Arachidonate 5-lipoxygenase

From Wikipedia, the free encyclopedia
Jump to: navigation, search
Arachidonate 5-lipoxygenase
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols ALOX5 ; 5-LO; 5-LOX; 5LPG; LOG5
External IDs OMIM152390 MGI87999 HomoloGene561 ChEMBL: 215 GeneCards: ALOX5 Gene
EC number 1.13.11.34
RNA expression pattern
PBB GE ALOX5 204446 s at tn.png
PBB GE ALOX5 204445 s at tn.png
PBB GE ALOX5 214366 s at tn.png
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:
45.87 – 45.94 Mb
Chr 6:
116.41 – 116.46 Mb
PubMed search [1] [2]
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

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[edit]

EFA substrates and products of 5-LO include:

Function[edit]

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]

Eicosanoid synthesis.

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[edit]

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[edit]

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]

Activation[edit]

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

Interactions[edit]

Arachidonate 5-lipoxygenase has been shown to interact with:

References[edit]

  1. ^ 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. 
  2. ^ Reaction R01595 and R03058 at KEGG Pathway Database.
  3. ^ 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. 
  4. ^ Clark SR, Guy CJ, Scurr MJ, Taylor PR, Kift-Morgan AP, Hammond VJ et al. (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. 
  5. ^ Dorlands Medical Dictionary, entries at arachidonate 5-lipoxygenase and following. Retrieved on 2006-02-07.
  6. ^ "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. 
  7. ^ 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. PMID 14702425. 
  8. ^ 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". Neuropathology 26 (2): 99–106. doi:10.1111/j.1440-1789.2006.00658.x. PMID 16708542. 
  9. ^ "Entrez Gene: ALOX5 arachidonate 5-lipoxygenase". 
  10. ^ 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. 
  11. ^ arthritis.about.com: Minocin - Minocycline - Dosage - Side Effects - Drug Interactions
  12. ^ 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.  Vancouver style error (help)
  13. ^ Blazevic T, Schaible AM, Weinhäupl K, Schachner D, Nikels F, Weinigel C et al. (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.  Vancouver style error (help)
  14. ^ 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. 
  15. ^ 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. 
  16. ^ 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[edit]

External links[edit]