Biology:5-lipoxygenase-activating protein
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Short description: Protein-coding gene in the species Homo sapiens
 Generic protein structure example |
Arachidonate 5-lipoxygenase-activating protein also known as 5-lipoxygenase activating protein, or FLAP, is a protein that in humans is encoded by the ALOX5AP gene.[1][2]
Function
FLAP is necessary for the activation of 5-lipoxygenase and therefore for the production of leukotrienes, 5-hydroxyeicosatetraenoic acid, 5-oxo-eicosatetraenoic acid, and specialized pro-resolving mediators of the lipoxin and resolvin classes.[3][4] It is an integral protein within the nuclear membrane. FLAP is necessary in synthesis of leukotriene, which are lipid mediators of inflammation that is involved in respiratory and cardiovascular diseases. FLAP functions as a membrane anchor for 5-lipooxygenase and as an amine acid-bind protein. How FLAP activates 5-lipooxygenase is not completely understood, but there is a physical interaction between the two. [citation needed] FLAP structure consists of 4 transmembrane alpha helices, but they are found in trimer forming a barrel. The barrel is about 60 Å high and 36 Å wide.[5]
Clinical significance
Leukotrienes, which require the FLAP protein to be synthesized, have an established pathological role in allergic and respiratory diseases. Animal and human genetic evidence suggests they may also have an important role in atherosclerosis, myocardial infarction, and stroke.[6] The structure of FLAP provides a tool for the development of novel therapies for respiratory and cardiovascular diseases and for the design of focused experiments to probe the cell biology of FLAP and its role in leukotriene biosynthesis.[5][7]
Inhibitors
References
- ↑ "Gene characterization and promoter analysis of the human 5-lipoxygenase-activating protein (FLAP)". The Journal of Biological Chemistry 266 (13): 8511–6. May 1991. doi:10.1016/S0021-9258(18)93004-8. PMID 1673682.
- ↑ "Cytogenetic and radiation hybrid mapping of human arachidonate 5-lipoxygenase-activating protein (ALOX5AP) to chromosome 13q12". Genomics 56 (1): 131–3. February 1999. doi:10.1006/geno.1998.5651. PMID 10036194.
- ↑ "5-lipoxygenase and FLAP". Prostaglandins, Leukotrienes, and Essential Fatty Acids 69 (2–3): 99–109. 2003. doi:10.1016/S0952-3278(03)00070-X. PMID 12895592.
- ↑ "Lipid mediators in the resolution of inflammation". Cold Spring Harbor Perspectives in Biology 7 (2): a016311. 2015. doi:10.1101/cshperspect.a016311. PMID 25359497.
- ↑ 5.0 5.1 PDB: 2q7r;"Crystal structure of inhibitor-bound human 5-lipoxygenase-activating protein". Science 317 (5837): 510–2. July 2007. doi:10.1126/science.1144346. PMID 17600184. Bibcode: 2007Sci...317..510F.
- ↑ Kaushal, Ritesh; Pal, Prodipto; Alwell, Kathleen; Haverbusch, Mary; Flaherty, Matthew; Moomaw, Charles; Sekar, Padmini; Kissela, Brett et al. (2007-06-01). "Association of ALOX5AP with ischemic stroke: a population-based case-control study" (in en). Human Genetics 121 (5): 601–607. doi:10.1007/s00439-007-0338-y. ISSN 1432-1203. PMID 17387518. https://doi.org/10.1007/s00439-007-0338-y.
- ↑ Evans, Jilly F.; Ferguson, Andrew D.; Mosley, Ralph T.; Hutchinson, John H. (February 2008). "What's all the FLAP about?: 5-lipoxygenase-activating protein inhibitors for inflammatory diseases". Trends in Pharmacological Sciences 29 (2): 72–78. doi:10.1016/j.tips.2007.11.006. ISSN 0165-6147. PMID 18187210. https://pubmed.ncbi.nlm.nih.gov/18187210.
- ↑ "A novel 5-lipoxygenase-activating protein inhibitor, AM679, reduces inflammation in the respiratory syncytial virus-infected mouse eye". Clinical and Vaccine Immunology 16 (11): 1654–9. November 2009. doi:10.1128/CVI.00220-09. PMID 19759251.
- ↑ Gillard, J.; Ford-Hutchinson, A. W.; Chan, C.; Charleson, S.; Denis, D.; Foster, A.; Fortin, R.; Leger, S. et al. (1989-05-01). "L-663,536 (MK-886) (3-[1-(4-chlorobenzyl)-3-t-butyl-thio-5-isopropylindol-2-yl-2,2-dimethylpropanoic acid), a novel, orally active leukotriene biosynthesis inhibitor"]. Canadian Journal of Physiology and Pharmacology 67 (5): 456–464. doi:10.1139/y89-073. ISSN 0008-4212. PMID 2548691. http://dx.doi.org/10.1139/y89-073.
Further reading
- "Genetic variation in the leukotriene pathway and carotid intima-media thickness: a 2-stage replication study". Stroke 40 (3): 696–701. March 2009. doi:10.1161/STROKEAHA.108.525733. PMID 19131661.
- "Association of genetic variants with chronic kidney disease in Japanese individuals with type 2 diabetes mellitus". International Journal of Molecular Medicine 23 (4): 529–37. April 2009. doi:10.3892/ijmm_00000161. PMID 19288030.
- "[Relationship of polymorphism of SG13S114A/T in ALOX5AP gene with atherosclerotic cerebral infarction]". Zhejiang da Xue Xue Bao. Yi Xue Ban = Journal of Zhejiang University. Medical Sciences 38 (6): 630–3. November 2009. doi:10.3785/j.issn.1008-9292.2009.06.013. PMID 20014490.
- "Phosphodiesterase 4D and 5-lipoxygenase activating protein genes and risk of ischemic stroke in Sardinians". European Journal of Human Genetics 17 (11): 1448–53. November 2009. doi:10.1038/ejhg.2009.71. PMID 19417766.
- "Molecular genetics of coronary artery disease". Current Opinion in Cardiology 20 (3): 182–8. May 2005. doi:10.1097/01.hco.0000160373.77190.f1. PMID 15861005.
- "Integrative predictive model of coronary artery calcification in atherosclerosis". Circulation 120 (24): 2448–54. December 2009. doi:10.1161/CIRCULATIONAHA.109.865501. PMID 19948975.
- "Asthma pharmacogenetic study using finite mixture models to handle drug-response heterogeneity". Pharmacogenomics 10 (5): 753–67. May 2009. doi:10.2217/pgs.09.19. PMID 19450127.
- "Leukotriene pathway polymorphisms are associated with altered cysteinyl leukotriene production in children with acute asthma". Prostaglandins, Leukotrienes, and Essential Fatty Acids 81 (1): 9–15. July 2009. doi:10.1016/j.plefa.2009.05.022. PMID 19524426.
- "Variants of the arachidonate 5-lipoxygenase-activating protein (ALOX5AP) gene and risk of stroke: a HuGE gene-disease association review and meta-analysis". American Journal of Epidemiology 169 (5): 523–32. March 2009. doi:10.1093/aje/kwn368. PMID 19126581.
- "Usefulness of genetic polymorphisms and conventional risk factors to predict coronary heart disease in patients with familial hypercholesterolemia". The American Journal of Cardiology 103 (3): 375–80. February 2009. doi:10.1016/j.amjcard.2008.09.093. PMID 19166692.
- "Association of three-gene interaction among MTHFR, ALOX5AP and NOTCH3 with thrombotic stroke: a multicenter case-control study". Human Genetics 125 (5–6): 649–56. June 2009. doi:10.1007/s00439-009-0659-0. PMID 19373490.
- "Sex-specific association of depression and a haplotype in leukotriene A4 hydrolase gene". Psychosomatic Medicine 71 (7): 691–6. September 2009. doi:10.1097/PSY.0b013e3181b05c57. PMID 19622707.
- "Candidate gene polymorphisms for ischemic stroke". Stroke 40 (11): 3436–42. November 2009. doi:10.1161/STROKEAHA.109.558015. PMID 19729601.
- "Associations of genetic polymorphisms of arachidonate 5-lipoxygenase-activating protein with risk of coronary artery disease in a European-American population". Atherosclerosis 207 (2): 487–91. December 2009. doi:10.1016/j.atherosclerosis.2009.06.018. PMID 19596330.
- "Distinct parts of leukotriene C(4) synthase interact with 5-lipoxygenase and 5-lipoxygenase activating protein". Biochemical and Biophysical Research Communications 381 (4): 518–22. April 2009. doi:10.1016/j.bbrc.2009.02.074. PMID 19233132. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-17904.
- "Integrated associations of genotypes with multiple blood biomarkers linked to coronary heart disease risk". Human Molecular Genetics 18 (12): 2305–16. June 2009. doi:10.1093/hmg/ddp159. PMID 19336475.
- "5-Lipoxygenase-activating protein (FLAP)". Journal of Lipid Mediators and Cell Signalling 12 (2–3): 185–94. October 1995. doi:10.1016/0929-7855(95)00018-L. PMID 8777565.
- "The role of LTA4H and ALOX5AP genes in the risk for asthma in Latinos". Clinical and Experimental Allergy 40 (4): 582–9. April 2010. doi:10.1111/j.1365-2222.2009.03438.x. PMID 20067482.
- "5-Lipoxygenase: enzyme expression and regulation of activity". Pharmaceutica Acta Helvetiae 69 (1): 3–14. July 1994. doi:10.1016/0031-6865(94)90024-8. PMID 7938075.
- "5-Lipoxygenase activating protein (ALOX5AP) gene variants associate with the presence of xanthomas in familial hypercholesterolemia". Atherosclerosis 206 (1): 223–7. September 2009. doi:10.1016/j.atherosclerosis.2009.02.019. PMID 19361804.
External links
- 5-lipoxygenase-activating+protein at the US National Library of Medicine Medical Subject Headings (MeSH)
- Human ALOX5AP genome location and ALOX5AP gene details page in the UCSC Genome Browser.
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