Arachidonate 5-lipoxygenase, also known as 5-lipoxygenase, 5-LOX or 5-LO, is an enzyme that in humans is encoded by the ALOX5gene. Arachidonate 5-lipoxygenase is a member of the lipoxygenase family of enzymes. It transforms EFAs into leukotrienes and is a current target for pharmaceutical intervention in a number of diseases.
As well as being intermediates in the formation of leukotrienes, hydroperoxides are released from lipoxygenase enzymes. These hydroperoxides are rapidly reduced to their corresponding hydroxy- eicosatetraenoates which may then be further metabolize to active products. 5-LO releases 5-HpETE) which can be further metabolized to 5-oxo-ETE, a potent stimulator of cells involved in allergic reactions such as eosinophils and basophils, and a possible mediator of allergic reactions in humans.
Recently, oxidized lipid products of 5-LO have been measured in membranes of neutrophils in the form of esterified-5-HETE phospholipids. These novel products have biological activities including inhibition of neutrophil extracellular traps.
Two other lipoxygenases, 12-LO and 15-LO, act at the 12- and 15-positions, yielding 12- and 15-HPETE. These pathways lead to the leukotriene 12-hydroxyeicosatetraenoic acid (12-HETE) and to the lipoxins, respectively.
5-LO is a target for pharmaceutical intervention in CAD. Some people with variant alleles for 5-LO are at elevated risk for CAD. 5-LO is expressed in brain cells and may participate in neuropathologic processes.
Mutations in the promoter region of this gene lead to a diminished response to antileukotriene drugs used in the treatment of asthma and may also be associated with atherosclerosis and several cancers. Alternatively spliced transcript variants have been observed, but their full-length nature has not been determined.
As leukotrienes are important causes of pathological symptoms in asthma, 5-LO inhibitors were developed as asthma treatments. The only 5-LO inhibitor currently licensed for human use in asthma is zileuton.
^Dwyer JH, Allayee H, Dwyer KM, Fan J, Wu H, Mar R et al. (2004). "Arachidonate 5-lipoxygenase promoter genotype, dietary arachidonic acid, and atherosclerosis". N. Engl. J. Med.350 (1): 29–37. doi:10.1056/NEJMoa025079. PMID14702425.
^Zhang L, Zhang WP, Hu H, Wang ML, Sheng WW, Yao HT et al. (2006). "Expression patterns of 5-lipoxygenase in human brain with traumatic injury and astrocytoma". Neuropathology26 (2): 99–106. doi:10.1111/j.1440-1789.2006.00658.x. PMID16708542.
^can be used as DMARDS. Song Y, Wei EQ, Zhang WP, Zhang L, Liu JR, Chen Z (2004). "Minocycline protects PC12 cells from ischemic-like injury and inhibits 5-lipoxygenase activation". Neuroreport15 (14): 2181–4. doi:10.1097/00001756-200410050-00007. PMID15371729.
^Albert D, Zündorf I, Dingermann T, Müller WE, Steinhilber D, Werz O (2002). "Hyperforin is a dual inhibitor of cyclooxygenase-1 and 5-lipoxygenase". Biochem. Pharmacol.64 (12): 1767–75. doi:10.1016/s0006-2952(02)01387-4. PMID12445866.
^Provost P, Doucet J, Hammarberg T, Gerisch G, Samuelsson B, Radmark O (2001). "5-Lipoxygenase interacts with coactosin-like protein". J. Biol. Chem.276 (19): 16520–7. doi:10.1074/jbc.M011205200. PMID11297527.
^VanderNoot VA, Fitzpatrick FA (1995). "Competitive binding assay of src homology domain 3 interactions between 5-lipoxygenase and growth factor receptor binding protein 2". Anal. Biochem.230 (1): 108–14. doi:10.1006/abio.1995.1444. PMID8585605.
^Lepley RA, Fitzpatrick FA (1994). "5-Lipoxygenase contains a functional Src homology 3-binding motif that interacts with the Src homology 3 domain of Grb2 and cytoskeletal proteins". J. Biol. Chem.269 (39): 24163–8. PMID7929073.
Ishii S, Noguchi M, Miyano M, Matsumoto T, Noma M (1992). "Mutagenesis studies on the amino acid residues involved in the iron-binding and the activity of human 5-lipoxygenase". Biochem. Biophys. Res. Commun.182 (3): 1482–90. doi:10.1016/0006-291X(92)91901-2. PMID1540191.
Nguyen T, Falgueyret JP, Abramovitz M, Riendeau D (1991). "Evaluation of the role of conserved His and Met residues among lipoxygenases by site-directed mutagenesis of recombinant human 5-lipoxygenase". J. Biol. Chem.266 (32): 22057–62. PMID1939225.
Jakobsson PJ, Shaskin P, Larsson P, Feltenmark S, Odlander B, Aguilar-Santelises M et al. (1995). "Studies on the regulation and localization of 5-lipoxygenase in human B-lymphocytes". Eur. J. Biochem.232 (1): 37–46. doi:10.1111/j.1432-1033.1995.tb20778.x. PMID7556168.
Lepley RA, Fitzpatrick FA (1994). "5-Lipoxygenase contains a functional Src homology 3-binding motif that interacts with the Src homology 3 domain of Grb2 and cytoskeletal proteins". J. Biol. Chem.269 (39): 24163–8. PMID7929073.
Mancini JA, Li C, Vickers PJ (1993). "5-Lipoxygenase activity in the human pancreas". J Lipid Mediat8 (3): 145–50. PMID8268460.
VanderNoot VA, Fitzpatrick FA (1995). "Competitive binding assay of src homology domain 3 interactions between 5-lipoxygenase and growth factor receptor binding protein 2". Anal. Biochem.230 (1): 108–14. doi:10.1006/abio.1995.1444. PMID8585605.
Brock TG, McNish RW, Bailie MB, Peters-Golden M (1997). "Rapid import of cytosolic 5-lipoxygenase into the nucleus of neutrophils after in vivo recruitment and in vitro adherence". J. Biol. Chem.272 (13): 8276–80. doi:10.1074/jbc.272.13.8276. PMID9079648.
Nassar GM, Montero A, Fukunaga M, Badr KF (1997). "Contrasting effects of proinflammatory and T-helper lymphocyte subset-2 cytokines on the 5-lipoxygenase pathway in monocytes". Kidney Int.51 (5): 1520–8. doi:10.1038/ki.1997.209. PMID9150468.
Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene200 (1-2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID9373149.