologues. 15-lipoxygenating isoforms are found in primates (orangutans, humans), suggesting an evolution of ALOX15 specificity. Other primates (baboons, rhesus monkeys) express 12-lipoxygenating enzymes. Gibbons, which are flanked in evolution by rhesus monkeys (12-lipoxygenating ALOX15) and orangutans (15-lipoxygenating ALOX15), express an ALOX15 ortholog with pronounced dual specificity, an evolution of ALOX15 specificity, which is aimed at optimizing the biosynthetic capacity for antiinflammatory and proresolving lipoxins. Phylogenetic analysis
evolution
-
mammals (mice, rats, pigs) express 12-lipoxygenating ALOX15 orthologues. 15-lipoxygenating isoforms are found in primates (orangutans, humans), suggesting an evolution of ALOX15 specificity. Other primates (baboons, rhesus monkeys) express 12-lipoxygenating enzymes. Gibbons, which are flanked in evolution by rhesus monkeys (12-lipoxygenating ALOX15) and orangutans (15-lipoxygenating ALOX15), express an ALOX15 ortholog with pronounced dual specificity, an evolution of ALOX15 specificity, which is aimed at optimizing the biosynthetic capacity for antiinflammatory and proresolving lipoxins. Phylogenetic analysis
malfunction
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when 15-LOX-1 activity is knocked down by siRNA, the induction of MIP-1alpha, RANTES, and IP-10 is significantly attenuated
malfunction
Alox15 deletion impaired LSC function by affecting cell division and apoptosis, leading to an eventual depletion of leukemia stem cells. Chemical inhibition of enzyme 15-LO function impairs leukemia stem cell function and attenuates chronic myeloid leukemia in mice. The defective chronic myeloid leukemia phenotype in Alox15-deficient animals is rescued by depleting the gene encoding P-selectin, which is upregulated in Alox15-deficient animals. Both deletion and overexpression of P-selectin affects the survival of leukemia stem cells. Loss of Alox15 causes a functional defect in leukemia stem cells
malfunction
deletion of 12/15-LO negates endothelial tight junctions disruption and monocyte adhesion caused by the high-fat diet
malfunction
disruption of normal 12- and 15-LO function by the inflammatory obese condition promotes adipocyte dysfunction and overall metabolic disease including insulin resistance and diabetes
malfunction
streptozotocin (STZ)-induced diabetic mice show upregulated expression of 12/15-LOX and inflammatory cytokines such as tumor necrosis factor (TNF)-alpha and nuclear factor (NF)-kappaB in diabetic hearts. Disruption of 12/15-LOX significantly improves STZ-induced cardiac dysfunction and fibrosis. Deletion of 12/15-LOX inhibits the increases of TNF-alpha and NF-kappaB as well as the production of STZ-induced reactive oxygen species in the heart. Administration of N-acetylcysteine in diabetic mice prevents STZ-induced cardiac fibrosis. Neonatal cultured cardiomyocytes exposed to high glucose conditions induce the expression of 12/15-LOX as well as TNF-alpha, NF-kappaB, and collagen markers. These increases are inhibited by treatment of the 12/15-LOX inhibitor. Disruption of 12/15-LOX reduces inflammation, oxidative stress, and fibrosis in the diabetic heart, thereby improving systolic dysfunction. Disruption of 12/15-LOX decreases cardiac inflammation induced by hyperglycemia
malfunction
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streptozotocin (STZ)-induced diabetic mice show upregulated expression of 12/15-LOX and inflammatory cytokines such as tumor necrosis factor (TNF)-alpha and nuclear factor (NF)-kappaB in diabetic hearts. Disruption of 12/15-LOX significantly improves STZ-induced cardiac dysfunction and fibrosis. Deletion of 12/15-LOX inhibits the increases of TNF-alpha and NF-kappaB as well as the production of STZ-induced reactive oxygen species in the heart. Administration of N-acetylcysteine in diabetic mice prevents STZ-induced cardiac fibrosis. Neonatal cultured cardiomyocytes exposed to high glucose conditions induce the expression of 12/15-LOX as well as TNF-alpha, NF-kappaB, and collagen markers. These increases are inhibited by treatment of the 12/15-LOX inhibitor. Disruption of 12/15-LOX reduces inflammation, oxidative stress, and fibrosis in the diabetic heart, thereby improving systolic dysfunction. Disruption of 12/15-LOX decreases cardiac inflammation induced by hyperglycemia
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malfunction
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deletion of 12/15-LO negates endothelial tight junctions disruption and monocyte adhesion caused by the high-fat diet
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metabolism
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shifting linoleic acid metabolism from 15-LOX-1 to COX-2 is procarcinogenic
metabolism
cardiac 12/15-LOX pathway induced by high glucose condition increases the expression of cardiac inflammation in vitro
physiological function
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12/15-LOX is a critical mediator of the chronic type 1 inflammatory response. Evolution of the immune response to Toxoplasma gondii is accompanied by an increasing requirement for 12/15-LOX mediated signaling. Although 12/15-LOX deficient mice are resistant to acute Toxoplasma gondii infection, 80% of 12/15-LOX-deficient mice die during chronic toxoplasmosis, compared to no deaths in wild-type controls. The enhanced susceptibility of 12/15-LOX-deficient mice to chronic toxoplasmosis is associated with reduced production of IL-12 and gamma interferon (IFN-gamma) that is not evident during acute infection. Ex vivo IFN-gamma production by 12/15-LOX-deficient splenocytes can be rescued by the addition of recombinant IL-12. 12/15-LOX does not play a role in macrophage killing of Toxoplasma gondii in vitro
physiological function
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12/15LO activity in the vessel wall contributes to atherogenesis by impairing the macrophage ATP-binding cassette transporter G1 cholesterol efflux pathway. 12/15LO activity reduces high density lipoprotein-mediated cholesterol efflux, ATP-binding cassette transporter G1 cellular expression. 12/15LO activity does not affect ATP-binding cassette transporter G1 mRNA expression
physiological function
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12/15LO expression increases chemokine production. 12/15LO mediates early stages of adipose tissue inflammation and whole body insulin resistance induced by high fat feeding. Adipose tissue from high fat diet-fed 12/15LO KO mice is not infiltrated by macrophages and does not display any increase in the inflammatory markers compared to adipose tissue from normal chow-fed mice. 12/15LO KO mice exhibit no high fat diet-induced change in insulin-stimulated glucose disposal rate or hepatic glucose output. Insulin-stimulated Akt phosphorylation in muscle tissue from high fat diet-fed mice is significantly greater in 12/15LO KO mice than in wild-type mice
physiological function
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15-lipoxygenases may have chondroprotective properties by reducing metalloproteinase-1 and -13 expression. Their respective metabolites, 13(S)-hydroxy octadecadienoic and 15(S)-hydroxyeicosatetraenoic acids, suppress interleukin-1beta-induced metalloproteinase-1 and -13 expression in a PPARgamma-dependent pathway
physiological function
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15-LO-1 plays active roles in vascular remodeling, the progression of atherosclerosis and angiogenesis. The PC-3 prostate cancer cell line, which overexpresses 15-LO-1, secretes high levels of vascular endothelial growth factor and enhances tumor growth and angiogenesis as compared with the parental PC-3 cell lines. Angiogenesis and tumor formation is inhibited in transgenic mice overexpressing 15-LO-1 in endothelial cells under the control of preproendothelin promoter. Potential role of 15-LO-1 in regulating endothelium-derived NO, the expression level and activity of 15-LO-1 in endothelial cells may act as a potential NO barometer by modulating the level of eNOS enzyme and bioactive free NO in endothelial cells. 15-LO-1 in human endothelial cells can inhibit angiogenesis and vascular permeability by removing free NO, and its activity can in turn be modulated by the cytoplasmic NO level
physiological function
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15-LOX metabolites (15(S)-hydroxyeicosatetraenoic acid, 15-hydroxyeicosatrienoic acid or 13(S)-hydroxyoctadecadienoic acid) can inhibit insulin-like growth factor II-induced 12-LOX expression and keratinocytes proliferation
physiological function
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15-LOX-1 induces chemokine expression in A549 cells. Increased expression and activity of 15-LOX-1 in lung epithelial cells is a proinflammatory event in the pathogenesis of asthma and other inflammatory lung disorders. 15-LOX-1 overexpression results in upregulation of MIP-1alpha, MIP11beta, and RANTES, in increased migration of immature dendritic cells and of activated T cells and increases chemotaxis of mast cells. 15-LOX-1 ectopic expression upregulates NF-kappaB activity
physiological function
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15-LOX-1 induces phosphorylation of tumor suppressor p53 independent of enzymatic activity. HCT-116 cells transiently transfected with either native or mutant 15-LOX-1 show an increase in p53 phosphorylation and an increase in the expression of downstream genes. 15-LOX-1 interacts with, and binds to, DNA-dependent protein kinase, which causes an approximate 3fold enhancement in kinase activity, resulting in increased p53 phosphorylation at Ser15
physiological function
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15-LOX-1 promotes mitogenic response to epidermal growth factor in fibroblasts and NaBT-induced apoptosis in colon cancer cells. Non-steroidal anti-inflammatory drugs-induced apoptosis mediated by 15-LOX-1/GATA-6 in colon cancer
physiological function
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15-LOX-2 increases cell cycle arrest at G0/G1 phase. Injected into athymic nu/nu mice, prostate cancer cells with 15-LOX-2 expression can still form palpable tumors without significant changes in tumorigenicity. But, the tumors with 15-LOX-2 expression grow significantly slower than those derived from vector controls and are kept dormant for a long period of time. Increase in cell death in tumors derived from prostate cancer cells with 15- LOX-2 expression. 15-LOX-2 suppresses vascular endothelial growth factor A gene expression and sustains tumor dormancy in prostate cancer
physiological function
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endogenous 12/15-LOX defines the resident peritoneal macrophage population and regulates both the recruitment of monocytes/peritoneal macrophage and cytokine response to bacterial products in vivo
physiological function
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high degree of motional flexibility and a high membrane binding affinity
physiological function
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high levels of 15LO1 activity can contribute to the increases of MUC5AC observed in asthma
physiological function
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inhibits tumour growth and metastasis. Enzyme promotes atherosclerosis and can inhibit growth and spread of lung (Lewis lung carcinoma model) and breast (mouse mammary adenocarcinoma model) cancer cells
physiological function
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is a regulator of angiogenesis, antiangiogenic action in skeletal muscle system. 15-LO-1 significantly decreases all angiogenic effects induced by vascular endothelial growth factor-A and placental growth factor, including capillary perfusion, vascular permeability, vasodilatation, and the increase in capillary number
physiological function
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lower degree of motional flexibility in aqueous solutions than mammalian isozymes
physiological function
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macrophages that overexpress 15-LOX-2 show increased secretion of chemokine ligands CXCL10 and CCL2 after 24h incubation. Preconditioned medium from 15-LOX-2-overexpressing cells increases T cell migration, the expression of T cell activation marker CD69 and surface expression of chemokine receptor CXCR3, the CXCL10 chemokine ligand. Increased expression of 15-LOX-2 induced by hypoxia may participate in T cell recruitment in diseases such as atherosclerosis
physiological function
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overexpression of human 15-LO-1 in RAW macrophages promotes reverse cholesterol transport through increased cholesteryl ester hydrolysis and ABCA1-mediated cholesterol efflux
physiological function
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pathophysiological role of the enzyme in airway inflammation and atherosclerosis. Role in cell differentiation and importance for maturation of erythrocytes and degradation of cell organells. Role in neoplasia such as prostate cancer and colon carcinoma cells
physiological function
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pathophysiological role of the enzyme in respiratory inflammation. Mice deficient of 12/15-LO have an attenuated allergic airway inflammation compared to wild type controls
physiological function
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radiation-induced upregulation of 15-LOX-2 results in significant induction of apoptosis in head-and-neck cancer cells and and enhances killing effect of radiotherapy in head-and-neck cancer. The enzyme inhibits tumor growth through the effect of its main metabolite 15(S)-hydroxyeicosatetranoic acid on PPARgamma signaling pathway
physiological function
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the expression of 15-lipoxygenase-1 and the putative formation of eoxins by Hodgkin Reed-Sternberg cells in vivo are likely to contribute to the inflammatory features of Hodgkin lymphoma
physiological function
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high levels of 15LO1 interact with PEBP1 to displace Raf-1 and sustain MAPK/ERK activation
physiological function
12/15-lipoxygenase metabolites of arachidonic acid activate PPARgamma, involvement of 12(S)- and 15(S)-hydroperoxyicosatetraenoate in the regulation of PPARgamma following cerebral ischemia and effects on ischemia-induced inflammatory response. 12(S)-HETE and 15(S)-HETE elicit neuroprotection in rats exposed to focal ischemia. PPARgamma is a member of the nuclear hormone receptorfamily of ligand-dependent transcription factors. PPARgamma regulates genes that are implicated in adipocyte differentiation, lipid and glucose metabolism, and insulin sensitivity
physiological function
12/15-lipoxygenase plays a role in atherosclerosis. 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE), the major 12/15-LO metabolite of arachidonic acid, induces endothelial barrier permeability via Src and Pyk2-dependent zonula occluden (ZO)-2 tyrosine phosphorylation and its dissociation from the tight junction complexes. 15(S)-HETE also stimulates macrophage adhesion to the endothelial monolayer in Src and Pyk2-dependent manner. Exposure of arteries from wild-type mice to arachidonate or 15(S)-HETE leads to Src-Pyk2-dependent ZO-2 tyrosine phosphorylation, tight junction disruption, and macrophage adhesion, whereas the arteries from 12/15-LO knock-out mice are protected from these effects of arachidonate. Feeding wild-type mice with a high-fat diet induces the expression of 12/15-LO in the arteries leading to tight junction disruption and macrophage adhesion, and deletion of the 12/15-LO gene disallows these effects. 15(S)-HETE-induced endothelial tight junctions disruption promotes monocyte transmigration, 15(S)-HETE induces the dislocation of both claudin-1 and claudin-5 from ZO-2, that participates in tight junctions
physiological function
12/15-LOX is implicated in the pathogenesis of multiple chronic inflammatory diseases, and its physiologic functions seem to include potent immune modulatory properties that physiologically contribute to the resolution of inflammation and the clearance of inflammation-associated tissue damage. 12/15-LOXs are also involved in the synthesis of lipoxins, which likewise act as anti-inflammatory, pro-resolving mediators. Inflammatory eicosanoids are produced by eosinophils in a 12/15-LOX dependent manner. Docosahexaenoic acid (DHA) is a further substrate of 12/15-LOX. The oxidation of DHA leads to the production of 17S-hydroxy-DHA, an anti-inflammatory mediator, which can be further metabolized into highly active and potent anti-inflammatory resolvins and protectins. 12/15-LOX can metabolize not only free PUFAs, but also PUFAs esterified to membrane-bound phospholipids as well as PUFAs within cholesterol esters. 12/15-LOX-derived mediators as regulators of inflammation, role of 12/15-LOX during inflammation, detailed overview. 12/15-LOX activity in residentmacrophages interferes with theMFG-E8-dependent uptake of apoptotic cells (ACs) by inflammatory, immune-competent phagocytes and thereby fosters the non-immunogenic clearance of ACs, whereas 12/15-LOX-derived lipoxins directly increase the non-inflammatory uptake of dying cells. Possible role of 12/15-LOX in atherosclerosis
physiological function
ALOX15-encoded 12/15-lipoxygenase orthologs are implicated in maturational degradation of intracellular organelles and in the biosynthesis of antiinflammatory and proresolving eicosanoids
physiological function
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ALOX15-encoded 12/15-lipoxygenase orthologs are implicated in maturational degradation of intracellular organelles and in the biosynthesis of antiinflammatory and proresolving eicosanoids
physiological function
ALOX15-encoded 12/15-lipoxygenase orthologs are implicated in maturational degradation of intracellular organelles and in the biosynthesis of antiinflammatory and proresolving eicosanoids
physiological function
ALOX15-encoded 12/15-lipoxygenase orthologs are implicated in maturational degradation of intracellular organelles and in the biosynthesis of antiinflammatory and proresolving eicosanoids
physiological function
H2QBX9
ALOX15-encoded 12/15-lipoxygenase orthologs are implicated in maturational degradation of intracellular organelles and in the biosynthesis of antiinflammatory and proresolving eicosanoids
physiological function
ALOX15-encoded 12/15-lipoxygenase orthologs are implicated in maturational degradation of intracellular organelles and in the biosynthesis of antiinflammatory and proresolving eicosanoids
physiological function
ALOX15-encoded 12/15-lipoxygenase orthologs are implicated in maturational degradation of intracellular organelles and in the biosynthesis of antiinflammatory and proresolving eicosanoids
physiological function
ALOX15-encoded 12/15-lipoxygenase orthologs are implicated in maturational degradation of intracellular organelles and in the biosynthesis of antiinflammatory and proresolving eicosanoids
physiological function
ALOX15-encoded 12/15-lipoxygenase orthologs are implicated in maturational degradation of intracellular organelles and in the biosynthesis of antiinflammatory and proresolving eicosanoids
physiological function
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ALOX15-encoded 12/15-lipoxygenase orthologs are implicated in maturational degradation of intracellular organelles and in the biosynthesis of antiinflammatory and proresolving eicosanoids
physiological function
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ALOX15-encoded 12/15-lipoxygenase orthologs are implicated in maturational degradation of intracellular organelles and in the biosynthesis of antiinflammatory and proresolving eicosanoids
physiological function
arachidonate 15-lipoxygenase is required for chronic myeloid leukemia stem cell survival in a murine model of BCR-ABLinduced chronic myeloid leukemia, in the absence of Alox15, BCRABL is unable to induce CML in mice
physiological function
cardiac 12/15-LOX-induced inflammation and oxidative stress are involved in the development of diabetic cardiomyopathy. 12/15-LOX induces cardiac oxidative stress in the diabetic heart
physiological function
enzyme 15-lipoxygenase is involved in adipose tissue inflammation. The lipoxygenases (LOs) are principal enzymes involved in the oxidative metabolism of polyunsaturated fatty acids, including arachidonic acid. 12- and 15-LO and their lipid metabolites are implicated in the development of insulin resistance and diabetes. Adipose tissue, and in particular visceral adipose tissue, plays a primary role in the development of the inflammation seen in these conditions. 12- and 15-LO and their lipid metabolites act as upstream regulators of many of the cytokines involved in the inflammatory response in adipose tissue. 12- and 15-LO and their lipid metabolites act as upstream regulators of many of the cytokines involved in the inflammatory response in adipose tissue. Significant role for 12- and 15-LO function in white adipose tissue adipogenesis and adipocyte health. 12- and 15-LO function in adipogenesis and has anti-inflammatory roles in adipose tissue, detailed overview. Leukocyte-type 12-LO, or 12/15-LO appears to be a key player in the progression of adipocyte dysfunction and resultant systemic decline. 12/15-LO is upregulated in white adipose tissue in the obese state. Increased expression of all of the 12- and 15-LO enzyme isoforms in omental vs. subcutaneous white adipose tissue suggests that the pathways may contribute to the proinflammatory milieu prominently associated with visceral fat in obesity. The potent vasoconstricting and pro-inflammatory hormone angiotensin II (Ang II) led to increases in leukocyte-type 12-LO mRNA and protein levels, as well as increased enzyme activity
physiological function
enzyme LoxA is a poor catalyst against phosphoester fatty acids, suggesting that LoxA is not involved in membrane decomposition. LoxA also does not react with 5- or 15-HETEs, indicating poor involvement in lipoxin production. The level of LoxA expression is increased when Pseudomonas aeruginosa undergoes the transition to a biofilm mode of growth, but LoxA is not required for biofilm growth on abiotic surfaces. LoxA does appear to be required for biofilm growth in association with the host airway epithelium, suggesting a role for LoxA in mediating bacterium-host interactions during colonization
physiological function
isozyme 15-LOX-2 reaction in intact cells: Ca2+ concentrations in the cell increase in response to stress. The Ca2+ binds to the PLAT domain of 15-LOX-2, resulting in a translocation from the cytosol to the membrane. 15-LOX-2 then binds its substrate arachidonate and oxygenates it to form (5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyicosa-5,8,11,13-tetraenoate, 15-HpETE. 15-HpETE is further metabolized by downstream enzymes to form lipoxins, which initiate the resolution of inflammation
physiological function
lipoxygenases (LOX) form a family of lipid peroxidizing enzymes, which are implicated in a number of physiological processes and in the pathogenesis of inflammatory, hyperproliferative and neurodegenerative diseases. Physiological roles of ALOX15, detailed overview
physiological function
lipoxygenases (LOX) form a family of lipid peroxidizing enzymes, which are implicated in a number of physiological processes and in the pathogenesis of inflammatory, hyperproliferative and neurodegenerative diseases. Physiological roles of ALOX15, detailed overview
physiological function
lipoxygenases (LOX) form a family of lipid peroxidizing enzymes, which are implicated in a number of physiological processes and in the pathogenesis of inflammatory, hyperproliferative and neurodegenerative diseases. Physiological roles of ALOX15, detailed overview
physiological function
lipoxygenases (LOX) form a family of lipid peroxidizing enzymes, which are implicated in a number of physiological processes and in the pathogenesis of inflammatory, hyperproliferative and neurodegenerative diseases. Physiological roles of ALOX15, detailed overview
physiological function
roles of arachidonate 15-lipoxygenase in the clearance of dying adipocytes by adipose tissue macrophages, the Alox15 activation in adipose tissue macrophages functions as a mechanism of non-inflammatory removal of dying adipocytes, overview. Alox15 is required for efferocytosis of apoptotic adipocytes by macrophages in vitro. Alox15 can generate peroxisome proliferatoractivated receptor gamma (PPARgamma) ligands, including 13-HODE and 9-HODE in macrophages after CL316243 treatment. Alox15 is required for differentiation of adipocyte progenitors in beta3-adrenergic stimulation-induced adipose tissue remodeling
physiological function
the effects of 15-LOX-generated metabolites of alpha-linolenic acid on lipopolysaccharide-induced inflammation in RAW 264.7 cells and peritoneal macrophages, analysis of the effect of these metabolites on the survival of BALB/c mice in LPS mediated septic shock and also polymicrobial sepsis in Cecal Ligation and Puncture mouse model, overview. Anti-inflammatory effects of 13-(S)-hydroperoxyoctadecatrienoic acid and 13-(S)-hydroxyoctadecatrienoic acid by inactivating NLRP3 inflammasome complex through the PPAR-gama pathway. Both metabolites, especially 13-(S)-hydroperoxyoctadecatrienoic acid, also deactivate autophagy and induce apoptosis
physiological function
12/15-LOX-deficient mice display augmented IL-33-induced lung inflammation, characterized by an increased number of infiltrated eosinophils and group 2 innate lymphoid cells in the airway. The levels of a series of 12/15-LOX-derived metabolites are significantly decreased, and application of 14(S)-hydroxy docosahexaenoic acid suppresses IL-33-mediated eosinophilic inflammation in 12/15-LOX-deficient mice. 14(S)-hydroxy docosahexaenoic acid and 10(S),17(S)-dihydroxy docosahexaenoic acid markedly attenuate ILC2 proliferation and cytokine production at micromolar concentration in vitro
physiological function
15 lipoxygenase 1 is abundant in asthmatic human airway epithelial cells and binds phosphatidylethanolamine-binding protein 1 (PEBP1), leading to generation of hydroperoxy-phospholipids, which drive ferroptotic cell death. 15LO1, PEBP1, and glutathione peroxidase 4 GPX4 activity drives abnormal asthmatic redox biology, to enhance type 2 inflammatory responses. In vitro, type 2 inflammatory cytokine IL-13 induces 15LO1 generation of hydroperoxy-phospholipids, which lowers intracellular GSH and increased extracellular GSSG levels. Lowering GSH further by inhibiting cystine transporter SLC7A11 enhances type 2 inflammatory protein expression and ferroptosis. Ex vivo, redox imbalances correspond to 15LO1 and SLC7A11 expression, type 2 inflammatory biomarkers, and worsen clinical outcomes
physiological function
a sharp increase in protein expression of 12/15 lipoxygenase is found in the pancreatic islets of 10-week old db-/- obese diabetic mice compared to 8-week old counterparts. The increase in islet 12/15 lipoxygenase parallels a decline in islet number. A 2- to 3fold increase especially in 12(S)-hydroperoxytetraeicosanoid acid mirrors the increase in 12/15 lipoxygenase expression in islets. A significant increase of platelet 12/15 lipoxygenase gene expression is found along with 12-hydroperoxytetraeicosanoid acids and 15-hydroperoxytetraeicosanoid acids
physiological function
eosinophil-depleted neutrophils express the 15-lipoxygenase isoform 2 but not the 15-lipoxygenase -1, in contrast to eosinophils which express the 15-lipoxygenase-1 but not the 15-lipoxygenase-2. 15-lipoxygenase metabolite synthesis by neutrophils is not inhibited by the 15-LO-1 inhibitors BLX769, BLX3887, and ML351
physiological function
eosinophils are the major cell type expressing 12/15-LOX during the corneal wound healing process. Eosinophils are recruited into the conjunctiva after corneal epithelium wounding, and eosinophil-deficient and/or eosinophil-specific 12/15-LOX knockout mice show delayed corneal wound healing compared with wild-type mice. A series of 12/15-LOX-derived mediators are significantly decreased in eosinophil-deficient mice and topical application of 17-hydroxydocosahexaenoic acid restores the phenotype
physiological function
eosinophils express the 15-lipoxygenase-1 but not the 15-lipoxygenase-2. The synthesis of 15-lipoxygenase metabolites by neutrophils does not involve the 15-lipoxygenase-1
physiological function
lipoxin B4 is the primary product of 12-LOX and 15-LOX-1 catalysis, if 5S,15S-dihydroperoxyeicosatetraenoic acid is the substrate, with 15-LOX-1 being 20fold more efficient than 12-LOX
physiological function
male Balb/c mice subjected to simulated hypobaric hypoxia for three consecutive days show a robust increase in intra-hippocampal (5Z,8Z,10E,14Z)-(12S)-12-hydroperoxyeicosa-5,8,10,14-tetraenoate level, which is significantly reduced following baicalein treatment. The elevated level of (5Z,8Z,10E,14Z)-(12S)-12-hydroperoxyeicosa-5,8,10,14-tetraenoate correlates with simultaneous increase in expression of 12/15 LOX in neurons and microglia lining the hippocampal CA3 region. 12/15 LOX gets embedded onto the periphery of mitochondria following hypobaric hypoxia and a strong correlation is observed with loss of mitochondrial integrity
physiological function
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12/15-lipoxygenase metabolites of arachidonic acid activate PPARgamma, involvement of 12(S)- and 15(S)-hydroperoxyicosatetraenoate in the regulation of PPARgamma following cerebral ischemia and effects on ischemia-induced inflammatory response. 12(S)-HETE and 15(S)-HETE elicit neuroprotection in rats exposed to focal ischemia. PPARgamma is a member of the nuclear hormone receptorfamily of ligand-dependent transcription factors. PPARgamma regulates genes that are implicated in adipocyte differentiation, lipid and glucose metabolism, and insulin sensitivity
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physiological function
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the effects of 15-LOX-generated metabolites of alpha-linolenic acid on lipopolysaccharide-induced inflammation in RAW 264.7 cells and peritoneal macrophages, analysis of the effect of these metabolites on the survival of BALB/c mice in LPS mediated septic shock and also polymicrobial sepsis in Cecal Ligation and Puncture mouse model, overview. Anti-inflammatory effects of 13-(S)-hydroperoxyoctadecatrienoic acid and 13-(S)-hydroxyoctadecatrienoic acid by inactivating NLRP3 inflammasome complex through the PPAR-gama pathway. Both metabolites, especially 13-(S)-hydroperoxyoctadecatrienoic acid, also deactivate autophagy and induce apoptosis
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physiological function
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12/15-LOX is a critical mediator of the chronic type 1 inflammatory response. Evolution of the immune response to Toxoplasma gondii is accompanied by an increasing requirement for 12/15-LOX mediated signaling. Although 12/15-LOX deficient mice are resistant to acute Toxoplasma gondii infection, 80% of 12/15-LOX-deficient mice die during chronic toxoplasmosis, compared to no deaths in wild-type controls. The enhanced susceptibility of 12/15-LOX-deficient mice to chronic toxoplasmosis is associated with reduced production of IL-12 and gamma interferon (IFN-gamma) that is not evident during acute infection. Ex vivo IFN-gamma production by 12/15-LOX-deficient splenocytes can be rescued by the addition of recombinant IL-12. 12/15-LOX does not play a role in macrophage killing of Toxoplasma gondii in vitro
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physiological function
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endogenous 12/15-LOX defines the resident peritoneal macrophage population and regulates both the recruitment of monocytes/peritoneal macrophage and cytokine response to bacterial products in vivo
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physiological function
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cardiac 12/15-LOX-induced inflammation and oxidative stress are involved in the development of diabetic cardiomyopathy. 12/15-LOX induces cardiac oxidative stress in the diabetic heart
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physiological function
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12/15-lipoxygenase plays a role in atherosclerosis. 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE), the major 12/15-LO metabolite of arachidonic acid, induces endothelial barrier permeability via Src and Pyk2-dependent zonula occluden (ZO)-2 tyrosine phosphorylation and its dissociation from the tight junction complexes. 15(S)-HETE also stimulates macrophage adhesion to the endothelial monolayer in Src and Pyk2-dependent manner. Exposure of arteries from wild-type mice to arachidonate or 15(S)-HETE leads to Src-Pyk2-dependent ZO-2 tyrosine phosphorylation, tight junction disruption, and macrophage adhesion, whereas the arteries from 12/15-LO knock-out mice are protected from these effects of arachidonate. Feeding wild-type mice with a high-fat diet induces the expression of 12/15-LO in the arteries leading to tight junction disruption and macrophage adhesion, and deletion of the 12/15-LO gene disallows these effects. 15(S)-HETE-induced endothelial tight junctions disruption promotes monocyte transmigration, 15(S)-HETE induces the dislocation of both claudin-1 and claudin-5 from ZO-2, that participates in tight junctions
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physiological function
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12/15LO expression increases chemokine production. 12/15LO mediates early stages of adipose tissue inflammation and whole body insulin resistance induced by high fat feeding. Adipose tissue from high fat diet-fed 12/15LO KO mice is not infiltrated by macrophages and does not display any increase in the inflammatory markers compared to adipose tissue from normal chow-fed mice. 12/15LO KO mice exhibit no high fat diet-induced change in insulin-stimulated glucose disposal rate or hepatic glucose output. Insulin-stimulated Akt phosphorylation in muscle tissue from high fat diet-fed mice is significantly greater in 12/15LO KO mice than in wild-type mice
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additional information
conformational dynamics of native 15-LOX-2, mass spectrometric analysis, overview
additional information
molecular dynamics simulations and quantum mechanics/molecular mechanics calculations
additional information
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molecular dynamics simulations and quantum mechanics/molecular mechanics calculations
additional information
molecular dynamics simulations and quantum mechanics/molecular mechanics calculations
additional information
molecular dynamics simulations and quantum mechanics/molecular mechanics calculations
additional information
H2QBX9
molecular dynamics simulations and quantum mechanics/molecular mechanics calculations
additional information
molecular dynamics simulations and quantum mechanics/molecular mechanics calculations
additional information
molecular dynamics simulations and quantum mechanics/molecular mechanics calculations
additional information
molecular dynamics simulations and quantum mechanics/molecular mechanics calculations
additional information
molecular dynamics simulations and quantum mechanics/molecular mechanics calculations
additional information
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molecular dynamics simulations and quantum mechanics/molecular mechanics calculations
additional information
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molecular dynamics simulations and quantum mechanics/molecular mechanics calculations
additional information
quantum mechanics/molecular mechanics calculations with molecular dynamics simulations to study the addition of O2 to the pentadienyl radical of arachidonic acid catalyzed by the Leu597Val and Leu597Ala mutants of rabbit 15-lipoxygenase, detailed overview