ALOX5

This gene encodes a member of the lipoxygenase gene family and plays a dual role in the synthesis of leukotrienes from arachidonic acid. The encoded protein, which is expressed specifically in bone marrow-derived cells, catalyzes the conversion of arachidonic acid to 5(S)-hydroperoxy-6-trans-8,11,14-cis-eicosatetraenoic acid, and further to the allylic epoxide 5(S)-trans-7,9-trans-11,14-cis-eicosatetrenoic acid (leukotriene A4). Leukotrienes are important mediators of a number of inflammatory and allergic conditions. Mutations in the promoter region of this gene lead to a diminished response to antileukotriene drugs used in the treatment of asthma and may also be associated with atherosclerosis and several cancers. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]

Arachidonate 5-Lipoxygenase

Catalyzes the oxygenation of arachidonate ((5Z,8Z,11Z,14Z)-eicosatetraenoate) to 5-hydroperoxyeicosatetraenoate (5-HPETE) followed by the dehydration to 5,6- epoxyeicosatetraenoate (Leukotriene A4/LTA4), the first two steps in the biosynthesis of leukotrienes, which are potent mediators of inflammation (PubMed:8631361, PubMed:21233389, PubMed:22516296, PubMed:24282679, PubMed:19022417, PubMed:23246375, PubMed:8615788, PubMed:24893149, PubMed:31664810). Also catalyzes the oxygenation of arachidonate into 8-hydroperoxyicosatetraenoate (8-HPETE) and 12-hydroperoxyicosatetraenoate (12-HPETE) (PubMed:23246375). Displays lipoxin synthase activity being able to convert (15S)-HETE into a conjugate tetraene (PubMed:31664810). Although arachidonate is the preferred substrate, this enzyme can also metabolize oxidized fatty acids derived from arachidonate such as (15S)-HETE, eicosapentaenoate (EPA) such as (18R)- and (18S)-HEPE or docosahexaenoate (DHA) which lead to the formation of specialized pro-resolving mediators (SPM) lipoxin and resolvins E and D respectively, therefore it participates in anti-inflammatory responses (PubMed:21206090, PubMed:31664810, PubMed:8615788, PubMed:17114001, PubMed:32404334). Oxidation of DHA directly inhibits endothelial cell proliferation and sprouting angiogenesis via peroxisome proliferator-activated receptor gamma (PPARgamma) (By similarity). It does not catalyze the oxygenation of linoleic acid and does not convert (5S)-HETE to lipoxin isomers (PubMed:31664810). In addition to inflammatory processes, it participates in dendritic cell migration, wound healing through an antioxidant mechanism based on heme oxygenase-1 (HO-1) regulation expression, monocyte adhesion to the endothelium via ITGAM expression on monocytes (By similarity). Moreover, it helps establish an adaptive humoral immunity by regulating primary resting B cells and follicular helper T cells and participates in the CD40-induced production of reactive oxygen species (ROS) after CD40 ligation in B cells through interaction with PIK3R1 that bridges ALOX5 with CD40 (PubMed:21200133). Also may play a role in glucose homeostasis, regulation of insulin secretion and palmitic acid-induced insulin resistance via AMPK (By similarity). Can regulate bone mineralization and fat cell differentiation increases in induced pluripotent stem cells (By similarity).

Arachidonic acid metabolic process Source: GO_Central
Cytokine-mediated signaling pathway Source: Reactome
Dendritic cell migration Source: UniProtKB
Glucose homeostasis Source: UniProtKB
Hepoxilin biosynthetic process Source: GO_Central
Humoral immune response Source: UniProtKB
Interleukin-18-mediated signaling pathway Source: Reactome
Leukocyte chemotaxis involved in inflammatory response Source: UniProtKB
Leukocyte migration involved in inflammatory response Source: UniProtKB
Leukotriene A4 biosynthetic process Source: UniProtKB
Leukotriene biosynthetic process Source: UniProtKB
Leukotriene metabolic process Source: Reactome
Leukotriene production involved in inflammatory response Source: Ensembl
Linoleic acid metabolic process Source: GO_Central
Lipid oxidation Source: GO_Central
Lipoxin biosynthetic process Source: UniProtKB
Lipoxygenase pathway Source: GO_Central
Long-chain fatty acid biosynthetic process Source: Reactome
Negative regulation of angiogenesis Source: UniProtKB
Negative regulation of endothelial cell proliferation Source: UniProtKB
Negative regulation of inflammatory response Source: UniProtKB
Negative regulation of response to endoplasmic reticulum stress Source: UniProtKB
Negative regulation of sprouting angiogenesis Source: UniProtKB
Negative regulation of vascular wound healing Source: UniProtKB
Negative regulation of wound healing Source: UniProtKB
Neutrophil degranulation Source: Reactome
Positive regulation of bone mineralization Source: UniProtKB
Positive regulation of leukocyte adhesion to arterial endothelial cell Source: UniProtKB
Regulation of cellular response to oxidative stress Source: UniProtKB
Regulation of cytokine production involved in inflammatory response Source: UniProtKB
Regulation of fat cell differentiation Source: UniProtKB
Regulation of inflammatory response Source: UniProtKB
Regulation of inflammatory response to wounding Source: UniProtKB
Regulation of insulin secretion Source: UniProtKB
Regulation of reactive oxygen species biosynthetic process

Cytoplasm; Cytosol; Nucleus matrix; Nucleus membrane; Nucleus envelope; Nucleus intermembrane space; Perinuclear region. Shuttles between cytoplasm and nucleus (PubMed:19233132). Found exclusively in the nucleus, when phosphorylated on Ser-272 (PubMed:18978352). Calcium binding promotes translocation from the cytosol and the nuclear matrix to the nuclear envelope and membrane association (PubMed:19233132, PubMed:3118366, PubMed:8245774, PubMed:16275640).

Serine phosphorylation by MAPKAPK2 is stimulated by arachidonic acid (PubMed:11844797, PubMed:18978352). Phosphorylation on Ser-524 by PKA has an inhibitory effect (PubMed:15280375). Phosphorylation on Ser-272 prevents export from the nucleus (PubMed:11844797, PubMed:18978352). Phosphorylation at Ser-524 is stimulated by 8-bromo-3',5'-cyclic AMP or prostaglandin E2 (PubMed:26210919).