arachidonate 5 lipoxygenase

Summary

Summary: An enzyme that catalyzes the oxidation of arachidonic acid to yield 5-hydroperoxyarachidonate (5-HPETE) which is rapidly converted by a peroxidase to 5-hydroxy-6,8,11,14-eicosatetraenoate (5-HETE). The 5-hydroperoxides are preferentially formed in leukocytes.

Top Publications

  1. Duroudier N, Tulah A, Sayers I. Leukotriene pathway genetics and pharmacogenetics in allergy. Allergy. 2009;64:823-39 pubmed publisher
    ..The aim of this review was to summarize the recent advances in the knowledge of these important mediators, focusing on genetic and pharmacogenetic aspects in the context of allergic phenotypes. ..
  2. Firuzi O, Zhuo J, Chinnici C, Wisniewski T, Pratico D. 5-Lipoxygenase gene disruption reduces amyloid-beta pathology in a mouse model of Alzheimer's disease. FASEB J. 2008;22:1169-78 pubmed
    ..Our work suggests that pharmacological inhibition of 5LO could provide a novel therapeutic tool for AD. ..
  3. Zou Y, Kim D, Jung K, Heo H, Kim C, Baik H, et al. Lysophosphatidylcholine enhances oxidative stress via the 5-lipoxygenase pathway in rat aorta during aging. Rejuvenation Res. 2009;12:15-24 pubmed publisher
    ..LPC may well be an important contributor to age-related oxidative stress in aging aorta. ..
  4. Radmark O, Samuelsson B. 5-Lipoxygenase: mechanisms of regulation. J Lipid Res. 2009;50 Suppl:S40-5 pubmed publisher
    ..Furthermore, possible effects of 5-LO metabolites in relation to tumorigenesis have emerged. Thus, an understanding of the biochemistry of this lipoxygenase has potential implications for treatment of various diseases. ..
  5. Qiu H, Gabrielsen A, Agardh H, Wan M, Wetterholm A, Wong C, et al. Expression of 5-lipoxygenase and leukotriene A4 hydrolase in human atherosclerotic lesions correlates with symptoms of plaque instability. Proc Natl Acad Sci U S A. 2006;103:8161-6 pubmed
    ..The abundant expression of LTA4H and correlation with plaque instability identify LTA4H as a potential target for pharmacological intervention in treatment of human atherosclerosis. ..
  6. Covey T, Edes K, Fitzpatrick F. Akt activation by arachidonic acid metabolism occurs via oxidation and inactivation of PTEN tumor suppressor. Oncogene. 2007;26:5784-92 pubmed
  7. Cao R, St Amand T, Grabner R, Habenicht A, Funk C. Genetic and pharmacological inhibition of the 5-lipoxygenase/leukotriene pathway in atherosclerotic lesion development in ApoE deficient mice. Atherosclerosis. 2009;203:395-400 pubmed publisher
    ..These results do not support a role for the 5-LO/LT pathway in intermediate to advanced atherosclerotic lesion development in mice. ..
  8. Uz T, Dimitrijevic N, Imbesi M, Manev H, Manev R. Effects of MK-886, a 5-lipoxygenase activating protein (FLAP) inhibitor, and 5-lipoxygenase deficiency on the forced swimming behavior of mice. Neurosci Lett. 2008;436:269-72 pubmed publisher
    ..Future research is needed to evaluate the clinical relevance of our findings. ..
  9. Cook Moreau J, El Makhour Hojeij Y, Barrière G, Rabinovitch Chable H, Faucher K, Sturtz F, et al. Expression of 5-lipoxygenase (5-LOX) in T lymphocytes. Immunology. 2007;122:157-66 pubmed
    ..The presence of 5-LOX in T lymphocytes but the absence of endogenous lipoxygenase metabolite production compared to Jurkat cells may constitute a fundamental difference between resting peripheral lymphocytes and leukaemic cells. ..

More Information

Publications62

  1. Adamek A, Jung S, Dienesch C, Laser M, Ertl G, Bauersachs J, et al. Role of 5-lipoxygenase in myocardial ischemia-reperfusion injury in mice. Eur J Pharmacol. 2007;571:51-4 pubmed
    ..In summary, inhibition of 5-lipoxygenase does not affect cardiac ischemia-reperfusion injury but the post-ischemic inflammatory response. ..
  2. Radmark O, Werz O, Steinhilber D, Samuelsson B. 5-Lipoxygenase: regulation of expression and enzyme activity. Trends Biochem Sci. 2007;32:332-41 pubmed
    ..With regard to the control of enzyme activity, many of these findings focus on the N-terminal domain of 5-LO. ..
  3. Goossens L, Pommery N, Henichart J. COX-2/5-LOX dual acting anti-inflammatory drugs in cancer chemotherapy. Curr Top Med Chem. 2007;7:283-96 pubmed
    ..This will lead us to evoke and to justify alternative strategies to develop agents that modulate multiple targets simultaneously with the aim of enhancing efficacy or improving safety relative to drugs that address only a single enzyme. ..
  4. Zhou Y, Fang S, Ye Y, Chu L, Zhang W, Wang M, et al. Caffeic acid ameliorates early and delayed brain injuries after focal cerebral ischemia in rats. Acta Pharmacol Sin. 2006;27:1103-10 pubmed
    ..Caffeic acid has protective effect on both early and delayed injuries after focal cerebral ischemia in rats; and this effect may partly relate to 5-lipoxygenase inhibition. ..
  5. Radmark O, Samuelsson B. 5-lipoxygenase: regulation and possible involvement in atherosclerosis. Prostaglandins Other Lipid Mediat. 2007;83:162-74 pubmed
    ..This review article focuses on two aspects regarding 5-lipoxygenase. First, mechanisms for activation of the enzyme. Second, the involvement of 5-lipoxygenase and leukotrienes in atherosclerosis. ..
  6. Manev H, Manev R, Vidovich M. Depression, inflammation, and cardiovascular disease: is 5-lipoxygenase the missing link?. J Am Coll Cardiol. 2008;51:1990-1; author reply 1991 pubmed publisher
  7. Adamjee J, Suh Y, Park H, Choi J, Penrose J, Lam B, et al. Expression of 5-lipoxygenase and cyclooxygenase pathway enzymes in nasal polyps of patients with aspirin-intolerant asthma. J Pathol. 2006;209:392-9 pubmed
    ..05), while the other enzymes were not different. Our results indicate that a marked over-representation of LTC4 synthase in mucosal eosinophils is closely linked to aspirin intolerance in the nasal airway, as in the bronchial airways. ..
  8. Melstrom L, Bentrem D, Salabat M, Kennedy T, Ding X, Strouch M, et al. Overexpression of 5-lipoxygenase in colon polyps and cancer and the effect of 5-LOX inhibitors in vitro and in a murine model. Clin Cancer Res. 2008;14:6525-30 pubmed publisher
    ..The blockade of 5-LOX inhibits colon cancer cell proliferation both in vitro and in vivo and may prove a beneficial chemopreventive therapy in colon cancer. ..
  9. Seuter S, Sorg B, Steinhilber D. The coding sequence mediates induction of 5-lipoxygenase expression by Smads3/4. Biochem Biophys Res Commun. 2006;348:1403-10 pubmed
    ..Sequence analysis and deletion studies indicate the existence of up to four Smad binding elements and at least one TGFbeta responsive element far downstream of the transcriptional start site. ..
  10. Rakonjac M, Fischer L, Provost P, Werz O, Steinhilber D, Samuelsson B, et al. Coactosin-like protein supports 5-lipoxygenase enzyme activity and up-regulates leukotriene A4 production. Proc Natl Acad Sci U S A. 2006;103:13150-5 pubmed
    ..Furthermore, in stimulated cells, CLP appears to function in a complex together with 5LO and membranes, increasing the capacity of 5LO for leukotriene biosynthesis. ..
  11. Werz O, Steinhilber D. Therapeutic options for 5-lipoxygenase inhibitors. Pharmacol Ther. 2006;112:701-18 pubmed
    ..In this review, we summarize the knowledge on possible functions of the 5-LO pathway in various diseases like asthma, cancer and cardiovascular events and review the corresponding potential therapeutic roles of 5-LO inhibitors. ..
  12. Chu L, Fang S, Zhou Y, Yu G, Wang M, Zhang W, et al. Minocycline inhibits 5-lipoxygenase activation and brain inflammation after focal cerebral ischemia in rats. Acta Pharmacol Sin. 2007;28:763-72 pubmed
    ..Minocycline inhibited postischemic brain inflammation, which might be partly mediated by the inhibition of 5-LOX expression and enzymatic activation. ..
  13. Li C, Zhang W, Lu Y, Fang S, Yuan Y, Qi L, et al. Oxygen-glucose deprivation activates 5-lipoxygenase mediated by oxidative stress through the p38 mitogen-activated protein kinase pathway in PC12 cells. J Neurosci Res. 2009;87:991-1001 pubmed publisher
    ..Thus, we conclude that OGD/recovery-induced ischemic-like injury induces 5-LOX activation, which is mediated by oxidative stress through activating the p38 MAPK pathway. ..
  14. Sobrado M, Pereira M, Ballesteros I, Hurtado O, Fernández López D, Pradillo J, et al. Synthesis of lipoxin A4 by 5-lipoxygenase mediates PPARgamma-dependent, neuroprotective effects of rosiglitazone in experimental stroke. J Neurosci. 2009;29:3875-84 pubmed publisher
  15. Chen X, Sood S, Yang C, Li N, Sun Z. Five-lipoxygenase pathway of arachidonic acid metabolism in carcino-genesis and cancer chemoprevention. Curr Cancer Drug Targets. 2006;6:613-22 pubmed
    ..Inhibition of the 5-lipoxygenase pathways clearly has chemopreventive effects on various cancers, and hence further studies on its enzymes, metabolites and receptors for cancer chemoprevention and therapy are warranted. ..
  16. Ge Q, Wei E, Zhang W, Hu X, Huang X, Zhang L, et al. Activation of 5-lipoxygenase after oxygen-glucose deprivation is partly mediated via NMDA receptor in rat cortical neurons. J Neurochem. 2006;97:992-1004 pubmed
    ..From these results, we conclude that OGD can activate 5-LOX in primary rat cortical neurons, and that this activation may be partly mediated via activating NMDA receptor. ..
  17. Soumaoro L, Iida S, Uetake H, Ishiguro M, Takagi Y, Higuchi T, et al. Expression of 5-lipoxygenase in human colorectal cancer. World J Gastroenterol. 2006;12:6355-60 pubmed
    ..392, P = 0.0002), depth or vessel invasion. These results suggest that 5-Lox is up-regulated in colorectal cancer and that inhibition of its expression might be valuable in the prevention and treatment of colorectal cancer. ..
  18. Hashimoto A, Hayashi I, Murakami Y, Sato Y, Kitasato H, Matsushita R, et al. Antiinflammatory mediator lipoxin A4 and its receptor in synovitis of patients with rheumatoid arthritis. J Rheumatol. 2007;34:2144-53 pubmed
    ..These findings could lead to the development of new therapy for inflammatory arthritis such as RA. ..
  19. Ge Q, Hu X, Ma Z, Liu J, Zhang W, Chen Z, et al. Baicalin attenuates oxygen-glucose deprivation-induced injury via inhibiting NMDA receptor-mediated 5-lipoxygenase activation in rat cortical neurons. Pharmacol Res. 2007;55:148-57 pubmed
    ..These results indicate that baicalin attenuates ischemic-like injury in the neurons, and this effect partly relates to the inhibition of NMDA receptor-mediated 5-LOX activation. ..
  20. Wang Q, Zhang W, Liu Q, Zhang X, Lv N, Ye L, et al. A mutant of hepatitis B virus X protein (HBxDelta127) promotes cell growth through a positive feedback loop involving 5-lipoxygenase and fatty acid synthase. Neoplasia. 2010;12:103-15 pubmed
    ..Thus, our finding provides a new insight into the mechanism involving the promotion of cell growth mediated by HBxDelta127. ..
  21. Cottrell J, O Connor J. Pharmacological inhibition of 5-lipoxygenase accelerates and enhances fracture-healing. J Bone Joint Surg Am. 2009;91:2653-65 pubmed publisher
    ..The goal of this study was to determine if systemic inhibition of 5-lipoxygenase with an orally delivered drug could accelerate fracture-healing...
  22. Chinnici C, Yao Y, Pratico D. The 5-lipoxygenase enzymatic pathway in the mouse brain: young versus old. Neurobiol Aging. 2007;28:1457-62 pubmed
    ..This observation supports the hypothesis that 5-LO may be involved in diseases of the brain associated with aging. ..
  23. Mahshid Y, Lisy M, Wang X, Spanbroek R, Flygare J, Christensson B, et al. High expression of 5-lipoxygenase in normal and malignant mantle zone B lymphocytes. BMC Immunol. 2009;10:2 pubmed publisher
  24. Ikonomovic M, Abrahamson E, Uz T, Manev H, DeKosky S. Increased 5-lipoxygenase immunoreactivity in the hippocampus of patients with Alzheimer's disease. J Histochem Cytochem. 2008;56:1065-73 pubmed publisher
    ..The relationship between elevated intracellular 5-LOX and hallmark AD pathological lesions provides further evidence that neuroinflammatory pathways contribute to the pathogenesis of AD. ..
  25. Burnett B, Jia Q, Zhao Y, Levy R. A medicinal extract of Scutellaria baicalensis and Acacia catechu acts as a dual inhibitor of cyclooxygenase and 5-lipoxygenase to reduce inflammation. J Med Food. 2007;10:442-51 pubmed
    ..These results suggest that this natural, flavonoid mixture acts via "dual inhibition" of COX and LOX enzymes to reduce production of pro-inflammatory eicosanoids and attenuate edema in an in vivo model of inflammation...
  26. Riccioni G, Bucciarelli T, Mancini B, Di Ilio C, D Orazio N. Antileukotriene drugs: clinical application, effectiveness and safety. Curr Med Chem. 2007;14:1966-77 pubmed
    ..The aim of this review is to show the most recent applications and effectiveness in clinical practice of the LTRAs. ..
  27. Song Y, Wei E, Zhang W, Ge Q, Liu J, Wang M, et al. Minocycline protects PC12 cells against NMDA-induced injury via inhibiting 5-lipoxygenase activation. Brain Res. 2006;1085:57-67 pubmed
    ..Therefore, we conclude that the protective effect of minocycline on NMDA-induced injury is partly mediated by inhibiting 5-LOX activation. ..
  28. Maxis K, Delalandre A, Martel Pelletier J, Pelletier J, Duval N, Lajeunesse D. The shunt from the cyclooxygenase to lipoxygenase pathway in human osteoarthritic subchondral osteoblasts is linked with a variable expression of the 5-lipoxygenase-activating protein. Arthritis Res Ther. 2006;8:R181 pubmed
    ..The expression of FLAP in OA osteoblasts is also modulated differently by 1,25(OH)2D3 and TGF-beta depending on their endogenous low and high PGE2 levels. ..
  29. Wei N, Wang B, Zhang Q, Mi M, Zhu J, Yu X, et al. Effects of different dietary fatty acids on the fatty acid compositions and the expression of lipid metabolic-related genes in mammary tumor tissues of rats. Nutr Cancer. 2008;60:810-25 pubmed publisher
    ..05). These results suggest that 1:1 n-6/n-3 in the diet is effective in the prevention of mammary tumor development by increasing the n-3 PUFA content and reducing the expression of lipid metabolic-related genes. ..
  30. Ferguson A, McKeever B, Xu S, Wisniewski D, Miller D, Yamin T, et al. Crystal structure of inhibitor-bound human 5-lipoxygenase-activating protein. Science. 2007;317:510-2 pubmed
    ..This structural information provides a platform for the development of therapeutics for respiratory and cardiovascular diseases. ..
  31. Zhou Y, Wei E, Fang S, Chu L, Wang M, Zhang W, et al. Spatio-temporal properties of 5-lipoxygenase expression and activation in the brain after focal cerebral ischemia in rats. Life Sci. 2006;79:1645-56 pubmed
    ..Thus, we conclude that 5-LOX expression and the enzymatic activity are increased after focal cerebral ischemia, and spatio-temporally involved in neuron injury in the acute phase and astrocyte proliferation in the late phase. ..
  32. Hu M, Zhang X, Liu W, Cui H, Di N. Longitudinal changes of defensive and offensive factors in focal cerebral ischemia-reperfusion in rats. Brain Res Bull. 2009;79:371-5 pubmed publisher
    ..With these results we inferred that both defensive factors, such as PDGF-BB, AQP-4 and IGF-1, and offensive factor, like 5-LO, play some roles in the ischemia-reperfusion injury. ..
  33. De Caterina R, Zampolli A. From asthma to atherosclerosis--5-lipoxygenase, leukotrienes, and inflammation. N Engl J Med. 2004;350:4-7 pubmed
  34. Dwyer J, Allayee H, Dwyer K, Fan J, Wu H, Mar R, et al. Arachidonate 5-lipoxygenase promoter genotype, dietary arachidonic acid, and atherosclerosis. N Engl J Med. 2004;350:29-37 pubmed
    ..The observed diet-gene interactions further suggest that dietary n-6 polyunsaturated fatty acids promote, whereas marine n-3 fatty acids inhibit, leukotriene-mediated inflammation that leads to atherosclerosis in this subpopulation. ..
  35. Perez Novo C, Watelet J, Claeys C, Van Cauwenberge P, Bachert C. Prostaglandin, leukotriene, and lipoxin balance in chronic rhinosinusitis with and without nasal polyposis. J Allergy Clin Immunol. 2005;115:1189-96 pubmed
    ..Changes of tissue eicosanoid metabolism do occur in CRS, even in the absence of clinical aspirin sensitivity, and these changes appear to be related to the severity of eosinophilic inflammation. ..
  36. Lotzer K, Funk C, Habenicht A. The 5-lipoxygenase pathway in arterial wall biology and atherosclerosis. Biochim Biophys Acta. 2005;1736:30-7 pubmed
    ..We will attempt to propose strategies to further explore potential links between the 5-LO pathway and blood vessel physiology and disease progression. ..
  37. Song Y, Wei E, Zhang W, Zhang L, Liu J, Chen Z. Minocycline protects PC12 cells from ischemic-like injury and inhibits 5-lipoxygenase activation. Neuroreport. 2004;15:2181-4 pubmed
    ..Thus, minocycline can protect PC12 cells from in vitro ischemic-like injury, and this effect may be partly related to the inhibition of 5-lipoxygenase activation. ..
  38. Zhang Z, Chen C, Manev H. DNA methylation as an epigenetic regulator of neural 5-lipoxygenase expression: evidence in human NT2 and NT2-N cells. J Neurochem. 2004;88:1424-30 pubmed
    ..This is the first report demonstrating that the dynamics of DNA methylation relates to neural 5-lipoxygenase gene expression. ..
  39. Luo M, Jones S, Flamand N, Aronoff D, Peters Golden M, Brock T. Phosphorylation by protein kinase a inhibits nuclear import of 5-lipoxygenase. J Biol Chem. 2005;280:40609-16 pubmed
  40. Li N, Sood S, Wang S, Fang M, Wang P, Sun Z, et al. Overexpression of 5-lipoxygenase and cyclooxygenase 2 in hamster and human oral cancer and chemopreventive effects of zileuton and celecoxib. Clin Cancer Res. 2005;11:2089-96 pubmed
    ..Zileuton and celecoxib prevented oral carcinogenesis at the post-initiation stage through their inhibitory effects on arachidonic acid metabolism. ..
  41. Eriksson E. Mechanisms of leukocyte recruitment to atherosclerotic lesions: future prospects. Curr Opin Lipidol. 2004;15:553-8 pubmed
    ..Detailed study of certain subclasses of leukocytes in the recruitment process will be important in future studies in this field. ..
  42. Zhao L, Moos M, Grabner R, Pedrono F, Fan J, Kaiser B, et al. The 5-lipoxygenase pathway promotes pathogenesis of hyperlipidemia-dependent aortic aneurysm. Nat Med. 2004;10:966-73 pubmed
    ..These data link the 5-LO pathway to hyperlipidemia-dependent inflammation of the arterial wall and to pathogenesis of aortic aneurysms through a potential chemokine intermediary route. ..
  43. Menard C, Valastro B, Martel M, Chartier E, Marineau A, Baudry M, et al. AMPA receptor phosphorylation is selectively regulated by constitutive phospholipase A(2) and 5-lipoxygenase activities. Hippocampus. 2005;15:370-80 pubmed
  44. Werz O, Steinhilber D. Development of 5-lipoxygenase inhibitors--lessons from cellular enzyme regulation. Biochem Pharmacol. 2005;70:327-33 pubmed
    ..This comment focuses on the impact of these stimulatory and inhibitory pathways on the efficacy of 5-LO inhibitors and suggests additional criteria for the development of this class of compounds. ..
  45. Choi J, Park H, Oh H, Lee J, Suh Y, Park C, et al. Leukotriene-related gene polymorphisms in ASA-intolerant asthma: an association with a haplotype of 5-lipoxygenase. Hum Genet. 2004;114:337-44 pubmed
    ..However, the possible involvement of ALOX5-ht1[G-C-G-A] in AIA development is suggested. ..
  46. Werz O, Tretiakova I, Michel A, Ulke Lemee A, Hörnig M, Franke L, et al. Caspase-mediated degradation of human 5-lipoxygenase in B lymphocytic cells. Proc Natl Acad Sci U S A. 2005;102:13164-9 pubmed
    ..We suggest that splitting of BL41-E95-A cells induces de novo synthesis of a protein involved in the activation of casp-6, which cleaves 5-LO. ..
  47. Yoshimura R, Matsuyama M, Mitsuhashi M, Takemoto Y, Tsuchida K, Kawahito Y, et al. Relationship between lipoxygenase and human testicular cancer. Int J Mol Med. 2004;13:389-93 pubmed
    ..The LOX inhibitors inhibited the growth of TC cells. LOX is induced in TC, and results may suggest that LOXs are essential for cell growth of TC cells. ..
  48. Serhan C, Jain A, Marleau S, Clish C, Kantarci A, Behbehani B, et al. Reduced inflammation and tissue damage in transgenic rabbits overexpressing 15-lipoxygenase and endogenous anti-inflammatory lipid mediators. J Immunol. 2003;171:6856-65 pubmed
    ..Moreover, they suggest that LXs can be targets for novel approaches to diseases, e.g., periodontitis and arthritis, where inflammation and bone destruction are features. ..
  49. Catalano A, Caprari P, Soddu S, Procopio A, Romano M. 5-lipoxygenase antagonizes genotoxic stress-induced apoptosis by altering p53 nuclear trafficking. FASEB J. 2004;18:1740-2 pubmed
    ..Moreover, they provide a rationale to the therapeutic use of 5-LO inhibitors to enhance cancer chemosensitivity in selected tumors. ..
  50. Boileau C, Pelletier J, Tardif G, Fahmi H, Laufer S, Lavigne M, et al. The regulation of human MMP-13 by licofelone, an inhibitor of cyclo-oxygenases and 5-lipoxygenase, in human osteoarthritic chondrocytes is mediated by the inhibition of the p38 MAP kinase signalling pathway. Ann Rheum Dis. 2005;64:891-8 pubmed
    ..This may explain some of the mechanisms whereby licofelone exerts its positive effect on osteoarthritic changes. ..
  51. Martel Pelletier J, Mineau F, Fahmi H, Laufer S, Reboul P, Boileau C, et al. Regulation of the expression of 5-lipoxygenase-activating protein/5-lipoxygenase and the synthesis of leukotriene B(4) in osteoarthritic chondrocytes: role of transforming growth factor beta and eicosanoids. Arthritis Rheum. 2004;50:3925-33 pubmed
    ..We also demonstrated that LTB(4) likely contributes to the up-regulation of important catabolic factors involved in the pathophysiology of OA, such as MMP. ..
  52. Gosselin J, Borgeat P, Flamand L. Leukotriene B4 protects latently infected mice against murine cytomegalovirus reactivation following allogeneic transplantation. J Immunol. 2005;174:1587-93 pubmed
  53. Chen X, Wang S, Wu N, Sood S, Wang P, Jin Z, et al. Overexpression of 5-lipoxygenase in rat and human esophageal adenocarcinoma and inhibitory effects of zileuton and celecoxib on carcinogenesis. Clin Cancer Res. 2004;10:6703-9 pubmed
    ..Both zileuton and celecoxib had inhibitory effects on esophageal adenocarcinogenesis through inhibition on their respective enzymes of AA metabolism. ..