Lipoxygenase Pathway of the Arachidonate Cascade


Lipoxygenases (LOXs) are iron‐containing enzymes that catalyse the peroxidation of polyunsaturated fatty acids. In mammals, LOX products and their metabolites are potent lipid mediators that provoke diverse biological responses. These eicosanoids, derived from arachidonic acid, play important roles in inflammation and the resolution of inflammation. Moreover, they have been implicated in the development of cardiovascular disease. Although several LOX isoforms are expressed in individual organisms, each generates a specific product. How structurally and mechanistically related enzymes generate different products from a common substrate is not fully understood. In addition, the biological effects of many of the lipid mediators produced through LOX pathways remain to be uncovered.

Key Concepts:

  • Arachidonic acid is a substrate for lipoxygenases, iron enzymes that catalyse the peroxidation of polyunsaturated fatty acids.

  • Mammalian lipoxygenases transform the common substrate (arachidonic acid) to a unique stereo‐ and regiospecific product.

  • Leukotriene synthesis is initiated by 5‐lipoxygenase.

  • Lipoxygenase products and their downstream metabolites are potent signalling molecules, some of which play roles in inflammation or its resolution.

  • Lipoxygenase products are associated with cardiovascular diseases, but their molecular mechanism of action remains unclear.

Keywords: eicosanoids; lipoxygenase; leukotriene; lipid signalling; lipoxin; arachidonic acid

Figure 1.

Stable 5‐LOX. The N‐terminal domain is in blue, and the catalytic domain in green with helix α2 as positioned in 5‐LOX (solid ribbon) and 15‐LOX (2P0M) in transparent ribbon. The catalytic Fe is shown as a rust coloured sphere.

Figure 2.

Lipid mediators derived from AA. A total of 12 isomers of HPETE can be derived from AA, four from the reaction centred at each of three pentadienes. Enzymes that initiate the reaction at C7 (red), C10 (blue) and C13 (green) are 5‐LOX, 12‐LOX and 15‐LOX, respectively.

Figure 3.

LTA4 hydrolase (1HS6). (a) The thermolysin‐like (M1‐peptidase) core of LTA4 hydrolase. Zn2+ is a grey sphere. (b) LTA4 hydrolase: N‐terminal domain yellow and C‐terminal domain red.

Figure 4.

FLAP and LTC4 synthase. (a) Cartoon rendering of a FLAP trimer (pdb 2QZM), protomers are in distinct colours. An iodinated analogue of the inhibitor MK‐591 is depicted in sphere rendering (C, light blue; O, red; N, blue and I, deep purple). (b) A superposition of an LTC4 synthase protomer (green) (pdb 2UUH) onto FLAP. The GSH is in sphere rendering (C, magenta and S, orange) as well as a detergent molecule (C, green and O, red), which is presumed to indicate the binding site for LTA4. The stick rendering is MK‐591.



Ago H, Kanaoka Y, Irikura D et al. (2007) Crystal structure of a human membrane protein involved in cysteinyl leukotriene biosynthesis. Nature 448(7153): 609–612.

Bair AM, Turman MV, Vaine CA , Panettieri RA and Soberman RJ (2012) The nuclear membrane leukotriene synthetic complex is a signal integrator and transducer. Molecular Biology of the Cell 23(22): 4456–4464.

Boyington JC, Gaffney BJ and Amzel LM (1993) The three‐dimensional structure of an arachidonic acid 15‐lipoxygenase. Science 260(5113): 1482–1486.

Brash AR (1999) Lipoxygenases: occurrence, functions, catalysis, and acquisition of substrate. Journal of Biological Chemistry 274(34): 23679–23682.

Brash AR, Boeglin WE and Chang MS (1997) Discovery of a second 15S‐lipoxygenase in humans. Proceedings of the National Academy of Sciences of the USA 94(12): 6148–6152.

Chen XS and Funk CD (2001) The N‐terminal ‘beta‐barrel’ domain of 5‐lipoxygenase is essential for nuclear membrane translocation. Journal of Biological Chemistry 276(1): 811–818.

Choi J, Chon JK, Kim S and Shi W (2008) Conformational flexibility in mammalian 15S‐lipoxygenase: reinterpretation of the crystallographic data. Proteins 70(3): 1023–1032.

Cyrus T, Pratico D, Zhao L et al. (2001) Absence of 12/15‐lipoxygenase expression decreases lipid peroxidation and atherogenesis in apolipoproteine‐deficient mice. Circulation 103(18): 2277–2282.

Dahlen SE, Hansson G, Hedqvist P et al. (1983) Allergen challenge of lung tissue from asthmatics elicits bronchial contraction that correlates with the release of leukotrienes C4, D4, and E4. Proceedings of the National Academy of Sciences of the USA 80(6): 1712–1716.

Danielsson KN, Rydberg EK, Ingelsten M et al. (2008) 15‐Lipoxygenase‐2 expression in human macrophages induces chemokine secretion and T cell migration. Atherosclerosis 199(1): 34–40.

Eek P, Jarving R, Jarving I et al. (2012) Structure of a calcium‐dependent 11R‐lipoxygenase suggests a mechanism for Ca2+ regulation. Journal of Biological Chemistry 287(26): 22377–22386.

Ferguson AD, McKeever BM, Xu S et al. (2007) Crystal structure of inhibitor‐bound human 5‐lipoxygenase‐activating protein. Science 317(5837): 510–512.

Funk CD, Chen XS, Johnson EN and Zhao L (2002) Lipoxygenase genes and their targeted disruption. Prostaglandins and Other Lipid Mediators 68–69: 303–312.

Funk CD, Furci L and FitzGerald GA (1990) Molecular cloning, primary structure, and expression of the human platelet/erythroleukemia cell 12‐lipoxygenase. Proceedings of the National Academy of Sciences of the USA 87(15): 5638–5642.

George J, Afek A, Shaish A et al. (2001) 12/15‐Lipoxygenase gene disruption attenuates atherogenesis in LDL receptor‐deficient mice. Circulation 104(14): 1646–1650.

Gertow K, Nobili E, Folkersen L et al. (2011) 12‐ and 15‐lipoxygenases in human carotid atherosclerotic lesions: associations with cerebrovascular symptoms. Atherosclerosis 215(2): 411–416.

Gilbert NC, Bartlett SG, Waight MT et al. (2011) The structure of human 5‐lipoxygenase. Science 331(6014): 217–219.

Guo Y, Zhang W, Giroux C et al. (2011) Identification of the orphan G protein‐coupled receptor GPR31 as a receptor for 12‐(S)‐hydroxyeicosatetraenoic acid. Journal of Biological Chemistry 286(39): 33832–33840.

Hammarberg T, Provost P, Persson B and Radmark O (2000) The N‐terminal domain of 5‐lipoxygenase binds calcium and mediates calcium stimulation of enzyme activity. Journal of Biological Chemistry 275(49): 38787–38793.

Hammel M, Walther M, Prassl R and Kuhn M (2004) Structural flexibility of the N‐terminal beta‐barrel domain of 15‐lipoxygenase‐1 Probed by small angle X‐ray scattering. Functional consequences for activity regulation and membrane binding. Journal of Molecular Biology 343(4): 917–929.

Hill E, Maclouf J, Murphy RC and Henson PM (1992) Reversible membrane association of neutrophil 5‐lipoxygenase is accompanied by retention of activity and a change in substrate specificity. Journal of Biological Chemistry 267(31): 22048–22053.

Huang JT, Welch JS, Ricote M et al. (1999) Interleukin‐4‐dependent production of PPAR‐gamma ligands in macrophages by 12/15‐lipoxygenase. Nature 400(6742): 378–382.

Hulten LM, Olson FJ, Aberg H et al. (2010) 15‐Lipoxygenase‐2 is expressed in macrophages in human carotid plaques and regulated by hypoxia‐inducible factor‐1alpha. European Journal of Clinical Investigation 40(1): 11–17.

Huo Y, Zhao L, Hyman MC et al. (2004) Critical role of macrophage 12/15‐lipoxygenase for atherosclerosis in apolipoprotein E‐deficient mice. Circulation 110(14): 2024–2031.

Hutchins PM and Murphy RC (2012) Cholesteryl ester acyl oxidation and remodeling in murine macrophages: formation of oxidized phosphatidylcholine. Journal of Lipid Research 53(8): 1588–1597.

Izumi T, Hoshiko S, Radmark O and Samelsson B (1990) Cloning of the cDNA for human 12‐lipoxygenase. Proceedings of the National Academy of Sciences of the USA 87(19): 7477–7481.

Jakobsson PJ, Morgenstern R, Mancini J, Ford-Hutchinson A and Persson B (1999) Common structural features of MAPEG – a widespread superfamily of membrane associated proteins with highly divergent functions in eicosanoid and glutathione metabolism. Protein Science 8(3): 689–692.

Kammerer I, Ringseis R, Biemann R , Wen G and Eder K (2011) 13‐Hydroxy linoleic acid increases expression of the cholesterol transporters ABCA1, ABCG1 and SR‐BI and stimulates apoA‐I‐dependent cholesterol efflux in RAW264.7 macrophages. Lipids in Health and Disease 10: 222.

Kilty I, Logan A and Vickers PJ (1999) Differential characteristics of human 15‐lipoxygenase isozymes and a novel splice variant of 15S‐lipoxygenase. European Journal of Biochemistry 266(1): 83–93.

Kuhn H and Thiele BJ (1999) The diversity of the lipoxygenase family. Many sequence data but little information on biological significance. FEBS Letters 449(1): 7–11.

Magnusson LU, Lundqvist A, Karlsson MN et al. (2012) Arachidonate 15‐lipoxygenase type B knockdown leads to reduced lipid accumulation and inflammation in atherosclerosis. PloS One 7(8): e43142.

Mandal AK, Jones PB, Bair AM et al. (2008) The nuclear membrane organization of leukotriene synthesis. Proceedings of the National Academy of Sciences of the USA 105(51): 20434–20439.

Mandal AK, Skoch J, Bacskai BJ et al. (2004) The membrane organization of leukotriene synthesis. Proceedings of the National Academy of Sciences of the USA 101(17): 6587–6592.

Martinez Molina D, Eshaghi S and Nordlund P (2008) Catalysis within the lipid bilayer‐structure and mechanism of the MAPEG family of integral membrane proteins. Current Opinion in Structural Biology 18(4): 442–449.

Martinez Molina D, Wetterholm A, Kohl A et al. (2007) Structural basis for synthesis of inflammatory mediators by human leukotriene C4 synthase. Nature 448(7153): 613–616.

Naruhn S, Meissner W, Adhikary T et al. (2010) 15‐hydroxyeicosatetraenoic acid is a preferential peroxisome proliferator‐activated receptor beta/delta agonist. Molecular Pharmacology 77(2): 171–184.

Neau DB, Gilbert NC, Bartlett SG et al. (2009) The 1.85 A structure of an 8R‐lipoxygenase suggests a general model for lipoxygenase product specificity. Biochemistry 48(33): 7906–7915.

Nie D, Nemeth J, Qiao Y et al. (2003) Increased metastatic potential in human prostate carcinoma cells by overexpression of arachidonate 12‐lipoxygenase. Clinical and Experimental Metastasis 20(7): 657–663.

Noguchi M, Miyano M, Matsumoto T and Noma M (1994) Human 5‐lipoxygenase associates with phosphatidylcholine liposomes and modulates LTA4 synthetase activity. Biochimica et Biophysica Acta 1215(3): 300–306.

Oldham ML, Brash AR and Newcomer ME (2005) Insights from the X‐ray crystal structure of coral 8R‐lipoxygenase: calcium activation via A C2‐like domain and a structural basis of product chirality. Journal of Biological Chemistry 280(47): 39545–39552.

Piqueras L, Sanz MJ, Perretti M et al. (2009) Activation of PPARbeta/delta inhibits leukocyte recruitment, cell adhesion molecule expression, and chemokine release. Journal of Leukocyte Biology 86(1): 115–122.

Rudberg PC, Tholander F, Thunnissen MM et al. (2002) Leukotriene A4 hydrolase: selective abrogation of leukotriene B4 formation by mutation of aspartic acid 375. Proceedings of the National Academy of Sciences of the USA 99(7): 4215–4220.

Schneider C, Pratt DA, Porter NA and Brash AR (2007) Control of oxygenation in lipoxygenase and cyclooxygenase catalysis. Chemistry and Biology 14(5): 473–488.

Serhan CN, Chiang N and Van Dyke TE (2008) Resolving inflammation: dual anti‐inflammatory and pro‐resolution lipid mediators. Nature Reviews Immunology 8(5): 349–361.

Serhan CN, Jain A, Marleau S et al. (2003) Reduced inflammation and tissue damage in transgenic rabbits overexpressing 15‐lipoxygenase and endogenous anti‐inflammatory lipid mediators. Journal of Immunology 171(12): 6856–6865.

Shen J, Herderick E, Cornhill JF et al. (1996) Macrophage‐mediated 15‐lipoxygenase expression protects against atherosclerosis development. Journal of Clinical Investigation 98(10): 2201–2208.

Snelgrove RJ, Jackson PL, Hardison MT et al. (2010) A critical role for LTA4H in limiting chronic pulmonary neutrophilic inflammation. Science 330(6000): 90–94.

Walther M, Wiesner R and Kuhn H (2004) Investigations into calcium‐dependent membrane association of 15‐lipoxygenase‐1. Mechanistic roles of surface‐exposed hydrophobic amino acids and calcium. Journal of Biological Chemistry 279(5): 3717–3725.

Weibel GL, Joshi MR, Alexander ET et al. (2009) Overexpression of human 15(S)‐lipoxygenase‐1 in RAW macrophages leads to increased cholesterol mobilization and reverse cholesterol transport. Arteriosclerosis, Thrombosis, and Vascular Biology 29(6): 837–842.

Wuest SJ, Crucet M, Gemperle C, Loretz C and Hersberger M (2012) Expression and regulation of 12/15‐lipoxygenases in human primary macrophages. Atherosclerosis 225(1): 121–127.

Xu S, Mueser TC, Marnett LJ and Funk MO (2012) Crystal structure of 12‐lipoxygenase catalytic‐domain‐inhibitor complex identifies a substrate‐binding channel for catalysis. Structure 20(9): 1490–1497.

Zhao L, Pratico D, Rader DJ and Funk CD (2005) 12/15‐Lipoxygenase gene disruption and vitamin E administration diminish atherosclerosis and oxidative stress in apolipoprotein E deficient mice through a final common pathway. Prostaglandins and Other Lipid Mediators 78(1–4): 185–193.

Zheng Y, Yin H, Boeglin WE and Brash AR (2011) Lipoxygenases mediate the effect of essential fatty acid in skin barrier formation: a proposed role in releasing omega‐hydroxyceramide for construction of the corneocyte lipid envelope. Journal of Biological Chemistry 286(27): 24046–24056.

Further Reading

Haeggstrom JZ and Funk CD (2011) Lipoxygenase and leukotriene pathways: biochemistry, biology, and roles in disease. Chemical Reviews 111(10): 5866–5898.

Murphy RC and Gijon MA (2007) Biosynthesis and metabolism of leukotrienes. Biochemical Journal 405(3): 379–395.

Nakamura M and Shimizu T (2011) Leukotriene receptors. Chemical Reviews 111(10): 6231–6298.

Radmark O and Samuelsson B (2009) 5‐Lipoxygenase: mechanisms of regulation. Journal of Lipid Research 50(Suppl): S40–45.

Sala A, Folco G and Murphy RC (2010) Transcellular biosynthesis of eicosanoids. Pharmacological Reports 62(3): 503–510.

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Kobe, Matthew J, and Newcomer, Marcia E(Sep 2013) Lipoxygenase Pathway of the Arachidonate Cascade. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0023400]