Arachidonate 5-lipoxygenase-activating protein also known as 5-lipoxygenase activating protein, or FLAP, is a protein that in humans is encoded by the ALOX5APgene.[1][2]
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. FLAP structure consist of 4 transmembrane alpha helices, but they are found in 3’s( trimer) forming a barrel. The barrel is about 60 A high and 36 A wide.[5]
Clinical significance
Gene polymorphisms in FLAP are suspected of playing a role in Alzheimer's disease.[6] Leukotrienes, which need the FLAP protein to be made, 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. 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]
↑Kennedy BP, Diehl RE, Boie Y, Adam M, Dixon RA (May 1991). "Gene characterization and promoter analysis of the human 5-lipoxygenase-activating protein (FLAP)". The Journal of Biological Chemistry. 266 (13): 8511–6. PMID1673682.
↑Yandava CN, Kennedy BP, Pillari A, Duncan AM, Drazen JM (February 1999). "Cytogenetic and radiation hybrid mapping of human arachidonate 5-lipoxygenase-activating protein (ALOX5AP) to chromosome 13q12". Genomics. 56 (1): 131–3. doi:10.1006/geno.1998.5651. PMID10036194.
↑Peters-Golden M, Brock TG (2003). "5-lipoxygenase and FLAP". Prostaglandins, Leukotrienes, and Essential Fatty Acids. 69 (2–3): 99–109. doi:10.1016/S0952-3278(03)00070-X. PMID12895592.
↑Manev H, Manev R (2006). "5-Lipoxygenase (ALOX5) and FLAP (ALOX5AP) gene polymorphisms as factors in vascular pathology and Alzheimer's disease". Medical Hypotheses. 66 (3): 501–3. doi:10.1016/j.mehy.2005.09.031. PMID16278051.
Bevan S, Lorenz MW, Sitzer M, Markus HS (March 2009). "Genetic variation in the leukotriene pathway and carotid intima-media thickness: a 2-stage replication study". Stroke: A Journal of Cerebral Circulation. 40 (3): 696–701. doi:10.1161/STROKEAHA.108.525733. PMID19131661.
Yoshida T, Kato K, Yokoi K, Watanabe S, Metoki N, Yoshida H, Satoh K, Aoyagi Y, Nishigaki Y, Suzuki T, Nozawa Y, Yamada Y (April 2009). "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. doi:10.3892/ijmm_00000161. PMID19288030.
He YL, Zhu M, Jin XP, Zhou YL (November 2009). "[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. PMID20014490.
York TP, Vargas-Irwin C, Anderson WH, van den Oord EJ (May 2009). "Asthma pharmacogenetic study using finite mixture models to handle drug-response heterogeneity". Pharmacogenomics. 10 (5): 753–67. doi:10.2217/pgs.09.19. PMID19450127.
Bizzintino JA, Khoo SK, Zhang G, Martin AC, Rueter K, Geelhoed GC, Goldblatt J, Laing IA, Le Souëf PN, Hayden CM (July 2009). "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. doi:10.1016/j.plefa.2009.05.022. PMID19524426.
Zintzaras E, Rodopoulou P, Sakellaridis N (March 2009). "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. doi:10.1093/aje/kwn368. PMID19126581.
van der Net JB, Janssens AC, Defesche JC, Kastelein JJ, Sijbrands EJ, Steyerberg EW (February 2009). "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. doi:10.1016/j.amjcard.2008.09.093. PMID19166692.
Liu J, Sun K, Bai Y, Zhang W, Wang X, Wang Y, Wang H, Chen J, Song X, Xin Y, Liu Z, Hui R (June 2009). "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. doi:10.1007/s00439-009-0659-0. PMID19373490.
Tsai AK, Li N, Hanson NQ, Tsai MY, Tang W (December 2009). "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. doi:10.1016/j.atherosclerosis.2009.06.018. PMID19596330.
Strid T, Svartz J, Franck N, Hallin E, Ingelsson B, Söderström M, Hammarström S (April 2009). "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. doi:10.1016/j.bbrc.2009.02.074. PMID19233132.
Steinhilber D (July 1994). "5-Lipoxygenase: enzyme expression and regulation of activity". Pharmaceutica Acta Helvetiae. 69 (1): 3–14. doi:10.1016/0031-6865(94)90024-8. PMID7938075.
Oosterveer DM, Versmissen J, Yazdanpanah M, van der Net JB, Defesche JC, Kastelein JJ, Sijbrands EJ (September 2009). "5-Lipoxygenase activating protein (ALOX5AP) gene variants associate with the presence of xanthomas in familial hypercholesterolemia". Atherosclerosis. 206 (1): 223–7. doi:10.1016/j.atherosclerosis.2009.02.019. PMID19361804.