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Information on EC 1.13.11.33 - arachidonate 15-lipoxygenase and Organism(s) Mus musculus and UniProt Accession P39654
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1.13.11.33 arachidonate 15-lipoxygenaseIUBMB Comments
The product is rapidly reduced to the corresponding 15S-hydroxy compound.
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Word Map
- 1.13.11.33
- lipoxygenases
- cox-2
- 15-hete
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polyunsaturated
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leukotriene
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eicosanoids
- hydroperoxide
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12-lipoxygenase
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cyclooxygenases
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lipoxins
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15s-hydroxyeicosatetraenoic
- ndga
- alox15b
- 12/15-lipoxygenase
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nordihydroguaiaretic
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pro-resolving
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lipoxygenation
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resolvins
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hodes
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13-hydroxyoctadecadienoic
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lipid-peroxidating
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leukocyte-type
- oxylipins
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platelet-type
- medicine
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protectins
- drug development
The taxonomic range for the selected organisms is: Mus musculus
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota
Reaction Schemes
Synonyms
15-lox, 15-lo-1, 15-lox-2, 15-lox2, arachidonate 15-lipoxygenase, soybean 15-lipoxygenase, 15-lipoxygenase-2, 15lo1, 15-hlo, 15-lipoxygenase 1, 
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topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
15-lipoxygenase
15-LOX
arachidonic acid 15-lipoxygenase
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linoleic acid omega-6-lipoxygenase
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omega-6 lipoxygenase
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oxygenase, arachidonate 15-lip-
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15-lipoxygenase
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15-LOX
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
arachidonate + O2 = (5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyicosa-5,8,11,13-tetraenoate
the reaction proceeds via hydrogen abstraction, peroxide cleavage, radical rearrangement, and epoxide formation. To initiate the reaction the ferrous LOX is first activated by peroxide-dependent oxidation to a ferric form. The lipohydroperoxidase activity is initiatedwhen a lipid hydroperoxide (ROOH) is bound at the active site of the enzyme. The enzyme then catalyzes a homolytic cleavage of the hydroperoxy bond, which leads to the formation of an oxygen-centered alkoxy radical, a hydroxyl and oxidizes the ferrous iron to a ferric form. Then the enzyme binds a linoleic acid molecule (or an alterative reductant such as guaiacol) and releases a carbon-centered linoleic radical. This reaction reduces the ferric LOX back to its ferrous form to start the next catalytic cycle. The released radical intermediates may then initiate free radical secondary reactions leading to the formation of mixed oxygenated and non-oxygenated linoleic acid dimer
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
redox reaction
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oxidation
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reduction
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dioxygenation
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PATHWAY SOURCE
PATHWAYS
BRENDA
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-, -, -, -, -, -, -, -, -, -
SYSTEMATIC NAME
IUBMB Comments
arachidonate:oxygen 15-oxidoreductase
The product is rapidly reduced to the corresponding 15S-hydroxy compound.
CAS REGISTRY NUMBER
COMMENTARY
82249-77-2
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
alpha-linolenate + O2
(9Z,11E,13S,15Z)-13-hydroperoxyoctadeca-9,11,15-trienoic acid + (9Z,11E,13S,15Z)-13-hydroxyoctadeca-9,11,15-trienoic acid
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?
2 arachidonate + 2 O2 + H+
(5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyeicosa-5,8,11,13-tetraenoate + (5Z,8Z,11Z,13E)-(15S)-15-hydroxyeicosa-5,8,11,13-tetraenoate + H2O
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(5Z,8Z,11Z,13E)-(15S)-15-hydroxyeicosa-5,8,11,13-tetraenoate slightly increases expression of monocyte chemoattractant protein MCP-1 in macrophages, also but more potent by 12(S)-hydroxyeicosatetranoic acid, overview, i.e. 15(S)-HPETE and 15(S)-HETE, the first is the predominant product
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?
arachidonate + O2
(5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyicosa-5,8,11,13-tetraenoate
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?
arachidonate + O2
(5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyicosa-5,8,11,13-tetraenoate
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-
?
arachidonate + O2
(5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyicosa-5,8,11,13-tetraenoate
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-
?
arachidonate + O2
(5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyicosa-5,8,11,13-tetraenoate
best substrate
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?
arachidonate + O2
(5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyicosa-5,8,11,13-tetraenoate
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best substrate
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?
arachidonate + O2
(5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyeicosa-5,8,11,13-tetraenoate
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?
arachidonate + O2
(5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyeicosa-5,8,11,13-tetraenoate
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?
arachidonate + O2
(5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyeicosa-5,8,11,13-tetraenoate
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the enzyme is regulated pretranslational, translational and posttranslational
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?
arachidonate + O2
(5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyeicosa-5,8,11,13-tetraenoate
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induction of experimental anemia leads to a systemic up-regulation of 12/15-lipoxygenases expression
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?
arachidonate + O2
(5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyicosa-5,8,11,13-tetraenoate
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?
arachidonate + O2
(5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyicosa-5,8,11,13-tetraenoate
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main product is 12(S)-hydroxyeicosatetranoic acid
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?
additional information
?
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the major reaction products are identified as(8S,15S,5Z,9E,11Z,13E)-8,15-dihydroperoxy-5,9,11,13-eicosatetraenoic acid (8S,15S-DiHpETE) and (5S,15S,6E,8Z,11Z,13E)-5,15-dihydroperoxy-6,8,11,13-eicosatetraenoic acid (5S,15S-DiHPETE) and the stereochemistry of the reaction is compatible with an inverse substrate orientation
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?
additional information
?
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the major reaction products are identified as(8S,15S,5Z,9E,11Z,13E)-8,15-dihydroperoxy-5,9,11,13-eicosatetraenoic acid (8S,15S-DiHpETE) and (5S,15S,6E,8Z,11Z,13E)-5,15-dihydroperoxy-6,8,11,13-eicosatetraenoic acid (5S,15S-DiHPETE) and the stereochemistry of the reaction is compatible with an inverse substrate orientation
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?
additional information
?
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enzyme substrate specificity, overview. The ALOX15 enzyme activity is not restricted to free polyenoic fatty acids since phospholipids and even biomembranes and lipoproteins are suitable ALOX15 substrates. The ALOX15 orthologue is capable of converting hydroperoxy fatty acids to epoxy leukotrienes. Product specificity with polyenoic acids and with complex substrates, and alteration of product specificity by substrate modification. Intraenzyme oxygen movement
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additional information
?
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enzyme substrate specificity, overview. The ALOX15 enzyme activity is not restricted to free polyenoic fatty acids since phospholipids and even biomembranes and lipoproteins are suitable ALOX15 substrates. The ALOX15 orthologue is capable of converting hydroperoxy fatty acids to epoxy leukotrienes. Product specificity with polyenoic acids and with complex substrates, and alteration of product specificity by substrate modification. Intraenzyme oxygen movement
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additional information
?
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the enzymatic peroxidation reaction consists of four consecutive steps: At first a hydrogen atom is stereoselectively abstracted from one of the bisallylic methylene-groups forming an enzyme-bound radical. Secondly one of the two associated cis-double bonds is rearranged and forms a conjugated cis-trans-diene. Consecutively a peroxy radical is produced by inserting molecular oxygen. Finally the radical is reduced by antarafacial re-inserting of a hydrogen atom. The resulting product of this peroxidation reaction depends on the respective fatty acid, which is used as a substrate
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additional information
?
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a bifunctional enzyme exhibiting 12-LO and 15-LO activity, the enzyme is also able to catalyze stereoselective oxidation of linoleic acid at position 13 over 9 to preferentially form 13(S)-hydroperoxyoctadienoic acid, which enhances MCP-1 expression, overview
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?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
2 arachidonate + 2 O2 + H+
(5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyeicosa-5,8,11,13-tetraenoate + (5Z,8Z,11Z,13E)-(15S)-15-hydroxyeicosa-5,8,11,13-tetraenoate + H2O
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(5Z,8Z,11Z,13E)-(15S)-15-hydroxyeicosa-5,8,11,13-tetraenoate slightly increases expression of monocyte chemoattractant protein MCP-1 in macrophages, also but more potent by 12(S)-hydroxyeicosatetranoic acid, overview
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?
arachidonate + O2
(5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyicosa-5,8,11,13-tetraenoate
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?
arachidonate + O2
(5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyicosa-5,8,11,13-tetraenoate
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?
arachidonate + O2
(5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyicosa-5,8,11,13-tetraenoate
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?
arachidonate + O2
(5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyicosa-5,8,11,13-tetraenoate
best substrate
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?
arachidonate + O2
(5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyicosa-5,8,11,13-tetraenoate
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best substrate
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?
arachidonate + O2
(5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyeicosa-5,8,11,13-tetraenoate
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the enzyme is regulated pretranslational, translational and posttranslational
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?
arachidonate + O2
(5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyeicosa-5,8,11,13-tetraenoate
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induction of experimental anemia leads to a systemic up-regulation of 12/15-lipoxygenases expression
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?
additional information
?
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the major reaction products are identified as(8S,15S,5Z,9E,11Z,13E)-8,15-dihydroperoxy-5,9,11,13-eicosatetraenoic acid (8S,15S-DiHpETE) and (5S,15S,6E,8Z,11Z,13E)-5,15-dihydroperoxy-6,8,11,13-eicosatetraenoic acid (5S,15S-DiHPETE) and the stereochemistry of the reaction is compatible with an inverse substrate orientation
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?
additional information
?
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the major reaction products are identified as(8S,15S,5Z,9E,11Z,13E)-8,15-dihydroperoxy-5,9,11,13-eicosatetraenoic acid (8S,15S-DiHpETE) and (5S,15S,6E,8Z,11Z,13E)-5,15-dihydroperoxy-6,8,11,13-eicosatetraenoic acid (5S,15S-DiHPETE) and the stereochemistry of the reaction is compatible with an inverse substrate orientation
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?
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Fe2+
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
PD146176
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selective inhibitor of 12/15-LOX, macrophages treated with PD146176 elaborate reduced levels of interleukin-12 in response to Toxoplasma gondii antigen
siRNA
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cholesterol-tagged siRNAs targeting mouse leukocyte 12/15-LO reduce 12/15-LO expression in the kidney and confer beneficial effects on diabetes-induced changes in glomerular structure and ECM accumulation
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additional information
certain oxazole-4-carbonitrile based LOX inhibitors share a high inhibitory potency for human and mouse ALOX15 but hardly inhibit other mammalian LOX-isoforms
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additional information
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certain oxazole-4-carbonitrile based LOX inhibitors share a high inhibitory potency for human and mouse ALOX15 but hardly inhibit other mammalian LOX-isoforms
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additional information
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physico-chemical state of the substrate and the complex equilibrium between fatty acid monomers, acid soaps and micelles may impact the reaction specificity of LOX-isoforms
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
ALOX15 is usually present as catalytically silent ferrous enzyme. To initiate fatty acid oxygenation, the enzyme must first be oxidized to a ferric form capable of initiating hydrogen abstraction. Unfortunately, single activation of the enzyme is not sufficient to keep it running, since during catalysis small quantities of radical intermediates might escape from the active site leaving the enzyme in an inactive ferrous (Fe2+) form. To keep the reaction at quasistationary levels, repeated enzyme activation is required and the primary oxygenation products appear to serve as enzyme activators. In this sense, the LOX exhibits autocatalytic properties
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additional information
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ALOX15 is usually present as catalytically silent ferrous enzyme. To initiate fatty acid oxygenation, the enzyme must first be oxidized to a ferric form capable of initiating hydrogen abstraction. Unfortunately, single activation of the enzyme is not sufficient to keep it running, since during catalysis small quantities of radical intermediates might escape from the active site leaving the enzyme in an inactive ferrous (Fe2+) form. To keep the reaction at quasistationary levels, repeated enzyme activation is required and the primary oxygenation products appear to serve as enzyme activators. In this sense, the LOX exhibits autocatalytic properties
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
expression of 12/15-LOX pathway is upregulated in the diabetic heart
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12/15-LOX is selectively enhanced in the periphery, 12/15-LOX-expressing myeloid cells are enriched in the brain during chronic toxoplasmosis
additional information
eosinophils are the major cell type expressing 12/15-LOX during the corneal wound healing process
high level expression in peritoneal macrophages, while murine peripheral monocytes, alveolar macrophages and bone marrow-derived macrophages express alox15 only at low levels
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12/15-LOX is a macrophage-selective regulator of interleukin-12 production
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12/15-LOX is expressed by 95% of resident peritoneal CD11bhigh cells, with the remaining 5% being 12/15-LOX-. 12/15-LOX+ cells are phenotypically defined by high F4/80, SR-A, and Siglec1 expression, and enhanced IL-10 and G-CSF generation. In contrast, 12/15-LOX- cells are a dendritic cell population. Resident peritoneal macrophage numbers are significantly increased in 12/15-LOX-/- mice, suggesting alterations in migratory trafficking or cell differentiation in vivo
additional information
tissue specific expression of ALOX15 and transcriptional expression regulation, overview
additional information
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tissue specific expression of ALOX15 and transcriptional expression regulation, overview
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
malfunction
metabolism
cardiac 12/15-LOX pathway induced by high glucose condition increases the expression of cardiac inflammation in vitro
physiological function
physiological function
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
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
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
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
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
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
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
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
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-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 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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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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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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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
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). LOX15_MOUSE
663
0
75445
Swiss-Prot
other Location (Reliability: 2)
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
lipoxygenases are composed of a N-terminal beta-barrel domain and a larger C-terminal catalytic domain harboring a non-heme iron in its active side
additional information
mammalian ALOX15 enzyme structure comparisons, overview
additional information
-
mammalian ALOX15 enzyme structure comparisons, overview
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
generation of Alox15-deficient (12/15-LOX KO) mice
additional information
-
12/15-LO knockout mice show reduced monocyte chemoattractant protein MCP-1 expression
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
ligated into the pQE-9 plasmid and expressed as N-terminal His-tag fusion protein in Escherichia coli (XL-1 Blue)
-
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
12/15-LOX mRNA expression in cultured aortic smooth muscle cells is upregulated by angiotensin II, ATII. ATII also stimulates production of LOX-derived HETEs in arterial vessels and the kidney
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
allergen challenge up-regulates the expression of 12/15-LO in airway epithelial cells in mice. Interleukin-4 and interleukin-13 are inducers
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
drug development
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systemic delivery of cholesterol-tagged siRNAs targeting 12/15-LO has renoprotective effects under diabetic conditions and therefore can be a novel therapeutic approach for diabetic nephropathy
medicine
gene ALOX15 has potential as a therapeutic target for eradicating leukemia stem cells in chronic myeloid leukemia
medicine
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. Maresin 1 (MaR1) and resolvin D1 (RvD1), 12/15-LOX-derived specialized proresolving mediators (SPMs), inhibited cytokine production of ILC2s at nanomolar concentration
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Kuehn, H.; Heydeck, D.; Brinckman, R.; Trebus, F.
Regulation of cellular 15-lipoxygenase activity on pretranslational, translational, and posttranslational levels
Lipids
34
S273-S279
1999
Oryctolagus cuniculus, Homo sapiens, Mus musculus, Rattus norvegicus
-
Kim, K.S.; Chun, H.S.; Yoon, J.H.; Lee, J.G.; Lee, J.H.; Yoo, J.B.
Expression of 15-lipoxygenase-1 in human nasal epithelium: its implication in mucociliary differentiation
Prostaglandins Leukot. Essent. Fatty Acids
73
77-83
2005
Homo sapiens, Mus musculus
Fischer, K.A.; Van Leyen, K.; Lovercamp, K.W.; Manandhar, G.; Sutovsky, M.; Feng, D.; Safranski, T.; Sutovsky, P.
15-Lipoxygenase is a component of the mammalian sperm cytoplasmic droplet
Reproduction
130
213-222
2005
Babyrousa babyrussa, Equus caballus, Homo sapiens, Mus musculus, Sus scrofa
Wen, Y.; Gu, J.; Vandenhoff, G.E.; Liu, X.; Nadler, J.L.
Role of 12/15-lipoxygenase in the expression of MCP-1 in mouse macrophages
Am. J. Physiol. Heart Circ. Physiol.
294
H1933-H1938
2008
Mus musculus, Mus musculus C57BL/6
Yuan, H.; Lanting, L.; Xu, Z.; Li, S.; Swiderski, P.; Putta, S.; Jonnalagadda, M.; Kato, M.; Natarajan, R.
Effects of cholesterol-tagged small interfering RNAs targeting 12/15-lipoxygenase on parameters of diabetic nephropathy in a mouse model of type 1 diabetes
Am. J. Physiol. Renal Physiol.
295
F605-F617
2008
Mus musculus, Mus musculus DBA/2J
Walther, M.; Roffeis, J.; Jansen, C.; Anton, M.; Ivanov, I.; Kuhn, H.
Structural basis for pH-dependent alterations of reaction specificity of vertebrate lipoxygenase isoforms
Biochim. Biophys. Acta
1791
827-835
2009
Oryctolagus cuniculus, Homo sapiens, Mus musculus
Middleton, M.K.; Zukas, A.M.; Rubinstein, T.; Kinder, M.; Wilson, E.H.; Zhu, P.; Blair, I.A.; Hunter, C.A.; Pure, E.
12/15-lipoxygenase-dependent myeloid production of interleukin-12 is essential for resistance to chronic toxoplasmosis
Infect. Immun.
77
5690-5700
2009
Mus musculus, Mus musculus C57BL/6
Dioszeghy, V.; Rosas, M.; Maskrey, B.H.; Colmont, C.; Topley, N.; Chaitidis, P.; Kuehn, H.; Jones, S.A.; Taylor, P.R.; ODonnell, V.B.
12/15-Lipoxygenase regulates the inflammatory response to bacterial products in vivo
J. Immunol.
181
6514-6524
2008
Mus musculus, Mus musculus C57BL/6
Sears, D.D.; Miles, P.D.; Chapman, J.; Ofrecio, J.M.; Almazan, F.; Thapar, D.; Miller, Y.I.
12/15-lipoxygenase is required for the early onset of high fat diet-induced adipose tissue inflammation and insulin resistance in mice
PLoS ONE
4
e7250
2009
Mus musculus, Mus musculus C57BL6
Claesson, H.E.
On the biosynthesis and biological role of eoxins and 15-lipoxygenase-1 in airway inflammation and Hodgkin lymphoma
Prostaglandins Other Lipid Mediat.
89
120-125
2009
Homo sapiens, Mus musculus, Oryctolagus cuniculus, Sus scrofa
Bhattacharya, S.; Mathew, G.; Jayne, D.G.; Pelengaris, S.; Khan, M.
15-lipoxygenase-1 in colorectal cancer: a review
Tumour Biol.
30
185-199
2009
Homo sapiens, Mus musculus, Rattus norvegicus
Ackermann, J.A.; Hofheinz, K.; Zaiss, M.M.; Kroenke, G.
The double-edged role of 12/15-lipoxygenase during inflammation and immunity
Biochim. Biophys. Acta
1862
371-381
2017
Homo sapiens (P16050), Mus musculus (P39654)
Kwon, H.J.; Kim, S.N.; Kim, Y.A.; Lee, Y.H.
The contribution of arachidonate 15-lipoxygenase in tissue macrophages to adipose tissue remodeling
Cell Death Dis.
7
e2285
2016
Mus musculus (P39654)
Suzuki, H.; Kayama, Y.; Sakamoto, M.; Iuchi, H.; Shimizu, I.; Yoshino, T.; Katoh, D.; Nagoshi, T.; Tojo, K.; Minamino, T.; Yoshimura, M.; Utsunomiya, K.
Arachidonate 12/15-lipoxygenase-induced inflammation and oxidative stress are involved in the development of diabetic cardiomyopathy
Diabetes
64
618-630
2015
Mus musculus (P39654), Mus musculus C57BL/6 (P39654)
Ivanov, I.; Kuhn, H.; Heydeck, D.
Structural and functional biology of arachidonic acid 15-lipoxygenase-1 (ALOX15)
Gene
573
1-32
2015
Oryctolagus cuniculus (P12530), Oryctolagus cuniculus, Homo sapiens (P16050), Homo sapiens, Mus musculus (P39654), Mus musculus, Rattus norvegicus (Q02759)
Kundumani-Sridharan, V.; Dyukova, E.; Hansen, D.E.; Rao, G.N.
12/15-Lipoxygenase mediates high-fat diet-induced endothelial tight junction disruption and monocyte transmigration a new role for 15(S)-hydroxyeicosatetraenoic acid in endothelial cell dysfunction
J. Biol. Chem.
288
15830-15842
2013
Mus musculus (P39654), Mus musculus C57BL/6 (P39654)
Chen, Y.; Peng, C.; Abraham, S.A.; Shan, Y.; Guo, Z.; Desouza, N.; Cheloni, G.; Li, D.; Holyoake, T.L.; Li, S.
Arachidonate 15-lipoxygenase is required for chronic myeloid leukemia stem cell survival
J. Clin. Invest.
124
3847-3862
2014
Mus musculus (P39654), Mus musculus
Kumar, N.; Gupta, G.; Anilkumar, K.; Fatima, N.; Karnati, R.; Reddy, G.; Giri, P.; Reddanna, P.
15-Lipoxygenase metabolites of alpha-linolenic acid, [13-(S)-HPOTrE and 13-(S)-HOTrE], mediate anti-inflammatory effects by inactivating NLRP3 inflammasome
Sci. Rep.
6
31649
2016
Mus musculus (P39654), Mus musculus, Mus musculus BALB/c (P39654)
Ogawa, M.; Ishihara, T.; Isobe, Y.; Kato, T.; Kuba, K.; Imai, Y.; Uchino, Y.; Tsubota, K.; Arita, M.
Eosinophils promote corneal wound healing via the 12/15-lipoxygenase pathway
FASEB J.
34
12492-12501
2020
Mus musculus (P39654)
Miyata, J.; Yokokura, Y.; Moro, K.; Arai, H.; Fukunaga, K.; Arita, M.
12/15-Lipoxygenase regulates IL-33-induced eosinophilic airway inflammation in mice
Front. Immunol.
12
687192
2021
Mus musculus (P39654)
Dobrian, A.D.; Huyck, R.W.; Glenn, L.; Gottipati, V.; Haynes, B.A.; Hansson, G.I.; Marley, A.; McPheat, W.L.; Nadler, J.L.
Activation of the 12/15 lipoxygenase pathway accompanies metabolic decline in db/db pre-diabetic mice
Prostaglandins Other Lipid Mediat.
136
23-32
2018
Mus musculus (P39654)
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