Arachidonate 5-lipoxygenase
arachidonate 5-lipoxygenase | |||||||||
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Identifiers | |||||||||
EC number | 1.13.11.34 | ||||||||
CAS number | 80619-02-9 | ||||||||
Databases | |||||||||
IntEnz | IntEnz view | ||||||||
BRENDA | BRENDA entry | ||||||||
ExPASy | NiceZyme view | ||||||||
KEGG | KEGG entry | ||||||||
MetaCyc | metabolic pathway | ||||||||
PRIAM | profile | ||||||||
PDB structures | RCSB PDB PDBe PDBsum | ||||||||
Gene Ontology | AmiGO / EGO | ||||||||
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Arachidonate 5-lipoxygenase, also known as 5-lipoxygenase, 5-LOX or 5-LO, is an enzyme that in humans is encoded by the ALOX5 gene.[1] 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.
Substrates and products
EFA substrates and products of 5-LO include:
- Arachidonic acid (AA) yields 5-hydroperoxyeicosatetraenoic acids (5-HpETE), 5-hydroxyeicosatetraenoic acids (5-HETE), 5-oxo-eicosatetraenoate (5-oxo-ETE), and the 4-series leukotrienes (LTB4, LTC4, LTD4, LTE4).
- Eicosapentaenoic acid (EPA) yields the 5-series (LTB5, LTC5, LTD5, LTE5).
- Gamma-linolenic acid (GLA via the DGLA intermediary) yields no leukotrienes, but inhibits the conversion of AA.
Function
5-LO catalyzes oxidation of AA at the 5-position to yield 5-HpETE. 5-LO then converts 5-HpETE to leukotriene A4.[2]
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.[3]
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.[4]
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]
Clinical significance
5-LO is a target for pharmaceutical intervention in CAD.[6] Some people with variant alleles for 5-LO are at elevated risk for CAD.[7] 5-LO is expressed in brain cells and may participate in neuropathologic processes.[8]
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.[9]
5-LO inhibitors
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.
Minocycline, although primarily a tetracycline antibiotic, is also a 5-LO inhibitor.[10] It may therefore be used as a DMARD-medication in mild rheumatoid arthritis and other rheumatic conditions.[11]
Hyperforin, an active constituent of the herb St John's wort, is a highly potent 5-LO inhibitor.[12] Another natural product, indirubin-3'-monoxime, was also described as selective 5-LO inhibitor effective in a range of cell-free and cell-based models.[13] In addition, curcumin, a constituent of turmeric, is a 5-LO inhibitor in vitro.[14]
Activation
5-LO is activated by 5-lipoxygenase activating protein (FLAP).
Interactions
Arachidonate 5-lipoxygenase has been shown to interact with:
References
- ↑ Funk CD, Hoshiko S, Matsumoto T, Rdmark O, Samuelsson B (1989). "Characterization of the human 5-lipoxygenase gene". Proc. Natl. Acad. Sci. U.S.A. 86 (8): 2587–91. doi:10.1073/pnas.86.8.2587. PMC 286962. PMID 2565035.
- ↑ Reaction R01595 and R03058 at KEGG Pathway Database.
- ↑ Powell WS, Rokach J (2013). "The eosinophil chemoattractant 5-oxo-ETE and the OXE receptor". Prog. Lipid Res. 52 (4): 651–65. doi:10.1016/j.plipres.2013.09.001. PMID 24056189.
- ↑ Clark SR, Guy CJ, Scurr MJ, Taylor PR, Kift-Morgan AP, Hammond VJ, Thomas CP, Coles B, Roberts GW, Eberl M, Jones SA, Topley N, Kotecha S, O'Donnell VB (2011). "Esterified eicosanoids are acutely generated by 5-lipoxygenase in primary human neutrophils and in human and murine infection". Blood 117 (6): 2033–43. doi:10.1182/blood-2010-04-278887. PMC 3374621. PMID 21177434.
- ↑ Dorlands Medical Dictionary, entries at arachidonate 5-lipoxygenase and following. Retrieved on 2006-02-07.
- ↑ "5-Lipoxygenase, A New Therapeutic And Diagnostic Target For Heart Disease Management". UCLA Case No. 2001-429 PCT Publication Number: WO 03/035670 A2. Archived from the original on 2006-08-30. Retrieved 2007-11-18.
- ↑ Dwyer JH, Allayee H, Dwyer KM, Fan J, Wu H, Mar R, Lusis AJ, Mehrabian M (2004). "Arachidonate 5-lipoxygenase promoter genotype, dietary arachidonic acid, and atherosclerosis". N. Engl. J. Med. 350 (1): 29–37. doi:10.1056/NEJMoa025079. PMID 14702425.
- ↑ Zhang L, Zhang WP, Hu H, Wang ML, Sheng WW, Yao HT, Ding W, Chen Z, Wei EQ (2006). "Expression patterns of 5-lipoxygenase in human brain with traumatic injury and astrocytoma". Neuropathology 26 (2): 99–106. doi:10.1111/j.1440-1789.2006.00658.x. PMID 16708542.
- ↑ "Entrez Gene: ALOX5 arachidonate 5-lipoxygenase".
- ↑ 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". NeuroReport 15 (14): 2181–4. doi:10.1097/00001756-200410050-00007. PMID 15371729.
- ↑ arthritis.about.com: Minocin - Minocycline - Dosage - Side Effects - Drug Interactions
- ↑ 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. PMID 12445866.
- ↑ Blazevic T, Schaible AM, Weinhäupl K, Schachner D, Nikels F, Weinigel C, Barz D, Atanasov AG, Pergola C, Werz O, Dirsch VM, Heiss EH (2014). "Indirubin-3'-monoxime exerts a dual mode of inhibition towards leukotriene-mediated vascular smooth muscle cell migration". Cardiovasc. Res. 101 (3): 522–32. doi:10.1093/cvr/cvt339. PMC 3928003. PMID 24368834.
- ↑ Bishayee K, Khuda-Bukhsh AR (September 2013). "5-lipoxygenase antagonist therapy: a new approach towards targeted cancer chemotherapy". Acta Biochim. Biophys. Sin. (Shanghai) 45 (9): 709–719. doi:10.1093/abbs/gmt064. PMID 23752617.
- ↑ 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. PMID 11297527.
- ↑ 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. PMID 8585605.
- ↑ 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. PMID 7929073.
Further reading
- Rådmark OP (2000). "The molecular biology and regulation of 5-lipoxygenase". Am. J. Respir. Crit. Care Med. 161 (2 Pt 2): S11–5. doi:10.1164/ajrccm.161.supplement_1.ltta-3. PMID 10673219.
- Hammarberg T, Reddy KV, Persson B, Rådmark O (2002). "Calcium binding to 5-lipoxygenase". Adv. Exp. Med. Biol. Advances in Experimental Medicine and Biology 507: 117–21. doi:10.1007/978-1-4615-0193-0_19. ISBN 978-0-306-47283-1. PMID 12664574.
- 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. PMID 1540191.
- 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. PMID 1939225.
- Hoshiko S, Rådmark O, Samuelsson B (1990). "Characterization of the human 5-lipoxygenase gene promoter". Proc. Natl. Acad. Sci. U.S.A. 87 (23): 9073–7. doi:10.1073/pnas.87.23.9073. PMC 55106. PMID 2251250.
- Matsumoto T, Funk CD, Rådmark O, Höög JO, Jörnvall H, Samuelsson B (1988). "Molecular cloning and amino acid sequence of human 5-lipoxygenase". Proc. Natl. Acad. Sci. U.S.A. 85 (1): 26–30. doi:10.1073/pnas.85.1.26. PMC 279474. PMID 2829172.
- Rouzer CA, Kargman S (1988). "Translocation of 5-lipoxygenase to the membrane in human leukocytes challenged with ionophore A23187". J. Biol. Chem. 263 (22): 10980–8. PMID 3134355.
- Dixon RA, Jones RE, Diehl RE, Bennett CD, Kargman S, Rouzer CA (1988). "Cloning of the cDNA for human 5-lipoxygenase". Proc. Natl. Acad. Sci. U.S.A. 85 (2): 416–20. doi:10.1073/pnas.85.2.416. PMC 279559. PMID 3422434.
- Jakobsson PJ, Shaskin P, Larsson P, Feltenmark S, Odlander B, Aguilar-Santelises M, Jondal M, Biberfeld P, Claesson HE (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. PMID 7556168.
- Janssen-Timmen U, Vickers PJ, Wittig U, Lehmann WD, Stark HJ, Fusenig NE, Rosenbach T, Rådmark O, Samuelsson B, Habenicht AJ (1995). "Expression of 5-lipoxygenase in differentiating human skin keratinocytes". Proc. Natl. Acad. Sci. U.S.A. 92 (15): 6966–70. doi:10.1073/pnas.92.15.6966. PMC 41452. PMID 7624354.
- 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. PMID 7929073.
- Shaw KJ, Ng C, Kovacs BW (1994). "Cyclooxygenase gene expression in human endometrium and decidua". Prostaglandins Leukot. Essent. Fatty Acids 50 (5): 239–43. doi:10.1016/0952-3278(94)90160-0. PMID 8066098.
- Maruyama K, Sugano S (1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene 138 (1-2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
- Woods JW, Evans JF, Ethier D, Scott S, Vickers PJ, Hearn L, Heibein JA, Charleson S, Singer II (1993). "5-lipoxygenase and 5-lipoxygenase-activating protein are localized in the nuclear envelope of activated human leukocytes". J. Exp. Med. 178 (6): 1935–46. doi:10.1084/jem.178.6.1935. PMC 2191287. PMID 8245774.
- Mancini JA, Li C, Vickers PJ (1993). "5-Lipoxygenase activity in the human pancreas". J Lipid Mediat 8 (3): 145–50. PMID 8268460.
- 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. PMID 8585605.
- 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. PMID 9079648.
- 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. PMID 9150468.
- 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". Gene 200 (1-2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
External links
- Arachidonate 5-Lipoxygenase at the US National Library of Medicine Medical Subject Headings (MeSH)
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