ALOX15

Arachidonate 15-lipoxygenase is an is_associated_with::enzyme (is_associated_with::molecular weight of 75 kDa) that in humans is encoded by the ALOX15 is_associated_with::gene. ALOX15 is also known as 15-lipoxygenase-1 (15-LO-1 or 15-LOX-1) and is distinguished from its related oxygenase, is_associated_with::ALOX15B or 15-lipoxygenase-2.

Nomenclature
15-lipoxygenase is a is_associated_with::lipoxygenase-type is_associated_with::enzyme that metabolizes is_associated_with::arachidonic acid primarily to a 15-hydroperoxy product. The enzyme was initially named is_associated_with::arachidonate 15-lipoxygenase but subsequent studies uncovered a second enzyme with 15-lipoxygenase-like activity; consequently, the ALOX15 product is now referred to as arachidonate-15-lipoxygenase-1, 15-lipoxygenase-1, 15-LOX-1, 12/15-lipoxygenase, arachidonate 12-lipoxygenase, leukocyte-type, or arachidonate omega-6 lipoxygenase while the second discovered 15-lipoxygenase, a product of the is_associated_with::ALOX15B gene, is termed arachidonate 15-lipoxygenase 2, 15-lipoxygenase-2, 15-LOX-2, arachidonate 15-lipoxygenase type II, arachidonate 15-lipoxygenase, second type, or arachidonate 15-lipoxygenase, platelet type. Human 15-LOX-1 and 15-LOX-2 genes are both located on chromosome 17 but their encoded lipoxygenases have an amino acid sequence identity of only ~38%, differ in theis_associated_with::polyunsaturated fatty acids that they prefer as substrates, and exhibit somewhat different product profiles when acting on the same substrates.

Human tissue distribution
15-LOX-1 protein is highly expressed in circulating blood is_associated_with::eosinophils, bronchial airway epithelial cells, mammary epithelial cells, the is_associated_with::Reed-Sternberg cells of is_associated_with::Hodgkin's lymphoma, is_associated_with::cornea epithelial cells, is_associated_with::reticulocytes, and is_associated_with::dendritic cells; it is less strongly expressed in alveolar is_associated_with::macrophages, tissue is_associated_with::mast cells, tissue is_associated_with::fibroblasts, circulating blood is_associated_with::neutrophils, vascular is_associated_with::endothelial cells, joint is_associated_with::Synovial membrane cells, is_associated_with::seminal fluid, prostate epithelium cells, and mammary ductal epithelial cells.

Function
Human 15-LOX-1 attaches molecular oxygen to the 15th or 12th carbon of is_associated_with::arachidonic acid and then adds a hydrogen atom to the attached  to form 15(S)-hydroperoxy-5Z,8Z,11Z,13E-eicosatetraenoic acid (15(S)-HpETE) and 12(S)-hydroperoxy-5Z,8Z,10E,15S-eicosatetraenoic acid (12(S)-HpETE), respectively, in a 15(S)-HpETE to 12(S)-HpETE product ratio of ~4-9 to 1. Both products may be rapidly reduced by ubiquitous cellular enzymes with peroxide-reducing activity to form their corresponding hydroxy analogs, 15(S)-HETE (see is_associated_with::15-hydroxyicosatetraenoic acid) and 12(S)-HETE (see is_associated_with::12-Hydroxyeicosatetraenoic acid). 15-(S)-HpETE and/or 15(S)-HETE may then be further metabolized by 15-LOX-1 or other lipoxygenases to various di-hydroxy and tri-hydroxy compounds, e.g., 8(S),15(S)-dihydroxy-eicosatetraenoic acid (8(S),15(S)-diHETE), 8(R),15(S)-diHETE, 5(S),15(S)-diHETE, 14(R),15(S)-diHETE, and various is_associated_with::lipoxins. Alternatively, 15-LOX-1 can further metabolize 15(S)-HpETE to its 14,15-is_associated_with::epoxide and then to various 14,15-is_associated_with::hepoxilins or to various is_associated_with::eoxins.

However, 15-LOX-1 prefers is_associated_with::linoleic acid over arachidonic acid as its primary ω-6 polyunsaturated fatty acid (see is_associated_with::Omega-6 fatty acid) substrate, oxygenating it at carbon 13 to form 13(S)-hydroperoxy-9Z,11E-octadecaenoic acid (13-HpODE or 13(S)-HpODE) which is then reduce to the corresponding hydroxy derivative, 13(S)-HODE or 13-HODE. Non-human 15-LOX1 orthologs such as mouse 12/15-LOX and soybean 15-LOX form, in addition to 13(S)-HODE, metabolize linoleic acid to 9-hydroperoxy-10E,12Z-octadecaenoic acid (9-HpODE or 9(S)-HpODE), which in mice is rapidly converted to 9(S)-HODE (9-HODE). These arachidonic and linoleic acid metabolites have significant bioactivities and potential but unproven clinical relevancies.

Human 15-LOX-1 also acts on ω-3 polyunsaturated fatty acids (see is_associated_with::Omega-3 fatty acid): it metabolizes is_associated_with::α-linolenic acid to 13(S)-hydroperoxy-9Z,11E,15Z)-octadecatrienoic acid; is_associated_with::eicosapentaenoic acid to 15(S)-hydroperoxy-5Z,8Z,11Z,13E,17Z-eicosatetraenoic acid (15(S)-HpEPA) and is_associated_with::docosahexaenoic acid to 17(S)-hydroperoxy-4Z,7Z,10Z,13Z,15E,19Z-docosahexaenoic acid (17-HpDHA) and to neuroprotectin D1 (i.e. 10(R),17(S)-dihydroxy-4Z,7Z,11E,13E,15Z,19Z-docosahexaenoic acid, also designated protectin D1).  15(S)-HpEPA and 17(S)-HpDHA are reduced to 15(S)-hydroxy-5Z,8Z,11Z,13E,17Z-eicosatetraenoic acid (15-HEPA or 15(S)-HEPA) and 17(S)-hydroxy-4Z,7Z,10Z,13Z,15E,19Z-docosahexaenoic acid (17-HDHA or 17(S)-HDHA), respectively; all of these metabolites possess various and often overlapping bioactivities.

15-LOX-1 also works in conjunction with other oxygenating enzymes to form a wide range of products that inhibit, limit, and resolve inflammatory reactions. 15-LOX-1 acts in series with: a) is_associated_with::5-LOX to metabolize arachidonic acid to is_associated_with::lipoxins; b) with 5-LOX to metabolize docosahexaenoic acid to is_associated_with::resolvins D1, D2, D3, D4, D5, and D6; and c) aspirin-treated is_associated_with::cyclooxygenase-2 or is_associated_with::cytochrome P450 enzymes to metabolize eicosapentaenoic acid to is_associated_with::resolvin E3.

Inflammatory diseases
A huge and growing number of studies in animal models suggest that 15-LOX-1 and its lipoxin, resolvin, and protectin metabolites act to inhibit, limit, and resolve diverse inflammatory diseases including is_associated_with::periodontitis, is_associated_with::peritonitis, is_associated_with::sepsis, and other pathogen-induced inflammatory responses, is_associated_with::eczema, is_associated_with::arthritis, is_associated_with::asthma, is_associated_with::cystic fibrosis, is_associated_with::atherosclerosis, is_associated_with::adipose tissue inflammation and subsequent is_associated_with::insulin resistance that occurs in obesity, is_associated_with::diabetes and the is_associated_with::metabolic syndrome, and is_associated_with::Alzheimer's disease. While these studies have not yet been shown to translate to human diseases, first and second generation synthetic resolvins and lipoxins have been made and may prove in future studies of clinical use for treating one or more of such diseases.

By metabolizing ω-3 polyunsaturated fatty acids, eicosapentaenoic acid and docosahexaenoic acid, into lipoxins, resolvins, and protectins, 15-LOX-1 is thought to be one mechanism by which dietary ω-3 polyunsaturated fatty acids, particularly is_associated_with::fish oil, may act to reduce inflammation and inflammation-related diseases.

Asthma
While studies have shown that is_associated_with::5-lipoxygenase and its is_associated_with::Leukotriene and possibly 5-oxo-eicosatatraenoic acid (see is_associated_with::5-Hydroxyicosatetraenoic acid) metabolites contribute to, and are important pharmacological in the treatment of, severe human allergen-induced is_associated_with::asthma and is_associated_with::aspirin-induced asthma, recent work suggests that 15-LOX-1 and its is_associated_with::eoxin metabolites may also be contributors to these diseases. Further work on this issue is needed.

Cancer
In colorectal, breast, and kidney cancers, 15-LOX-1 levels are low or absent compared to the cancers' normal tissue counterparts and/or these levels sharply decline as the cancers progress. These results, as well as a 15-LOX-1 transgene study on colon cancer in mice suggests but do not prove that 15-LOX-1 is a is_associated_with::tumor suppressor.

By metabolizing ω-3 polyunsaturated fatty acids, eicosapentaenoic acid and docosahexaenoic acid, into lipoxins and resolvins, 15-LOX-1 is thought to be one mechanism by which dietary ω-3 polyunsaturated fatty acids, particularly fish oil, may act to reduce the incidence and/or progression of certain cancers. 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 the 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)