Arachidonate 5-lipoxygenase

Arachidonate 5-lipoxygenase
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 2ABV​, 3O8Y​, 3V92​, 3V98​, 3V99​
Identifiers
Symbols	ALOX5 ; 5-LO; 5-LOX; 5LPG; LOG5
External IDs	OMIM: 152390 MGI: 87999 HomoloGene: 561 ChEMBL: 215 GeneCards: ALOX5 Gene
EC number	1.13.11.34
Gene ontology Molecular function • arachidonate 5-lipoxygenase activity • iron ion binding • protein binding Cellular component • extracellular space • nuclear envelope • nuclear envelope lumen • cytosol • nuclear matrix • dendrite • nuclear membrane • sarcolemma Biological process • acute inflammatory response • leukotriene production involved in inflammatory response • leukotriene metabolic process • response to nutrient • sensory perception of pain • arachidonic acid metabolic process • leukotriene biosynthetic process • lipoxygenase pathway • small molecule metabolic process • positive regulation of vasoconstriction • response to hyperoxia • oxidation-reduction process • lipoxin metabolic process Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	240	11689
Ensembl	ENSG00000012779	ENSMUSG00000025701
UniProt	P09917	P48999
RefSeq (mRNA)	NM_000698	NM_009662
RefSeq (protein)	NP_000689	NP_033792
Location (UCSC)	Chr 10: 45.37 – 45.45 Mb	Chr 6: 116.41 – 116.46 Mb
PubMed search

arachidonate 5-lipoxygenase
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
Search PMC articles PubMed articles NCBI proteins

Arachidonate 5-lipoxygenase, also known as ALOX5, 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

Polyunsaturated fatty acid substrates and products of 5-LO include:

• 5-LO metabolizes the omega-6 fatty acid, Arachidonic acid (AA), to 5-hydroperoxyeicosatetraenoic acids (5-HpETE) which is then converted to the physiologically and pathologically important products, 5-hydroxyeicosatetraenoic acid (5-HETE), 5-oxo-eicosatetraenoic acid (5-oxo-ETE), and the 4-series leukotrienes (LTB4, LTC4, LTD4, and LTE4). LTB4 and 5-HETE contribute to the innate immune response as leukocyte chemotactic factors, i.e. they recruit circulating blood neutrophils and monccytes to sites of microbial invasions, tissue injury, and foreign bodies. They thereby contributing to inflammatory responses, host defense, and subsequent tissue repair as well as to pathological inflammatory diseases (see 5-HETE and LTB4). 5-Oxo-ETE may contribute to physiological allergic reactions as well as to pathological allergic diseases as a chemotactic factor for circulating blood eosinophils to recruit these cells to sites of allergic reactivity in lung and other tissues (see 5-oxo-eicosatetraenoic acid). LTC4, LTD4, and LTE4 contribute to allergic airways reactions by contracting these airways (see LTC4, LTD4, and LTE4).
• 5-LO metabolizes the omega-6 fatty acid, Mead acid (i.e. 5Z,8Z,11Z-eicosatrienoic acid), to 3-series analogs viz., 5(S)-hydroxy-6E,8Z,11Z-eicosatrienoic acid (5-HETrE), 5-oxo-6,8,11-eicosatrienoic acid (5-oxo-ETrE), LTA3, and LTC3; since LTA3 inhibits LTA hydrolase, mead acid metabolizing cells produce relatively little LTB3 and are blocked from metabolizing arachidonic acid to LTB4. 5-oxo-ETrE is almost as potent as 5-oxo-ETE as an eosinophil chemotactic factor.^[2]
• 5-LO metabolizes the omega-3 fatty acid, Eicosapentaenoic acid (EPA), to 5-hydroxyeicosatentaenoic acid which is then converted to 5-series products that are analogous to the arachidonic acid products viz., 5-hydroxy-eioxapentaenoic acid (5-HEPE), 5-oxo-eiocosapentaenoic acid (5-oxo-HEPE), and the 5-series leukotrienes, LTB5, LTC5, LTD5, and LTE5. In general, these eicosapentaenoic acid metabolites are less potent in stimulating cells and tissues than their arachidonic acid metabolites.^[2][3]
• Certain other polyunsaturated fatty acids such as DGLA and linoleic acid inhibit 5-LO from metabolizing arachidonic acid.^[4]

Function

5-LO catalyzes oxidation of AA at the 5-position to yield 5-HpETE. 5-LO then converts 5-HpETE to leukotriene A4.^[5]

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.^[2]

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.^[6][7]

Eicosanoid synthesis.

Two other lipoxygenases, 12-LO and 15-LO, act at the 12- and 15-positions, metabolizing arachidonic acid 12- and 15-hydroperoxy intermediates which are then further metabolized to bioactive products including 12-hydroxyeicosatetraenoic acid (12-HETE), 15-hydroxyicosatetraenoic acid (15-HETE), lipoxins, and Hepoxilins.^[8]

Clinical significance

5-LO is a target for pharmaceutical intervention in CAD.^[9] Some people with variant alleles for 5-LO are at elevated risk for CAD.^[10] 5-LO is expressed in brain cells and may participate in neuropathologic processes.^[11]

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.^[12]

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.^[13] It may therefore be used as a DMARD-medication in mild rheumatoid arthritis and other rheumatic conditions.^[14]

Hyperforin, an active constituent of the herb St John's wort, is a highly potent 5-LO inhibitor.^[15] 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.^[16] In addition, curcumin, a constituent of turmeric, is a 5-LO inhibitor in vitro.^[17]

Activation

5-LO is activated by 5-lipoxygenase activating protein (FLAP).

Interactions

Arachidonate 5-lipoxygenase has been shown to interact with:

• COTL1,^[18] and
• Grb2.^[19][20]

References

1. Funk CD, Hoshiko S, Matsumoto T, Rdmark O, Samuelsson B (Apr 1989). "Characterization of the human 5-lipoxygenase gene". Proceedings of the National Academy of Sciences of the United States of America 86 (8): 2587–91. doi:10.1073/pnas.86.8.2587. PMC 286962. PMID 2565035.
2. Powell WS, Rokach J (Oct 2013). "The eosinophil chemoattractant 5-oxo-ETE and the OXE receptor". Progress in Lipid Research 52 (4): 651–65. doi:10.1016/j.plipres.2013.09.001. PMID 24056189.
3. Maaløe T, Schmidt EB, Svensson M, Aardestrup IV, Christensen JH (Jul 2011). "The effect of n-3 polyunsaturated fatty acids on leukotriene B₄ and leukotriene B₅ production from stimulated neutrophil granulocytes in patients with chronic kidney disease". Prostaglandins, Leukotrienes, and Essential Fatty Acids 85 (1): 37–41. doi:10.1016/j.plefa.2011.04.004. PMID 21530211.
4. Iversen L, Fogh K, Bojesen G, Kragballe K (Jul 1991). "Linoleic acid and dihomogammalinolenic acid inhibit leukotriene B4 formation and stimulate the formation of their 15-lipoxygenase products by human neutrophils in vitro. Evidence of formation of antiinflammatory compounds". Agents and Actions 33 (3-4): 286–91. doi:10.1007/bf01986575. PMID 1659156.
5. Reaction R01595 and R03058 at KEGG Pathway Database.
6. 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 (Feb 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.
7. Pace-Asciak CR (Apr 2015). "Pathophysiology of the hepoxilins". Biochimica et Biophysica Acta 1851 (4): 383–96. doi:10.1016/j.bbalip.2014.09.007. PMID 25240838.
8. Dorlands Medical Dictionary, entries at arachidonate 5-lipoxygenase and following. Retrieved on 2006-02-07.
9. "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.
10. Dwyer JH, Allayee H, Dwyer KM, Fan J, Wu H, Mar R, Lusis AJ, Mehrabian M (Jan 2004). "Arachidonate 5-lipoxygenase promoter genotype, dietary arachidonic acid, and atherosclerosis". The New England Journal of Medicine 350 (1): 29–37. doi:10.1056/NEJMoa025079. PMID 14702425.
11. Zhang L, Zhang WP, Hu H, Wang ML, Sheng WW, Yao HT, Ding W, Chen Z, Wei EQ (Apr 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.
12. "Entrez Gene: ALOX5 arachidonate 5-lipoxygenase".
13. can be used as DMARDS. Song Y, Wei EQ, Zhang WP, Zhang L, Liu JR, Chen Z (Oct 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.
14. arthritis.about.com: Minocin - Minocycline - Dosage - Side Effects - Drug Interactions
15. Albert D, Zündorf I, Dingermann T, Müller WE, Steinhilber D, Werz O (Dec 2002). "Hyperforin is a dual inhibitor of cyclooxygenase-1 and 5-lipoxygenase". Biochemical Pharmacology 64 (12): 1767–75. doi:10.1016/s0006-2952(02)01387-4. PMID 12445866.
16. Blazevic T, Schaible AM, Weinhäupl K, Schachner D, Nikels F, Weinigel C, Barz D, Atanasov AG, Pergola C, Werz O, Dirsch VM, Heiss EH (Mar 2014). "Indirubin-3'-monoxime exerts a dual mode of inhibition towards leukotriene-mediated vascular smooth muscle cell migration". Cardiovascular Research 101 (3): 522–32. doi:10.1093/cvr/cvt339. PMC 3928003. PMID 24368834.
17. Bishayee K, Khuda-Bukhsh AR (Sep 2013). "5-lipoxygenase antagonist therapy: a new approach towards targeted cancer chemotherapy". Acta Biochimica et Biophysica Sinica 45 (9): 709–19. doi:10.1093/abbs/gmt064. PMID 23752617.
18. 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.
19. 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.
20. 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)