24611687ENSG00000161905ENSMUSG00000018924P16050P39654NM_001140NM_009660NP_001131NP_033790ALOX15 (also termed arachidonate 15-lipoxygenase, 15-lipoxygenase-1, 15-LO-1, 15-LOX-1) is, like other lipoxygenases, a seminal enzyme in the metabolism of polyunsaturated fatty acids to a wide range of physiologically and pathologically important products.

[5] This 11 kilobase pair gene consists of 14 exons and 13 introns coding for a 75 kilodalton protein composed of 662 amino acids.

ALOX15 and Alox15 enzymes act with a high degree of stereospecificity to form products that position the hydroperoxy residue in the S stereoisomer configuration.

[14] Both products may be rapidly reduced by ubiquitous cellular glutathione peroxidase enzymes to their corresponding hydroxy analogs, 15(S)-HETE and 12(S)-HETE.

15(S)-HpETE and 15(S)-HETE bind to and activate the leukotriene B4 receptor 2, activate the peroxisome proliferator-activated receptor gamma, and at high concentrations cause cells to generate toxic reactive oxygen species; one or more of these effects may be at least in part responsible for their ability to promote inflammatory responses, alter the growth of various times of human cancer cell lines, contract various types of blood vessels, and stimulate pathological fibrosis in pulmonary arteries and liver (see 15-Hydroxyeicosatetraenoic acid § 15(S)-HpETE and 15(S)-HETE).

As one aspect of this processing, the two products are progressively esterified in mitochondria membrane phospholipids during the maturation of red blood cells and thereby may serve to signal for the degradation of the mitochondria and the maturation of these precursors to red blood cells in mice.

[22][23] 13(S)-HODE acts through peroxisome proliferator-activated receptors and the TRPV1 and human GPR132 receptors to stimulate a variety of responses related to monocyte maturation, lipid metabolism, and neuron activation (see 13-Hydroxyoctadecadienoic acid § Activities); 9(S)-HODE is a marker for diseases involving oxidative stress and may contribute to this disease as well as to pain perception and atherosclerosis (see 9-Hydroxyoctadecadienoic acid § Biological and clinical relevancy of 9-HODEs).

Alox15 overexpressing rabbits exhibited reduced tissue destruction and bone loss in a model of periodontitis.

À huge and growing number of studies in animal models suggest that 15-LOX-1 and its lipoxin, resolvin, and protectin metabolites (see Specialized proresolving mediators) to inhibit, limit, and resolve diverse inflammatory diseases including periodontitis, peritonitis, sepsis, and other pathogen-induced inflammatory responses; in eczema, arthritis, asthma, cystic fibrosis, atherosclerosis, and adipose tissue inflammation; in the insulin resistance that occurs in obesity that is associated with diabetes and the metabolic syndrome; and in Alzheimer's disease.

[27][28][29][30][31] While these studies have not yet been shown to translate to human diseases, first and second generation synthetic resolvins and lipoxins, which unlike their natural analogs, are relatively resistant to metabolic inactivation, have been made and tested as inflammation inhibitors in animal models.

[10][27][35] These results, as well as a 15-LOX-1 transgene study on colon cancer in mice[36] suggests but do not prove[37] that 15-LOX-1 is a tumor suppressor.

[27] Indeed, the ability of docosahexaenoic acid to inhibit the growth of cultured human prostate cancer cells is totally dependent upon the expression of 15-LOX-1 by these cells and appears due to this enzyme's production of docosahexaenoic acid metabolites such as 17(S)-HpETE, 17(S)-HETE, and/or and, possibly, an isomer of protectin DX (10S,17S-dihydroxy-4Z,7Z,11E,13Z,15E,19Z-docosahexaenoic acid)[11][16] Kelavkar et.al have shown that aberrant overexpression of 15-LO-1 occurs in human PCa, particularly high-grade PCa, and in high-grade prostatic intraepithelial neoplasia (HGPIN), and that the murine orthologue is increased in SV40-based genetically engineered mouse (GEM) models of PCa, such as LADY and TRansgenic Adenocarcinoma of Mouse Prostate.

These results support 15-LO-1 as having a role in prostate tumor initiation and as an early target for dietary or other prevention strategies.