Arachidonate 5-lipoxygenase

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ALOX5
Available structures
PDB Human UniProt search: PDBe RCSB
Identifiers
Aliases ALOX5, Alox5, 5-LO, 5-LOX, 5LO, 5LX, AI850497, F730011J02, 5LPG, LOG5, arachidonate 5-lipoxygenase
External IDs HomoloGene: 561 GeneCards: 240
RNA expression pattern
PBB GE ALOX5 204445 s at tn.png

PBB GE ALOX5 204446 s at tn.png

PBB GE ALOX5 214366 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_000698
NM_001256153
NM_001256154
NM_001320861
NM_001320862

n/a

RefSeq (protein)

NP_000689.1
NP_001243082.1
NP_001243083.1

n/a

Location (UCSC) Chr 10: 45.37 – 45.45 Mb n/a
PubMed search [1] n/a
Wikidata
View/Edit Human
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 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 EFA substates into leukotrienes as well as a wide range of other biologically active products. ALOX5 is a current target for pharmaceutical intervention in a number of diseases.

ALOX5 gene[edit]

The ALOX5 gene, which occupies 71.9 kilobase pairs (kb) on chromosome 10, is comprised of 14 exons divided by 13 introns encoding the mature 78 kilodalton (kD) ALOX5 protein consisting of 673 amino acids. The gene promoter region of ALOX5 contains 8 GC boxes but lacks TATA boxes or CAT boxes and thus resembles gene promoters of typical housekeeping genes. Five of the 8 GC boxes are arranged in tandem and recognized by the transcription factors Sp1 and Egr-1. A novel Sp1-binding site occurs close to the major transcription start site (position - 65); a GC-rich core region including the Sp1/Egr-1 sites may be critical for basal 5-LO promoter activity.[2]

ALOX5 expression[edit]

Cells primarily involved in regulating inflammation, allergy, and other immune responses, e.g. neutrophils, eosinophils, basophils, monocytes, macrophages, mast cells, dendritic cells, and B-lymphocytes express ALOX5. Platelets, T cells, and erythrocytes are ALOX5-negative. In skin, Langerhans cells strongly express ALOX5. Fibroblasts, smooth muscle cells and endothelial cells express low levels of ALOX5.[2][3]Up-regulation of ALOX5 may occur during the maturation of leukocytes and in human neutrophils treated with granulocyte macrophage colony-stimulating factor and then stimulated with physiological agents.

Aberrant expression of LOX5 is seen in various types of human cancer tumors in vivo as well as in various types of human cancer cell lines in vitro; these tumors and cell lines include those of the pancreas, prostate and colon. ALOX5 products, particularly 5-hydroxyeicosatetraenoic acid and 5-oxo-eicosatetraenoic acid, promote the proliferation of these ALOX5 aberrantly expressing tumor cell lines suggesting that ALOX5 acts as a pro-malignancy factor for them and by extension their parent tumors.[2]

Studies with cultured human cells have found that there are a large number of ALOX5 mRNA splice variants due to Alternative splicing. The physiological and/or pathological consequences of this slicing has yet to be defined. In one study, however, human brain tumors were shown to express three mRNA splice variants (2.7, 3.1, and 6.4 kb) in addition to the full 8.6lb species; the abundance of the variants correlated with the malignancy of these tumors suggesting that they may play a role in the development of these tumors.[2]

ALOX5 regulation[edit]

ALOX5 exists primarily in the cytoplasm and nucleoplasm of cells. Upon cell stimulation, ALOX5: a) becomes phosphorylated on serine 523, serine 271, and a third serine by Mitogen-activated protein kinases, S6 kinase, protein kinase A, protein kinase C, Cdc2, and/or a Ca2+/calmodulin-dependent protein kinase; b) moves to the nuclear membrane; c) binds with the 5-lipoxygenase-activating protein (FLAP); and d) becomes active in metabolizing its substrates. These events, along with rises in cytosolic Ca2+ levels are induced by cell stimulation such as that caused by chemotactic factors on leukocytes. Movement of ALOX5 to nuclear membrane, nuclear membrane Phosphatidylcholine, FLAP, ALOX5 phosphorylation on all three serines, and, perhaps, rises in cytosolic Ca2+ contribute to and/or are required for the activation of ALOX5.[3]

Substrates, products, product activities[edit]

ALOX5's Polyunsaturated fatty acid substrates, products , and product activities include:

On the other hand, certain polyunsaturated fatty acids such as DGLA and linoleic acid inhibit 5-LO from metabolizing arachidonic acid.[8]

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.[9]

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.[5]

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.[10][11]

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.[12]

Gene knockout studies[edit]

Alox5-deficient mice exhibit a worsened inflammatory component, failure to resolve inflammation-related responses, and decreased survival in experimental models of respiratory syncytial virus disease, Lyme disease, Toxoplasma gondii disease, and corneal injury. These studies indicate that the suppression of inflammation is a major function of Alox5 and, presumably, the anti-inflammatory specialized pro-resolving mediators (SPMs) that they make, at least in certain rodent inflammation-based model systems. Although rodent Alox5 may differ from human ALOX5 in the profile of the PUFA metabolites they make and their tissue distributions, these genetic studies allow that human ALOX5 along with the SPMs that they contribute to making may play a similar major anti-inflammatory function in humans.[13][14]

Clinical significance[edit]

5-LO is a target for pharmaceutical intervention in CAD.[15] Some people with variant alleles for 5-LO are at elevated risk for CAD.[16] 5-LO is expressed in brain cells and may participate in neuropathologic processes.[17]

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.[18]

Based on the gene knockout studies cited above, ALOX5 may function to reduce and resolve as well as promote diverse inflammation responses.

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.[19] It may therefore be used as a DMARD-medication in mild rheumatoid arthritis and other rheumatic conditions.[20]

Hyperforin, an active constituent of the herb St John's wort, is a highly potent 5-LO inhibitor.[21] 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.[22] In addition, curcumin, a constituent of turmeric, is a 5-LO inhibitor in vitro.[23]

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 (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. ^ a b c d Ochs MJ, Suess B, Steinhilber D (2014). "5-lipoxygenase mRNA and protein isoforms". Basic & Clinical Pharmacology & Toxicology 114 (1): 78–82. doi:10.1111/bcpt.12115. PMID 24020397. 
  3. ^ a b c Anwar Y, Sabir JS, Qureshi MI, Saini KS (2014). "5-lipoxygenase: a promising drug target against inflammatory diseases-biochemical and pharmacological regulation". Current Drug Targets 15 (4): 410–22. PMID 24313690. 
  4. ^ Rådmark O, Werz O, Steinhilber D, Samuelsson B (2015). "5-Lipoxygenase, a key enzyme for leukotriene biosynthesis in health and disease". Biochimica Et Biophysica Acta 1851 (4): 331–9. doi:10.1016/j.bbalip.2014.08.012. PMID 25152163. 
  5. ^ a b c Powell WS, Rokach J (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.  Cite error: Invalid <ref> tag; name "pmid24056189" defined multiple times with different content (see the help page).
  6. ^ Powell WS, Rokach J (2015). "Biosynthesis, biological effects, and receptors of hydroxyeicosatetraenoic acids (HETEs) and oxoeicosatetraenoic acids (oxo-ETEs) derived from arachidonic acid". Biochimica Et Biophysica Acta 1851 (4): 340–55. doi:10.1016/j.bbalip.2014.10.008. PMID 25449650. 
  7. ^ 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. 
  8. ^ 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. 
  9. ^ Reaction R01595 and R03058 at KEGG Pathway Database.
  10. ^ 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. 
  11. ^ 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. 
  12. ^ Dorlands Medical Dictionary, entries at arachidonate 5-lipoxygenase and following. Retrieved on 2006-02-07.
  13. ^ Serhan CN, Chiang N, Dalli J, Levy BD (2015). "Lipid mediators in the resolution of inflammation". Cold Spring Harbor Perspectives in Biology 7 (2): a016311. doi:10.1101/cshperspect.a016311. PMID 25359497. 
  14. ^ Serhan CN, Chiang N, Dalli J (2015). "The resolution code of acute inflammation: Novel pro-resolving lipid mediators in resolution". Seminars in Immunology 27 (3): 200–15. doi:10.1016/j.smim.2015.03.004. PMC 4515371. PMID 25857211. 
  15. ^ "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. 
  16. ^ 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. 
  17. ^ 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. 
  18. ^ "Entrez Gene: ALOX5 arachidonate 5-lipoxygenase". 
  19. ^ 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. 
  20. ^ arthritis.about.com: Minocin - Minocycline - Dosage - Side Effects - Drug Interactions
  21. ^ 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. 
  22. ^ 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. 
  23. ^ 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. 
  24. ^ 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. 
  25. ^ 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. 
  26. ^ 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]