5-lipoxygenase-activating protein explained

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. 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

• AM-679^[8]
• MK-886^[9]
• Veliflapon (BAY X1005)

Further reading

• Bevan S, Lorenz MW, Sitzer M, Markus HS . Genetic variation in the leukotriene pathway and carotid intima-media thickness: a 2-stage replication study . Stroke. 40 . 3 . 696–701 . March 2009 . 19131661 . 10.1161/STROKEAHA.108.525733 . free .
• Yoshida T, Kato K, Yokoi K, Watanabe S, Metoki N, Yoshida H, Satoh K, Aoyagi Y, Nishigaki Y, Suzuki T, Nozawa Y, Yamada Y . 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 . 19288030 . 10.3892/ijmm_00000161 . free .
• He YL, Zhu M, Jin XP, Zhou YL . [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 . 10.3785/j.issn.1008-9292.2009.06.013 . 20014490 .
• Quarta G, Stanzione R, Evangelista A, Zanda B, Di Angelantonio E, Marchitti S, Di Castro S, Di Vavo M, Volpe M, Rubattu S . 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 . 19417766 . 2986684 . 10.1038/ejhg.2009.71 .
• Wang Q . Molecular genetics of coronary artery disease . Current Opinion in Cardiology . 20 . 3 . 182–8 . May 2005 . 15861005 . 1579824 . 10.1097/01.hco.0000160373.77190.f1 .
• McGeachie M, Ramoni RL, Mychaleckyj JC, Furie KL, Dreyfuss JM, Liu Y, Herrington D, Guo X, Lima JA, Post W, Rotter JI, Rich S, Sale M, Ramoni MF . Integrative predictive model of coronary artery calcification in atherosclerosis . Circulation . 120 . 24 . 2448–54 . December 2009 . 19948975 . 2810344 . 10.1161/CIRCULATIONAHA.109.865501 .
• York TP, Vargas-Irwin C, Anderson WH, van den Oord EJ . Asthma pharmacogenetic study using finite mixture models to handle drug-response heterogeneity . Pharmacogenomics . 10 . 5 . 753–67 . May 2009 . 19450127 . 10.2217/pgs.09.19 .
• Bizzintino JA, Khoo SK, Zhang G, Martin AC, Rueter K, Geelhoed GC, Goldblatt J, Laing IA, Le Souëf PN, Hayden CM . 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 . 19524426 . 10.1016/j.plefa.2009.05.022 .
• Zintzaras E, Rodopoulou P, Sakellaridis N . 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 . 19126581 . 10.1093/aje/kwn368 . free .
• van der Net JB, Janssens AC, Defesche JC, Kastelein JJ, Sijbrands EJ, Steyerberg EW . 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 . 19166692 . 10.1016/j.amjcard.2008.09.093 .
• Liu J, Sun K, Bai Y, Zhang W, Wang X, Wang Y, Wang H, Chen J, Song X, Xin Y, Liu Z, Hui R . 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 . 19373490 . 10.1007/s00439-009-0659-0 . 21475249 .
• Zhao J, Quyyumi AA, Patel R, Zafari AM, Veledar E, Onufrak S, Shallenberger LH, Jones L, Vaccarino V . Sex-specific association of depression and a haplotype in leukotriene A4 hydrolase gene . Psychosomatic Medicine . 71 . 7 . 691–6 . September 2009 . 19622707 . 3113512 . 10.1097/PSY.0b013e3181b05c57 .
• Matarin M, Brown WM, Dena H, Britton A, De Vrieze FW, Brott TG, Brown RD, Worrall BB, Case LD, Chanock SJ, Metter EJ, Ferruci L, Gamble D, Hardy JA, Rich SS, Singleton A, Meschia JF . Candidate gene polymorphisms for ischemic stroke . Stroke. 40 . 11 . 3436–42 . November 2009 . 19729601 . 2784015 . 10.1161/STROKEAHA.109.558015 .
• Tsai AK, Li N, Hanson NQ, Tsai MY, Tang W . 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 . 19596330 . 10.1016/j.atherosclerosis.2009.06.018 .
• Strid T, Svartz J, Franck N, Hallin E, Ingelsson B, Söderström M, Hammarström S . 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 . 19233132 . 10.1016/j.bbrc.2009.02.074 .
• Drenos F, Talmud PJ, Casas JP, Smeeth L, Palmen J, Humphries SE, Hingorani AD . Integrated associations of genotypes with multiple blood biomarkers linked to coronary heart disease risk . Human Molecular Genetics . 18 . 12 . 2305–16 . June 2009 . 19336475 . 2685759 . 10.1093/hmg/ddp159 .
• Vickers PJ . 5-Lipoxygenase-activating protein (FLAP) . Journal of Lipid Mediators and Cell Signalling . 12 . 2–3 . 185–94 . October 1995 . 8777565 . 10.1016/0929-7855(95)00018-L .
• Via M, De Giacomo A, Corvol H, Eng C, Seibold MA, Gillett C, Galanter J, Sen S, Tcheurekdjian H, Chapela R, Rodríguez-Santana JR, Rodríguez-Cintrón W, Thyne S, Avila PC, Choudhry S, González Burchard E . The role of LTA4H and ALOX5AP genes in the risk for asthma in Latinos . Clinical and Experimental Allergy . 40 . 4 . 582–9 . April 2010 . 20067482 . 2866051 . 10.1111/j.1365-2222.2009.03438.x .
• Steinhilber D . 5-Lipoxygenase: enzyme expression and regulation of activity . Pharmaceutica Acta Helvetiae . 69 . 1 . 3–14 . July 1994 . 7938075 . 10.1016/0031-6865(94)90024-8 .
• Oosterveer DM, Versmissen J, Yazdanpanah M, van der Net JB, Defesche JC, Kastelein JJ, Sijbrands EJ . 5-Lipoxygenase activating protein (ALOX5AP) gene variants associate with the presence of xanthomas in familial hypercholesterolemia . Atherosclerosis . 206 . 1 . 223–7 . September 2009 . 19361804 . 10.1016/j.atherosclerosis.2009.02.019 .

Notes and References

1. Kennedy BP, Diehl RE, Boie Y, Adam M, Dixon RA . Gene characterization and promoter analysis of the human 5-lipoxygenase-activating protein (FLAP) . The Journal of Biological Chemistry . 266 . 13 . 8511–6 . May 1991 . 10.1016/S0021-9258(18)93004-8 . 1673682 . free .
2. Yandava CN, Kennedy BP, Pillari A, Duncan AM, Drazen JM . Cytogenetic and radiation hybrid mapping of human arachidonate 5-lipoxygenase-activating protein (ALOX5AP) to chromosome 13q12 . Genomics . 56 . 1 . 131–3 . February 1999 . 10036194 . 10.1006/geno.1998.5651 .
3. Peters-Golden M, Brock TG . 5-lipoxygenase and FLAP . Prostaglandins, Leukotrienes, and Essential Fatty Acids . 69 . 2–3 . 99–109 . 2003 . 12895592 . 10.1016/S0952-3278(03)00070-X .
4. Serhan CN, Chiang N, Dalli J, Levy BD . Lipid mediators in the resolution of inflammation . Cold Spring Harbor Perspectives in Biology . 7 . 2 . a016311 . 2015 . 25359497 . 10.1101/cshperspect.a016311 . 4315926.

5. Ferguson AD, McKeever BM, Xu S, Wisniewski D, Miller DK, Yamin TT, Spencer RH, Chu L, Ujjainwalla F, Cunningham BR, Evans JF, Becker JW . Crystal structure of inhibitor-bound human 5-lipoxygenase-activating protein . Science . 317 . 5837 . 510–2 . July 2007 . 17600184 . 10.1126/science.1144346 . 2007Sci...317..510F . 31544959 . free .

6. Kaushal . Ritesh . Pal . Prodipto . Alwell . Kathleen . Haverbusch . Mary . Flaherty . Matthew . Moomaw . Charles . Sekar . Padmini . Kissela . Brett . Kleindorfer . Dawn . Chakraborty . Ranajit . Broderick . Joseph . Deka . Ranjan . Woo . Daniel . 2007-06-01 . Association of ALOX5AP with ischemic stroke: a population-based case-control study . Human Genetics . en . 121 . 5 . 601–607 . 10.1007/s00439-007-0338-y . 17387518 . 20183625 . 1432-1203.
7. 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 . 10.1016/j.tips.2007.11.006 . 0165-6147 . 18187210.
8. Musiyenko A, Correa L, Stock N, Hutchinson JH, Lorrain DS, Bain G, Evans JF, Barik S . 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 . 19759251 . 2772391 . 10.1128/CVI.00220-09 .
9. Gillard . J. . Ford-Hutchinson . A. W. . Chan . C. . Charleson . S. . Denis . D. . Foster . A. . Fortin . R. . Leger . S. . McFarlane . C. S. . Morton . H. . Piechuta . H. . Riendeau . D. . Rouzer . C. A. . Rokach . J. . Young . R. . 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 . 10.1139/y89-073 . 2548691 . 0008-4212.