View source for ALOX15

[[File:1lox.jpg|thumb|300px|The arachidonate 15-lipoxygenase of the [[Oryctolagus cuniculus|European rabbit]].]]
{{Infobox_gene}}

'''ALOX15''' (also termed arachidonate 15-lipoxygenase, 15-lipoxygenase-1, 15-LO-1, 15-LOX-1) is, like other [[lipoxygenase]]s, a seminal [[enzyme]] in the metabolism of [[polyunsaturated fatty acid]]s to a wide range of physiologically and pathologically important products.
▼ Gene Function

Kelavkar and Badr (1999) stated that the ALOX15 gene product is implicated in antiinflammation, membrane remodeling, and cancer development/metastasis. Kelavkar and Badr (1999) described experiments yielding data that supported the hypothesis that loss of the TP53 gene, or gain-of-function activities resulting from the expression of its mutant forms, regulates ALOX15 promoter activity in human and in mouse, albeit in directionally opposite manners. These studies defined a direct link between ALOX15 gene activity and an established tumor-suppressor gene located in close chromosomal proximity. Kelavkar and Badr (1999) referred to this as evidence that 15-lipoxygenase is a mutator gene. 
▼ Mapping

By PCR analysis of a human-hamster somatic hybrid DNA panel, Funk et al. (1992) demonstrated that genes for 12-lipoxygenase and 15-lipoxygenase are located on human chromosome 17, whereas the most unrelated lipoxygenase (5-lipoxygenase) was mapped to chromosome 10. 

Kelavkar and Badr (1999) stated that the ALOX15 gene maps to 17p13.3 in close proximity to the tumor-suppressor gene TP53 (191170). In humans, it is encoded by the ALOX15 [[gene]] located on [[chromosome 17]]p13.3.<ref name="pmid1570320">{{cite journal | vauthors = Funk CD, Funk LB, FitzGerald GA, Samuelsson B | title = Characterization of human 12-lipoxygenase genes | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 89 | issue = 9 | pages = 3962–6 | date = May 1992 | pmid = 1570320 | pmc = 525611 | doi = 10.1073/pnas.89.9.3962 }}</ref> This 11 kilo[[base pair]] gene consists of 14 [[exons]] and 13 [[introns]] coding for a 75 [[kiloDalton]] protein composed of 662 amino acids. 15-LO is to be distinguished from another human 15-lipoxygenase enzyme, [[ALOX15B]] (also termed 15-lipoxygenase-2).<ref name="Gene 2015">{{cite journal | vauthors = Ivanov I, Kuhn H, Heydeck D | title = Structural and functional biology of arachidonic acid 15-lipoxygenase-1 (ALOX15) | journal = Gene | volume = 573 | issue = 1 | pages = 1–32 | date = November 2015 | pmid = 26216303 | doi = 10.1016/j.gene.2015.07.073 }}</ref> [[Orthologs]] of ALOX15, termed Alox15, are widely distributed in animal and plant species but commonly have different enzyme activities and make somewhat different products than ALOX15.

== Nomenclature ==

Human ALOX15 was initially named arachidonate 15-lipoxygenase or 15-lipoxygenase but subsequent studies uncovered a second human enzyme with 15-lipoxygenase activity as well as various non-human mammalian Alox15 enzymes that are closely related to and therefore [[orthologs]] of human ALOX15. Many of the latter Alox15 enzymes nonetheless possess predominantly or exclusively [[12-lipoxygenase]] rather than 15-lipoxygenase activity. Consequently, human ALOX15 is now referred to as arachidonate-15-lipoxygenase-1, 15-lipoxygenase-1, 15-LOX-1, 15-LO-1, human 12/15-lipoxygenase, leukocyte-type arachidonate 12-lipoxygenase, or arachidonate omega-6 lipoxygenase.  The second discovered human 15-lipoxygenase, a product of the [[ALOX15B]] gene, is termed ALOX15B, arachidonate 15-lipoxygenase 2, 15-lipoxygenase-2, 15-LOX-2, 15-LO-2, arachidonate 15-lipoxygenase type II, arachidonate 15-lipoxygenase, second type, and arachidonate 15-lipoxygenase; and mouse, rat, and rabbit rodent orthologs of human ALOX15, which share 74-81% amino acid identity with the human enzyme, are commonly termed Alox15, 12/15-lipoxygenase, 12/15-LOX, or 12/15-LO).<ref name="pmid1570320"/><ref name="Gene 2015"/>

Both human ALOX15 and ALOX15B genes are located on chromosome 17; their product proteins have an amino acid sequence identity of only ~38%; they also differ in the [[polyunsaturated fatty acid]]s that they prefer as substrates and exhibit different product profiles when acting on the same substrates.<ref name="Gene 2015"/><ref name="pmid9177185">{{cite journal | vauthors = Brash AR, Boeglin WE, Chang MS | title = Discovery of a second 15S-lipoxygenase in humans | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 94 | issue = 12 | pages = 6148–52 | date = June 1997 | pmid = 9177185 | pmc = 21017 | doi = 10.1073/pnas.94.12.6148 }}</ref>

== Tissue distribution ==

Human ALOX15 protein is highly expressed in circulating blood [[eosinophil]]s and [[reticulocytes]],  cells, bronchial airway epithelial cells, mammary epithelial cells, the [[Reed-Sternberg cells]] of [[Hodgkin's lymphoma]], [[cornea]]l epithelial cells, and [[dendritic cells]]; it is less strongly expressed in alveolar [[macrophages]], tissue [[mast cells]], tissue [[fibroblasts]], circulating blood [[neutrophils]], vascular [[endothelial cells]], joint [[Synovial membrane]] cells, [[seminal fluid]], prostate epithelium cells, and mammary ductal epithelial cells.<ref>{{cite journal | vauthors = Claesson HE | title = On the biosynthesis and biological role of eoxins and 15-lipoxygenase-1 in airway inflammation and Hodgkin lymphoma | journal = Prostaglandins & Other Lipid Mediators | volume = 89 | issue = 3–4 | pages = 120–5 | date = September 2009 | pmid = 19130894 | doi = 10.1016/j.prostaglandins.2008.12.003 }}</ref><ref>{{cite journal | vauthors = Jiang WG, Watkins G, Douglas-Jones A, Mansel RE | title = Reduction of isoforms of 15-lipoxygenase (15-LOX)-1 and 15-LOX-2 in human breast cancer | journal = Prostaglandins, Leukotrienes, and Essential Fatty Acids | volume = 74 | issue = 4 | pages = 235–45 | date = April 2006 | pmid = 16556493 | doi = 10.1016/j.plefa.2006.01.009 }}</ref><ref name="ReferenceB">{{cite journal | vauthors = Shureiqi I, Wu Y, Chen D, Yang XL, Guan B, Morris JS, Yang P, Newman RA, Broaddus R, Hamilton SR, Lynch P, Levin B, Fischer SM, Lippman SM | title = The critical role of 15-lipoxygenase-1 in colorectal epithelial cell terminal differentiation and tumorigenesis | journal = Cancer Research | volume = 65 | issue = 24 | pages = 11486–92 | date = December 2005 | pmid = 16357157 | doi = 10.1158/0008-5472.can-05-2180 | pmc=1564070}}</ref><ref name="ReferenceC">{{cite journal | vauthors = Hu Y, Sun H, O'Flaherty JT, Edwards IJ | title = 15-Lipoxygenase-1-mediated metabolism of docosahexaenoic acid is required for syndecan-1 signaling and apoptosis in prostate cancer cells | journal = Carcinogenesis | volume = 34 | issue = 1 | pages = 176–82 | date = January 2013 | pmid = 23066085 | doi = 10.1093/carcin/bgs324 | pmc=3584949}}</ref>

The distribution of Alox15 in sub-human primates and, in particular, rodents differs significantly from that of human ALOX15; this, along with there different principal product formation (e.g. 12-HETE rather than 15-HETE) has made the findings of Alox15 functions in rat, mouse, or rabbit models difficult to extrapolate to the function of ALOX15 in humans.<ref name="Gene 2015"/>

== Enzyme activities ==

=== Lipoxygenase activity ===

ALOX15 and Alox15 enzymes are non-heme, iron-containing [[dioxygenase]]s.  They commonly catalyze the attachment of molecular oxygen {{chem|O|2}} as a [[peroxy]] residue to [[polyunsaturated fatty acids]] (PUFA) that contain two carbon-carbon [[double bond]]s that for the human ALOX15 are located between carbons 10 and 9 and 7 and 6 as numbered counting backward from the last or omega (i.e. ω) carbon at the methyl end of the PUFA (these carbons are also termed ω-10 and ω-9 and ω-7 and ω-6).  In PUFAs that do not have a third carbon-carbon double bound between their ω-13 and ω-12 carbons, human ALOX15 forms ω-6 peroxy intermediates; in PUFAs that do have this third double bound, human ALOX15 makes the ω-6 peroxy intermediate but also small amounts of the ω-9 peroxy intermediate. Rodent Alox15 enzymes, in contrast, produce almost exclusively ω-9 peroxy intermediates. Concurrently, ALOX15 and rodent Alox15 enzymes rearrange the carbon-carbon double bonds to bring them into the 1''S''-hydroxy-2''E'',4''Z''-[[diene]] configuration. ALOX15 and Alox15 enzymes act with a high degree of [[Stereospecificity]] to form products that position the hydroperoxy residue in the ''S'' [[stereoisomer]] configuration.<ref>{{cite journal | vauthors = Kuhn H, Banthiya S, van Leyen K | title = Mammalian lipoxygenases and their biological relevance | journal = Biochimica et Biophysica Acta | volume = 1851 | issue = 4 | pages = 308–30 | date = April 2015 | pmid = 25316652 | pmc = 4370320 | doi = 10.1016/j.bbalip.2014.10.002 }}</ref>

=== Lipohydroperoxidase activity ===

Human ALOX15 can also convert the peroxy PUFA intermediate to a cyclic ether with a three-atom ring, i.e. an [[epoxide]] intermediate that is attacked by a water molecule to form epoxy-hydrpoxy PUFA products.<ref name="Gene 2015"/> Eoxins stimulate vascular permeability in an ex vivo human vascular endothelial model system.<ref name="pmid18184802">{{cite journal | vauthors = Feltenmark S, Gautam N, Brunnström A, Griffiths W, Backman L, Edenius C, Lindbom L, Björkholm M, Claesson HE | title = Eoxins are proinflammatory arachidonic acid metabolites produced via the 15-lipoxygenase-1 pathway in human eosinophils and mast cells | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 2 | pages = 680–5 | year = 2008 | pmid = 18184802 | pmc = 2206596 | doi = 10.1073/pnas.0710127105 | url = }}</ref>

=== Leukotriene synthase activity ===

The PUFA epoxide of arachidonic acid made by ALOX15 may also be conjugated with glutathione to form [[eoxin]] A4 which product can be further metabolized to eoxin B4, eoxin C4, and eoxin D4.<ref name="Gene 2015"/>

== Substrates, substrate metabolites, and metabolite activities ==
Among their physiological substrates, human and rodent AlOX15 enzymes act on [[linoleic acid]], [[alpha-linolenic acid]], [[gamma-linolenic acid]], arachidonic acid, [[eicosapentaenoic acid]], and [[docosahexaenoic acid]] when presented not only as free acids but also when incorporated as [[esters]] in [[phospholipids]], [[glycerides]], or [[Cholesteryl esters]].  The human enzyme is particularly active on linoleic acid, preferring it over arachidonic acid. It is less active on PUFA that are esters within the cited lipids.<ref name="Gene 2015"/>

===Arachidonic acid===
Arachidonic acid (AA) has [[double bond]]s between carbons 5-6, 8-9, 11-12, and 14-15; these double bonds are in the cis (see [[Cis–trans isomerism]] or '''Z''' as opposed to the trans or ''E'' configuration. ALOX15 adds a hydroperoxy residue to AA at carbons 15 and to a lesser extent 12 to from 15(''S'')-hydroperoxy-5''Z'',8''Z'',11''Z'',13''E''-eicosatetraenoic acid (15(''S'')-HpETE) and 12(''S'')-hydroperoxy-5''Z'',8''Z'',10''E'', 15''S''-eicosatetraenoic acid (12(''S'')-HpETE); the purified enzyme makes 15(''S'')-HpETE and 12(''S'')-HpETE in a product ratio of ~4-9 to 1.<ref>{{cite journal | vauthors = Bryant RW, Bailey JM, Schewe T, Rapoport SM | title = Positional specificity of a reticulocyte lipoxygenase. Conversion of arachidonic acid to 15-S-hydroperoxy-eicosatetraenoic acid | journal = The Journal of Biological Chemistry | volume = 257 | issue = 11 | pages = 6050–5 | date = June 1982 | pmid = 6804460 }}</ref> Both products may be rapidly reduced by ubiquitous cellular [[Glutathione peroxidase]] enzymes to their corresponding hydroxy analogs, 15(''S'')-HETE (see [[15-hydroxyeicosatetraenoic acid]]) and 12(''S'')-HETE (see [[12-Hydroxyeicosatetraenoic acid]]). 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-Hydroxyicosatetraenoic acid#15(S)-HpETE and 15(S)-HETE]]). 15(''S'')-HpETE and 15(''S'')-HETE are esterified into membrane [[phospholipids]] where they may be stored and subsequently released during cell stimulation. As one aspect of this processing, the two products are progressively esterified in [[mitochondria]] membrane phospholipids during the maturation of [[red blood cell]]s (see [[erythropoiesis]]) and thereby may serve to signal for the degradation of the mitochondria and the maturation of these precursors to red blood cells in mice. This pathway operates along with two other mitochondria-removing pathways and therefore does not appear essential for mouse red blood cell maturation.<ref name="Gene 2015"/>

15-(''S'')-HpETE and 15(''S'')-HETE may be further metabolized to various bioactive products including:

* lipoxin (LX)A4, LXB4, AT-LXA4, and AT-LXB4; these metabolites are members of the specialized proresolving mediator class of anti-inflammatory agents that contribute to the resolution of inflammatory responses and inflammation-based diseases in animal models and, potentially, humans (see [[specialized proresolving mediators]] and [[lipoxin]]s).
* Hepoxilin isomers (e.g. 1S-hydroxy-14S,15S-epoxy-5Z,8Z,12E-eicosatrienoic acid [14,15-HXA3] and 13R-hydroxy-14S,15S-epoxy-5Z,8Z,11Z-eicosatrienoic acid [14,15-HXB3]) which may contribute to the regulation of inflammation responses and [[insulin]] secretion (see [[hepoxilin]]s).
* Eoxins (e.g. eoxin C4, 14,15-eoxin D4, and eoxin E4) which have pro-inflammatory actions and contribute to severe [[asthma]], [[aspirin-induced asthma]] attacks, and other [[allergy]] reactions; they may also be involved in the pathology of [[Hodgkins disease]] (see [[Eoxins]]).
* 8(''S''),15(''S'')-dihydroxy-5''Z'',9''E'',ll''Z'',13''E''-eicosatetraenoic acid (8(''S''),15(''S'')-diHETE), an inhibitor of human platelet aggregation (see [[Dihydroxy-E,Z,E-PUFA]]).
* 5(''S''),15(''S'')-dihydroxy-6''Z'',8''E'',ll''E'',13''Z''-eicosatetraenoic acid (5''S''),15(''S'')-diHETE) and its 5-[[ketone]] analog, 5-oxo-15(''S'')-hydroxy-ETE. These are weak and potent, respectively, stimulators of human [[eosinophil]], [[neutrophil]], and [[monocyte]] [[chemotaxis]] and thereby possible contributors to human allergic and non-allergic [[inflammation]] responses (see [[5-Hydroxyicosatetraenoic acid#Inflammation]] and [[5-Hydroxyicosatetraenoic acid#Allergy]]).
* 15-Oxo-ETE which inhibits the growth of cultured [[Human umbilical vein endothelial cell]]s and various human cancer cell lines; it is also has activities on [[THP1 cell line]] cells suggesting that it might act as an inhibitor of inflammatory and [[oxidative stress]] reactions (see[[15-Hydroxyicosatetraenoic acid#15-oxo-ETE]]).

The minor products of ALOX15, 12-(''S'')-HpETE and 12(''S'')-HETE, possess a broad range of activities. One or both of these compounds stimulates cells by binding with and activating two [[G protein-coupled receptor]]s, [[GPR31]] and the [[Leukotriene B4 receptor 2]]; 12''S''-HETE also acts as a [[receptor antagonist]] by binding to but not stimulating the [[Thromboxane receptor]] thereby inhibiting the actions of [[Thromboxane A2]] and [[Prostaglandin H2]] (see [[12-Hydroxyeicosatetraenoic acid#Receptor targets and mechanisms of action]]). As at least a partial consequence of these receptor-directed actions, one or both the two ALOX15 products exhibit pro-inflammation, diabetes-inducing, and vasodilation activities in animal models; cancer-promoting activity on cultured human cancer cells; and other actions (see [[12-Hydroxyeicosatetraenoic acid#Activities and possible clinical significance]]). The two products are also further metabolized to various bioactive products including:

* Hepoxilin A3 and Hepoxilin B3 along with their respective tri-hydroxyl metabolites, trioxilin A3 and trioxilin B3. These metabolites have been reported to have anti-inflammatory activity, to have [[vasodilation]]activity, to promote pain perceptrion, to reverse oxidative stress in cells, and to promote insulin secretion in animal model systems (see [[Hepoxilin]].
* 12-Oxo-ETE, which along with 12''S''-HETE, activates the [[Leukotriene B4]] receptor, [[Leukotriene B4 receptor 2]] (BLT2) but not its [[Leukotriene B4 receptor]] 1 (BLT1). This allows the possibility that 12-oxo-ETE contributes to the pro-inflammatory and other activities that BLT2 regulates (see [[12-HETE#Inflammation and inflammatory diseases]] and [[Leukotriene B4 receptor 2]].<ref>{{cite journal | pmid = 11278893 | year = 2001 | author1 = Yokomizo | first1 = T | title = Hydroxyeicosanoids bind to and activate the low affinity leukotriene B4 receptor, BLT2 | journal = Journal of Biological Chemistry | volume = 276 | issue = 15 | pages = 12454–9 | last2 = Kato | first2 = K | last3 = Hagiya | first3 = H | last4 = Izumi | first4 = T | last5 = Shimizu | first5 = T | doi = 10.1074/jbc.M011361200 }}</ref>

===Docosahexaenoic acid===
Human ALOX15 metabolizes docosahexaenoic acid (DHA) to 17''S''-Hydroperoxy-4''Z'',7''Z'',10''Z'',13''Z'',15''E'',19''Z''-docosahexaenoic acid (17''S''-HpDHA) and 17''S''-hydroxy-4''Z'',7''Z'',10''Z'',13''Z'',15''E'',19''Z''-docosahexaenoic acid (17''S''-HDHA).<ref name="pmid23029040">{{cite journal | vauthors = O'Flaherty JT, Hu Y, Wooten RE, Horita DA, Samuel MP, Thomas MJ, Sun H, Edwards IJ | title = 15-lipoxygenase metabolites of docosahexaenoic acid inhibit prostate cancer cell proliferation and survival | journal = PLoS ONE | volume = 7 | issue = 9 | pages = e45480 | year = 2012 | pmid = 23029040 | pmc = 3447860 | doi = 10.1371/journal.pone.0045480 | url = }}</ref> One or both of these products stimulate human breast and prostate cell lines to proliferate in culture and 17''S''-HDHA possesses potent specialized proresolving mediator activity (see [[specialized proresolving mediators#DHA-derived Resolvins]]).<ref name="pmid23066085">{{cite journal | vauthors = Hu Y, Sun H, O'Flaherty JT, Edwards IJ | title = 15-Lipoxygenase-1-mediated metabolism of docosahexaenoic acid is required for syndecan-1 signaling and apoptosis in prostate cancer cells | journal = Carcinogenesis | volume = 34 | issue = 1 | pages = 176–82 | year = 2013 | pmid = 23066085 | pmc = 3584949 | doi = 10.1093/carcin/bgs324 | url = }}</ref><ref name="pmid23658799">{{cite journal | vauthors = O'Flaherty JT, Wooten RE, Samuel MP, Thomas MJ, Levine EA, Case LD, Akman SA, Edwards IJ | title = Fatty acid metabolites in rapidly proliferating breast cancer | journal = PLoS ONE | volume = 8 | issue = 5 | pages = e63076 | year = 2013 | pmid = 23658799 | pmc = 3642080 | doi = 10.1371/journal.pone.0063076 | url = }}</ref><ref name="pmid25392529">{{cite journal | vauthors = Ramon S, Baker SF, Sahler JM, Kim N, Feldsott EA, Serhan CN, Martínez-Sobrido L, Topham DJ, Phipps RP | title = The specialized proresolving mediator 17-HDHA enhances the antibody-mediated immune response against influenza virus: a new class of adjuvant? | journal = Journal of Immunology | volume = 193 | issue = 12 | pages = 6031–40 | year = 2014 | pmid = 25392529 | pmc = 4258475 | doi = 10.4049/jimmunol.1302795 | url = }}</ref><ref name="pmid26474728">{{cite journal | vauthors = Kim N, Ramon S, Thatcher TH, Woeller CF, Sime PJ, Phipps RP | title = Specialized proresolving mediators (SPMs) inhibit human B-cell IgE production | journal = European Journal of Immunology | volume = 46 | issue = 1 | pages = 81–91 | year = 2016 | pmid = 26474728 | pmc = 4710564 | doi = 10.1002/eji.201545673 | url = }}</ref> One or both of these products may be further metabolized enzymatically to:

* Resolvin Ds (RvDs), i.e. RvD-1, RvD2, RvD3, RvD4, RvD5, and RvD6 (see [[resolvin]] and [[specialized proresolving mediators#DHA-derived Resolvins]]) and protetin Ds (PDs), i.e. PD1, PDX,  20-hydroxy-PD1, 17-epi-PD1, and 10-epi-PD1 (see [[neuroprotectin D1]] and [[specialized proresolving mediators#DHA-derived protectins/neuroprotectins]]). These products are members of, and have a wide range of activities common to, the [[specialized proresolving mediators]] class of metabolites.

===Eicosapentaenoic acid===
Human ALOX15 metabolizes eicosapentaenoic acid to 15''S''-hydroperoxy-5''Z'',8''Z'',11''Z'',13''E'',17''E''-eicosapentaenoic acid (15''S''-HpEPA) and 15''S''-hydroxy-5''Z'',8''Z'',11''Z'',13''E'',17''E''-eicosapentaenoic acid (15''S''-HEPA); 15''S''-HEPA inhibits [[ALOX5]]-dependent production of the pro-inflammatory mediator, [[LTB4]], in cells, and may thereby serve an anti-inflammatory function.<ref name="pmid10617998">{{cite journal | vauthors = Ziboh VA, Miller CC, Cho Y | title = Metabolism of polyunsaturated fatty acids by skin epidermal enzymes: generation of antiinflammatory and antiproliferative metabolites | journal = The American Journal of Clinical Nutrition | volume = 71 | issue = 1 Suppl | pages = 361S–6S | year = 2000 | pmid = 10617998 | doi = | url = }}</ref> These products may be further metabolized to:
* Resolvin E3, a specialized proresolvin mediator with anti-inflammatory activity (see [[Specialized proresolving mediators#EPA-derived resolvins (i.e. RvE)]]).

===n-3 Docosaexaenoic acid===
Human cells and mouse tissues metabolize n-3 docosapentaenoic acid (i.e., 7''Z'',10''Z'',13''Z'',16''Z'',19''Z''-docosapentaenoic acid, see [[clupanodonic acid]]) to a series of products that have been classified as specialized proresolvin mediators. Base on the analogy to docosahexaenoic acid metabolism to resolving D's, it is presumed that a 15-lipoxygenase, most likely ALOX15 in humans, contributes to this metabolism. These products, termed n-3 Resolven D's (RvD<sub>n-3</sub>'s), are:
* RvD1<sub>n-3</sub>, RvD2<sub>n-3</sub>, and RvD3<sub>n-3</sub>; each of these products possesses potent anti-inflammatory activity (see [[Specialized proresolving mediators#n-3 DPA-derived resolvins]]).

===Linoleic acid===
Human 15-LOX-1 prefers linoleic acid over arachidonic acid as its primary substrate, oxygenating it at carbon 13 to form 13(''S'')-hydroperoxy-9''Z'',11''E''-octadecaenoic acid (13-HpODE or 13(''S'')-HpODE) which may then be reduce to the corresponding hydroxy derivative, 13(''S'')-HODE or 13-HODE (see [[13-Hydroxyoctadecadienoic acid]]). In addition to 13(''S'')-HpODE, non-human 15-LOX1 orthologs such as mouse 12/15-LOX and soybean 15-LOX metabolize linoleic acid to 9-hydroperoxy-10''E'', 12''Z''-octadecaenoic acid (9-HpODE or 9(''S'')-HpODE), which is rapidly converted to 9(''S'')-HODE (9-HODE) (see [[9-Hydroxyoctadecadienoic acid]])).<ref>{{cite journal | vauthors = Rankin SM, Parthasarathy S, Steinberg D | title = Evidence for a dominant role of lipoxygenase(s) in the oxidation of LDL by mouse peritoneal macrophages | journal = Journal of Lipid Research | volume = 32 | issue = 3 | pages = 449–56 | date = March 1991 | pmid = 1906087 }}</ref><ref>{{cite journal | vauthors =  | date = Feb 1970 | title =  Proof of the enzymatic formation of 9-hydroperoxy-10-trans, 12-cis-octadecadienoic acid from linoleic acid by soya lipoxygenase| url = | journal = Biochim Biophys Acta | volume = 202 | issue = 1| pages = 198–9 | doi = 10.1016/0005-2760(70)90235-3 | pmid = 5461374 | last1 = Veldink | first1 = G.A. | last2 = Vliegenthart | first2 = J.F.G. | last3 = Boldingh | first3 = J. }}</ref> 13(''S'')-HODE acts through [[Peroxisome proliferator-activated receptor]]s 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 of 13-HODEs]]; 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]]). The two HODEs can be further metabolized to their [[ketones]], 13-oxo-9''Z'',11''E''-octadecaenoic acid and 9-oxo-10''E'', 12''Z''-octadecaenoic acid; these ketones have been implicated as [[biomarkers]] for and possible contributors to the inflammatory component of atherosclerosis, [[Alzheimer's disease]], [[Steatohepatitis]], and other pathological conditions.<ref name="pmid23037960">{{cite journal | vauthors = Yuan ZX, Rapoport SI, Soldin SJ, Remaley AT, Taha AY, Kellom M, Gu J, Sampson M, Ramsden CE | title = Identification and profiling of targeted oxidized linoleic acid metabolites in rat plasma by quadrupole time-of-flight mass spectrometry | journal = Biomedical Chromatography | volume = 27 | issue = 4 | pages = 422–32 | year = 2013 | pmid = 23037960 | pmc = 3552117 | doi = 10.1002/bmc.2809 | url = }}</ref>

===Dihomo-γ-linolenic acid===
Human neutrophils, presumably using their ALOX 15, metabolize [[Dihomo-γ-linolenic acid]] (8''Z'',11''Z'',14''Z''-eicosatrienoic acid) to 15''S''-hydroperoxy-8''Z'',11''Z'',13''E''-eicosatrienoic acid and 15''S''-hydroxy-8''Z'',11''Z'',13''E''-eicosatrienoic acid (15''S''-HETrE).  15''S''-HETrE possesses anti-inflammatory activity.<ref name="pmid10617998"/><ref name="pmid8609415">{{cite journal | vauthors = Chilton-Lopez, Surette ME, Swan DD, Fonteh AN, Johnson MM, Chilton FH | title = Metabolism of gammalinolenic acid in human neutrophils | journal = Journal of Immunology | volume = 156 | issue = 8 | pages = 2941–7 | year = 1996 | pmid = 8609415 | doi = | url = }}</ref>

==Gene manipulation studies==
Mice made deficient in their 12/15-lipoxygenase gene (Alox15) exhibit a prolonged inflammatory response along with various other aspects of a pathologically enhanced inflammatory response in experimental models of [[cornea]] injury, airway inflammation, and [[peritonitis]]. These mice also show an accelerated rate of progression of atherosclerosis whereas mice made to overexpress 12/15-lipoxygenase exhibit a delayed rate of atherosclerosis development. Alox15 overexpressing rabbits exhibited reduced tissue destruction and bone loss in a model of [[periodontitis]]. Finally, Control mice, but not 12/15-lipoxygense deficient mice responded to eicospentaenoic acid administration by decreasing the number of lesions in a model of [[endometriosis]].<ref name="pmid25857211">{{cite journal | vauthors = Serhan CN, Chiang N, Dalli J | title = The resolution code of acute inflammation: Novel pro-resolving lipid mediators in resolution | journal = Seminars in Immunology | volume = 27 | issue = 3 | pages = 200–15 | year = 2015 | pmid = 25857211 | pmc = 4515371 | doi = 10.1016/j.smim.2015.03.004 | url = }}</ref> These studies indicate that the suppression of inflammation is a major function of 12/15-lipoxygenase and the [[Specialized proresolving mediators]] it produces in rodents; although rodent 12/15-lipoxygenase differs from human ALOX15 in the profile of the PUFA metabolites that it produces as well as various other parameters (e.g. tissue distribution), these genetic studies allow that human ALOX15 and the specialized proresolving mediators it produces may play a similar major anti-inflammatory function in humans.

== Clinical significance ==

=== Inflammatory diseases ===
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]].<ref name="DHA 2015">{{cite journal | vauthors = López-Vicario C, Rius B, Alcaraz-Quiles J, García-Alonso V, Lopategi A, Titos E, Clària J | title = Pro-resolving mediators produced from EPA and DHA: Overview of the pathways involved and their mechanisms in metabolic syndrome and related liver diseases | journal = European Journal of Pharmacology | volume =  785| issue =  | pages = 133–143 | date = May 2015 | pmid = 25987424 | doi = 10.1016/j.ejphar.2015.03.092 }}</ref><ref name="Eur J Pharmacol 2015">{{cite journal | vauthors = Romano M, Cianci E, Simiele F, Recchiuti A | title = Lipoxins and aspirin-triggered lipoxins in resolution of inflammation | journal = European Journal of Pharmacology | volume = 760 | issue =  | pages = 49–63 | date = August 2015 | pmid = 25895638 | doi = 10.1016/j.ejphar.2015.03.083 }}</ref><ref>{{cite journal | vauthors = Cole BK, Lieb DC, Dobrian AD, Nadler JL | title = 12- and 15-lipoxygenases in adipose tissue inflammation | journal = Prostaglandins & Other Lipid Mediators | volume = 104-105 | issue =  | pages = 84–92 | date = Jul 2013 | pmid = 22951339 | doi = 10.1016/j.prostaglandins.2012.07.004 | pmc=3526691}}</ref><ref>{{cite journal | vauthors = Russell CD, Schwarze J | title = The role of pro-resolution lipid mediators in infectious disease | journal = Immunology | volume = 141 | issue = 2 | pages = 166–73 | date = February 2014 | pmid = 24400794 | doi = 10.1111/imm.12206 | pmc=3904237}}</ref><ref>{{cite journal | vauthors = Serhan CN, Chiang N, Dalli J | title = The resolution code of acute inflammation: Novel pro-resolving lipid mediators in resolution | journal = Seminars in Immunology | volume = 27 | issue = 3 | pages = 200–15 | date = May 2015 | pmid = 25857211 | doi = 10.1016/j.smim.2015.03.004 | pmc=4515371}}</ref>  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.<ref>{{cite journal | vauthors = Orr SK, Colas RA, Dalli J, Chiang N, Serhan CN | title = Proresolving actions of a new resolvin D1 analog mimetic qualifies as an immunoresolvent | journal = American Journal of Physiology. Lung Cellular and Molecular Physiology | volume = 308 | issue = 9 | pages = L904–11 | date = May 2015 | pmid = 25770181 | doi = 10.1152/ajplung.00370.2014 | pmc=4421783}}</ref>  These synthetic analogs may prove to be clinically useful for treating the cited human inflammatory diseases.

By metabolizing the ω-3 polyunsaturated fatty acids, eicosapentaenoic acid and docosahexaenoic acid, into 17-HpDHA, 17-HDHA, and the resolvins and protectins, 15-LOX-1's metabolic action is thought to be one mechanism by which dietary ω-3 polyunsaturated fatty acids, particularly [[fish oil]], act to ameliorate inflammation, inflammation-related diseases, and certain cancers.<ref name="ReferenceC"/><ref name="DHA 2015"/>

=== Asthma ===
15-LOX-1 and its 5-oxo-15-hydroxy-ETE and [[eoxin]] metabolites have been suggested as potential contributors to, and therefore targets for the future study and treatment of, human allergen-induced [[asthma]], aspirin-induced asthma, and perhaps other allergic diseases.<ref>{{cite journal | vauthors = James A, Daham K, Backman L, Brunnström A, Tingvall T, Kumlin M, Edenius C, Dahlén SE, Dahlén B, Claesson HE | title = The influence of aspirin on release of eoxin C4, leukotriene C4 and 15-HETE, in eosinophilic granulocytes isolated from patients with asthma | journal = International Archives of Allergy and Immunology | volume = 162 | issue = 2 | pages = 135–42 | year = 2013 | pmid = 23921438 | doi = 10.1159/000351422 }}</ref><ref>{{cite journal | vauthors = Neighbour H | title = Mechanisms of aspirin-intolerant asthma: identifying inflammatory pathways in the pathogenesis of asthma | journal = International Archives of Allergy and Immunology | volume = 163 | issue = 1 | pages = 1–2 | year = 2014 | pmid = 24247362 | doi = 10.1159/000355949 }}</ref>

=== 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.<ref name="ReferenceB"/><ref name="DHA 2015"/><ref>{{cite journal | vauthors = Gohara A, Eltaki N, Sabry D, Murtagh D, Jankun J, Selman SH, Skrzypczak-Jankun E | title = Human 5-, 12- and 15-lipoxygenase-1 coexist in kidney but show opposite trends and their balance changes in cancer | journal = Oncology Reports | volume = 28 | issue = 4 | pages = 1275–82 | date = October 2012 | pmid = 22825379 | doi = 10.3892/or.2012.1924 }}</ref>  These results, as well as a 15-LOX-1 transgene study on colon cancer in mice<ref>{{cite journal | vauthors = Zuo X, Peng Z, Wu Y, Moussalli MJ, Yang XL, Wang Y, Parker-Thornburg J, Morris JS, Broaddus RR, Fischer SM, Shureiqi I | title = Effects of gut-targeted 15-LOX-1 transgene expression on colonic tumorigenesis in mice | journal = Journal of the National Cancer Institute | volume = 104 | issue = 9 | pages = 709–16 | date = May 2012 | pmid = 22472308 | doi = 10.1093/jnci/djs187 | pmc=3341308}}</ref> suggests but do not prove<ref>{{cite journal | vauthors = Umar A | title = Is 15-LOX-1 a tumor suppressor? | journal = Journal of the National Cancer Institute | volume = 104 | issue = 9 | pages = 645–7 | date = May 2012 | pmid = 22472307 | doi = 10.1093/jnci/djs192 }}</ref> that 15-LOX-1 is a [[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.<ref name="DHA 2015"/>  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)<ref name="ReferenceC"/><ref>{{cite journal | vauthors = O'Flaherty JT, Hu Y, Wooten RE, Horita DA, Samuel MP, Thomas MJ, Sun H, Edwards IJ | title = 15-lipoxygenase metabolites of docosahexaenoic acid inhibit prostate cancer cell proliferation and survival | journal = PLoS ONE | volume = 7 | issue = 9 | pages = e45480 | year = 2012 | pmid = 23029040 | pmc = 3447860 | doi = 10.1371/journal.pone.0045480 }}</ref>

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.Targeted overexpression of h15-LO-1 (a gene overexpressed in human PCa and HGPIN) to mouse prostate is sufficient to promote epithelial proliferation and mPIN development. 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. The FLiMP mouse model should also be useful in crosses with other GEM models to further define the combinations of molecular alterations necessary for PCa progression.  |PMID: 16820097 |PMCID: PMC1601466 |DOI: 10.1593/neo.06202| journal = Neoplasia | volume = 8 | issue = 6 | pages = 510-522 | year = 2006 |

== See also ==
* [[Arachidonate 15-lipoxygenase]]
* [[15-Hydroxyicosatetraenoic acid]]
* [[12-Hydroxyeicosatetraenoic acid]]

== References ==
{{Reflist|33em}}
Kelavkar UP, Badr KF (April 1999). "Effects of mutant p53 expression on human 15-lipoxygenase-promoter activity and murine 12/15-lipoxygenase gene expression: evidence that 15-lipoxygenase is a mutator gene". Proceedings of the National Academy of Sciences of the United States of America. 96 (8): 4378–83. PMC 16340 Freely accessible. {{PMID|10200270}}. doi:10.1073/pnas.96.8.4378.

==External links==
* {{UCSC gene info|ALOX15}}

== Further reading ==
{{refbegin|33em}}
* {{cite journal | vauthors = Kelavkar U, Glasgow W, Eling TE | title = The effect of 15-lipoxygenase-1 expression on cancer cells | journal = Current Urology Reports | volume = 3 | issue = 3 | pages = 207–14 | date = June 2002 | pmid = 12084190 | doi = 10.1007/s11934-002-0066-8 }}
* {{cite journal | vauthors = Sigal E, Dicharry S, Highland E, Finkbeiner WE | title = Cloning of human airway 15-lipoxygenase: identity to the reticulocyte enzyme and expression in epithelium | journal = The American Journal of Physiology | volume = 262 | issue = 4 Pt 1 | pages = L392–8 | date = April 1992 | pmid = 1566855 | doi =  }}
* {{cite journal | vauthors = Izumi T, Rådmark O, Jörnvall H, Samuelsson B | title = Purification of two forms of arachidonate 15-lipoxygenase from human leukocytes | journal = European Journal of Biochemistry / FEBS | volume = 202 | issue = 3 | pages = 1231–8 | date = December 1991 | pmid = 1662607 | doi = 10.1111/j.1432-1033.1991.tb16495.x }}
* {{cite journal | vauthors = Conrad DJ, Kuhn H, Mulkins M, Highland E, Sigal E | title = Specific inflammatory cytokines regulate the expression of human monocyte 15-lipoxygenase | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 89 | issue = 1 | pages = 217–21 | date = January 1992 | pmid = 1729692 | pmc = 48207 | doi = 10.1073/pnas.89.1.217 }}
* {{cite journal | vauthors = Lei ZM, Rao CV | title = The expression of 15-lipoxygenase gene and the presence of functional enzyme in cytoplasm and nuclei of pregnancy human myometria | journal = Endocrinology | volume = 130 | issue = 2 | pages = 861–70 | date = February 1992 | pmid = 1733732 | doi = 10.1210/en.130.2.861 }}
* {{cite journal | vauthors = Izumi T, Rådmark O, Samuelsson B | title = Purification of 15-lipoxygenase from human leukocytes, evidence for the presence of isozymes | journal = Advances in Prostaglandin, Thromboxane, and Leukotriene Research | volume = 21A | issue =  | pages = 101–4 | year = 1991 | pmid = 1825526 | doi =  }}
* {{cite journal | vauthors = Sloane DL, Leung R, Craik CS, Sigal E | title = A primary determinant for lipoxygenase positional specificity | journal = Nature | volume = 354 | issue = 6349 | pages = 149–52 | date = November 1991 | pmid = 1944593 | doi = 10.1038/354149a0 }}
* {{cite journal | vauthors = Nadel JA, Conrad DJ, Ueki IF, Schuster A, Sigal E | title = Immunocytochemical localization of arachidonate 15-lipoxygenase in erythrocytes, leukocytes, and airway cells | journal = The Journal of Clinical Investigation | volume = 87 | issue = 4 | pages = 1139–45 | date = April 1991 | pmid = 2010530 | pmc = 295116 | doi = 10.1172/JCI115110 }}
* {{cite journal | vauthors = Kroschwald P, Kroschwald A, Kühn H, Ludwig P, Thiele BJ, Höhne M, Schewe T, Rapoport SM | title = Occurrence of the erythroid cell specific arachidonate 15-lipoxygenase in human reticulocytes | journal = Biochemical and Biophysical Research Communications | volume = 160 | issue = 2 | pages = 954–60 | date = April 1989 | pmid = 2719708 | doi = 10.1016/0006-291X(89)92528-X }}
* {{cite journal | vauthors = Sigal E, Nadel JA | title = Arachidonic acid 15-lipoxygenase and airway epithelium. Biologic effects and enzyme purification | journal = The American Review of Respiratory Disease | volume = 138 | issue = 6 Pt 2 | pages = S35–40 | date = December 1988 | pmid = 3202520 | doi = 10.1164/ajrccm/138.6_pt_2.s35 }}
* {{cite journal | vauthors = Sigal E, Craik CS, Highland E, Grunberger D, Costello LL, Dixon RA, Nadel JA | title = Molecular cloning and primary structure of human 15-lipoxygenase | journal = Biochemical and Biophysical Research Communications | volume = 157 | issue = 2 | pages = 457–64 | date = December 1988 | pmid = 3202857 | doi = 10.1016/S0006-291X(88)80271-7 }}
* {{cite journal | vauthors = Sigal E, Grunberger D, Craik CS, Caughey GH, Nadel JA | title = Arachidonate 15-lipoxygenase (omega-6 lipoxygenase) from human leukocytes. Purification and structural homology to other mammalian lipoxygenases | journal = The Journal of Biological Chemistry | volume = 263 | issue = 11 | pages = 5328–32 | date = April 1988 | pmid = 3356688 | doi =  }}
* {{cite journal | vauthors = Nassar GM, Morrow JD, Roberts LJ, Lakkis FG, Badr KF | title = Induction of 15-lipoxygenase by interleukin-13 in human blood monocytes | journal = The Journal of Biological Chemistry | volume = 269 | issue = 44 | pages = 27631–4 | date = November 1994 | pmid = 7961680 | doi =  }}
* {{cite journal | vauthors = Kritzik MR, Ziober AF, Dicharry S, Conrad DJ, Sigal E | title = Characterization and sequence of an additional 15-lipoxygenase transcript and of the human gene | journal = Biochimica et Biophysica Acta | volume = 1352 | issue = 3 | pages = 267–81 | date = June 1997 | pmid = 9224951 | doi = 10.1016/s0167-4781(97)00005-5 }}
* {{cite journal | vauthors = Brinckmann R, Schnurr K, Heydeck D, Rosenbach T, Kolde G, Kühn H | title = Membrane translocation of 15-lipoxygenase in hematopoietic cells is calcium-dependent and activates the oxygenase activity of the enzyme | journal = Blood | volume = 91 | issue = 1 | pages = 64–74 | date = January 1998 | pmid = 9414270 | doi =  }}
* {{cite journal | vauthors = Kelavkar U, Wang S, Montero A, Murtagh J, Shah K, Badr K | title = Human 15-lipoxygenase gene promoter: analysis and identification of DNA binding sites for IL-13-induced regulatory factors in monocytes | journal = Molecular Biology Reports | volume = 25 | issue = 3 | pages = 173–82 | date = July 1998 | pmid = 9700053 | doi = 10.1023/A:1006813009006 }}
* {{cite journal | vauthors = Roy B, Cathcart MK | title = Induction of 15-lipoxygenase expression by IL-13 requires tyrosine phosphorylation of Jak2 and Tyk2 in human monocytes | journal = The Journal of Biological Chemistry | volume = 273 | issue = 48 | pages = 32023–9 | date = November 1998 | pmid = 9822675 | doi = 10.1074/jbc.273.48.32023 }}
* {{cite journal | vauthors = Kratky D, Lass A, Abuja PM, Esterbauer H, Kühn H | title = A sensitive chemiluminescence method to measure the lipoxygenase catalyzed oxygenation of complex substrates | journal = Biochimica et Biophysica Acta | volume = 1437 | issue = 1 | pages = 13–22 | date = January 1999 | pmid = 9931410 | doi = 10.1016/s0005-2760(98)00176-3 }}
* {{cite journal | vauthors = Kelavkar UP, Badr KF | title = Effects of mutant p53 expression on human 15-lipoxygenase-promoter activity and murine 12/15-lipoxygenase gene expression: evidence that 15-lipoxygenase is a mutator gene | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 96 | issue = 8 | pages = 4378–83 | date = April 1999 | pmid = 10200270 | pmc = 16340 | doi = 10.1073/pnas.96.8.4378 }}
{{refend}}

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