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Arachidonate 15-lipoxygenase
Available structures
PDB Ortholog search: PDBe, RCSB
Symbols ALOX15 ; 12-LOX; 15-LOX-1; 15LOX-1
External IDs OMIM152392 MGI87997 HomoloGene44935 ChEMBL: 2903 GeneCards: ALOX15 Gene
EC number,
RNA expression pattern
PBB GE ALOX15 207328 at tn.png
More reference expression data
Species Human Mouse
Entrez 246 11687
Ensembl ENSG00000161905 ENSMUSG00000018924
UniProt P16050 P39654
RefSeq (mRNA) NM_001140 NM_009660
RefSeq (protein) NP_001131 NP_033790
Location (UCSC) Chr 17:
4.63 – 4.64 Mb
Chr 11:
70.34 – 70.35 Mb
PubMed search [1] [2]

ALOX15 (also termed arachidonate 15-lipoxygenase, 15-lipoxygenase-1, 15-LO-1, 15-LOX-1) is an polyunsaturated fatty acid-metabolizing enzyme that in humans is encoded by the ALOX15 gene located on chromosome 17p13.3.[1] The 11 kilobase pair gene consists of 14 exons and 13 introns coding for a 75 kiloDalton protein composed of 662 amino acids. 15-LO is distinguished from another 15-lipoxygenase enzyme, ALOX15B (15-lipoxygenase-2).[2] Orthologs of ALOX15, termed Alox15, are widely distributed in animal and plant species.


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 orthologs of ALOX15 that possess 12-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 Alox15 orthologs, which share 74-81% amino acid identity with human ALOX15, are commonly termed 12/15-lipoxygenases (i.e. 12/15-LOX, and 12/15-LO).[1][3]

Human 15-LOX-1 (ALOX15) and 15-LOX-2 ALOX15B genes are both located on chromosome 17 but their product proteins have an amino acid sequence identity of only ~38%, differ in the polyunsaturated fatty acids that they prefer as substrates, and exhibit different product profiles when acting on the same substrates.[4]<refGene. 2015 Nov 15;573(1):1-32. doi: 10.1016/j.gene.2015.07.073. Epub 2015 Jul 26.></ref>

Tissue distribution[edit]

Human ALOX15 protein is highly expressed in circulating blood eosinophils, bronchial airway epithelial cells, mammary epithelial cells, the Reed-Sternberg cells of Hodgkin's lymphoma, cornea epithelial cells, reticulocytes, 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.[5][6][7][8]

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.[9]

Enzyme activities[edit]

Lipoxygenase acitivity[edit]

ALOX15 and mammalian Alox5 enzymes are primarily non-heme iron-containing dioxygenases. They catalyze the dioxygenation (i.e. attachment of molecular oxygen, O
), to polyunsaturated fatty acids (PUFA) that contain a 1,4 double bond configuration (i.e. 1,4 diene) located at carbons 9-10 and 7-8, respectively, as numbered counting backward from the omega [i.e. ω] carbon at the non-carboxy end of the molecule. The O
) is attached to either the 2nd or to a much greater extent 5th position of the 1,4 diene while the 1,4 diene is rearranged to a 1,3 Conjugated system. The enzyme then reduces the attached oxygen (i.e. peroxy) residue to its hydroperoxy counterpart to form a hydroperoxy fatty acid product ert the peroxy to a cyclic ether with a three-atom ring, i,e. an epoxide, to form an epoxy product.[10]

Liphydroperoxidase activity[edit]

Human ALOX15 may convert the peroxy PUFA intermediate to a cyclic ether with a three-atom ring, i.e. an epxoide intermediate that is attacked by a water molecule to form epoxy-hydrpoxy PUFA products.[11]

Substrates and products[edit]

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 present not only as free acids but also when incorporated as esters in phospholipids, glycerides, or cholesterol esters.<refGene. 2015 Nov 15;573(1):1-32. doi: 10.1016/j.gene.2015.07.073. Epub 2015 Jul 26.Review></ref> The human enzyme is particularly active on linoleic acid, preferring it over arachidonic acid.

Human ALOX15 metabolizes arachidonic acid, which has 4 double bonds all of which are in the cis (see Cis–trans isomerism or Z as opposed to the trans or E configuration between carbons 5-6, 8-9, 11-12, and 14-15. The reaction forms 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) with in a 15(S)-HpETE to 12(S)-HpETE product ratio of ~4-9 to 1.[12] Both products may be rapidly reduced by ubiquitous cellular enzymes with peroxide-reducing activity to form their corresponding hydroxy analogs, 15(S)-HETE (see 15-hydroxyicosatetraenoic acid) and 12(S)-HETE (see 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 dihydroxy, epoxy-hydroxy, and trihydroxy compounds such as 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, certain hepoxilin isomers (e.g. 11S-hydroxy-14S,15S-epoxy-5Z,8Z,12E-eicosatrienoic acid [14,15-HXA3] and 13R-hydroxy-14S,15S-epoxy-5Z,8Z,11Z-eicosatrienoic acid [HXB3]), various eoxins (e.g. eoxin C4, 14,15-eoxin D4, and eoxin E4), and lipoxins such as LXA4.[13][14][15]

Human 15-LOX-1 prefers linoleic acid over arachidonic acid as its primary ω-6 polyunsaturated fatty acid (see 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 may then be reduce to the corresponding hydroxy derivative, 13(S)-HODE or 13-HODE (see 13-Hydroxyoctadecadienoic acid). 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) (see 9-Hydroxyoctadecadienoic acid.[16][17] The sited arachidonic and linoleic acid metabolites have significant bioactivities and potential but unproven clinical relevancies.[14][18][19][20][21]

Human 15-LOX-1 also acts on ω-3 polyunsaturated fatty acids (see Omega-3 fatty acid): it metabolizes α-linolenic acid to 13(S)-hydroperoxy-9Z,11E,15Z)-octadecatrienoic acid;[22] eicosapentaenoic acid to 15(S)-hydroperoxy-5Z,8Z,11Z,13E,17Z-eicosatetraenoic acid (15(S)-HpEPA)[23] and 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).[8][24][25] 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.[23][26][27][28][29]

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) 5-LOX to metabolize arachidonic acid to lipoxins; b) with 5-LOX to metabolize docosahexaenoic acid to resolvins D1, D2, D3, D4, D5, and D6; and c) aspirin-treated cyclooxygenase-2 or cytochrome P450 enzymes to metabolize eicosapentaenoic acid to resolvin E3.[14][30][31]

Clinical significance[edit]

Inflammatory diseases[edit]

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 periodontitis, peritonitis, sepsis, and other pathogen-induced inflammatory responses, eczema, arthritis, asthma, cystic fibrosis, atherosclerosis, adipose tissue inflammation and subsequent insulin resistance that occurs in obesity, diabetes and the metabolic syndrome, and Alzheimer's disease.[14][32][33][34][35] While these studies have not yet been shown to translate to human diseases, first and second generation synthetic resolvins and lipoxins have been made[36] 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 fish oil, may act to reduce inflammation and inflammation-related diseases.[37]


While studies have shown that 5-lipoxygenase and its Leukotriene and possibly 5-oxo-eicosatatraenoic acid (see 5-Hydroxyicosatetraenoic acid) metabolites contribute to, and are important pharmacological in the treatment of, severe human allergen-induced asthma and aspirin-induced asthma, recent work suggests that 15-LOX-1 and its eoxin metabolites may also be contributors to these diseases.[38] Further work on this issue is needed.


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.[7][39][40] These results, as well as a 15-LOX-1 transgene study on colon cancer in mice[41] suggests but do not prove[42] 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.[43] 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)[8][44]

See also[edit]


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  2. ^ Gene. 2015 Nov 15;573(1):1-32. doi: 10.1016/j.gene.2015.07.073. Epub 2015 Jul 26.Review
  3. ^ Gene. 2015 Nov 15;573(1):1-32. doi: 10.1016/j.gene.2015.07.073. Epub 2015 Jul 26.
  4. ^ Brash AR, Boeglin WE, Chang MS (1997). "Discovery of a second 15S-lipoxygenase in humans". Proc. Natl. Acad. Sci. U.S.A. 94 (12): 6148–52. PMC 21017. PMID 9177185. 
  5. ^ Prostaglandins Other Lipid Mediat. 2009 Sep;89(3-4):120-5. doi: 10.1016/j.prostaglandins.2008.12.003
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  7. ^ a b Cancer Res. 2005 Dec 15;65(24):11486-92
  8. ^ a b c Carcinogenesis. 2013 Jan;34(1):176-82. doi: 10.1093/carcin/bgs324
  9. ^ Gene. 2015 Nov 15;573(1):1-32. doi: 10.1016/j.gene.2015.07.073. Epub 2015 Jul 26.Review
  10. ^ Gene. 2015 Nov 15;573(1):1-32. doi: 10.1016/j.gene.2015.07.073. Epub 2015 Jul 26.Review
  11. ^ Gene. 2015 Nov 15;573(1):1-32. doi: 10.1016/j.gene.2015.07.073. Epub 2015 Jul 26.Review
  12. ^ J Biol Chem. 1982 Jun 10;257(11):6050-5
  13. ^ FEBS J. 2008 Aug;275(16):4222-34. doi: 10.1111/j.1742-4658.2008.06570
  14. ^ a b c d Eur J Pharmacol. 2015 Aug 5;760:49-63. doi: 10.1016/j.ejphar.2015.03.083
  15. ^ Gene. 2015 Nov 15;573(1):1-32. doi: 10.1016/j.gene.2015.07.073. Epub 2015 Jul 26.Review
  16. ^ J Lipid Res. 1991 Mar;32(3):449-56
  17. ^ Biochim Biophys Acta. 1970 Feb 10;202(1):198-9
  18. ^ Biochem Pharmacol. 2009 Jan 1;77(1):1-10. doi: 10.1016/j.bcp.2008.07.033
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  20. ^ J Physiol Sci. 2012 May;62(3):163-72. doi: 10.1007/s12576-012-0196-9
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  22. ^ Prostaglandins Other Lipid Mediat. 2002 Aug;68-69:263-90
  23. ^ a b Prostaglandins Leukot Essent Fatty Acids. 2005 May;72(5):363-72
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  26. ^ Lipids. 1996 Mar;31 Suppl:S249-53
  27. ^ PLoS One. 2012;7(9):e4548010.1371/journal.pone.0045480
  28. ^ Diabetes. 2013 Jun;62(6):1945-56. doi: 10.2337/db12-0828
  29. ^ J Immunol. 2014 Dec 15;193(12):6031-40. doi: 10.4049/jimmunol.1302795
  30. ^ Proc Natl Acad Sci U S A. 1984 Sep;81(17):5335-9
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  33. ^ Immunology. 2014 Feb;141(2):166-73. doi: 10.1111/imm.12206
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  36. ^ Am J Physiol Lung Cell Mol Physiol. 2015 May 1;308(9):L904-11. doi: 10.1152/ajplung.00370.2014
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  38. ^ <Int Arch Allergy Immunol. 2013;162(2):135-42. doi: 10.1159/000351422/ref><refInt Arch Allergy Immunol. 2014;163(1):1-2. doi: 10.1159/000355949>
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Further reading[edit]

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