5-lipoxygenase-activating protein

ALOX5AP
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2Q7R, 2Q7M
Identifiers
Aliases	ALOX5AP , FLAP, arachidonate 5-lipoxygenase activating protein
External IDs	OMIM: 603700; MGI: 107505; HomoloGene: 1231; GeneCards: ALOX5AP; OMA:ALOX5AP - orthologs
Gene location (Mouse) Chr. Chromosome 5 (mouse) [1] Band 5|5 G3 Start 149,201,577 bp [1] End 149,224,963 bp [1]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in blood trabecular bone bone marrow right lung bone marrow cells monocyte upper lobe of left lung spleen lower lobe of lung periodontal fiber Top expressed in granulocyte stroma of bone marrow tibiofemoral joint blood right lung lobe ankle interventricular septum carotid body spleen sciatic nerve More reference expression data BioGPS More reference expression data
Gene ontology Molecular function glutathione transferase activity protein N-terminus binding leukotriene-C4 synthase activity glutathione peroxidase activity protein binding arachidonic acid binding enzyme activator activity Cellular component integral component of membrane nuclear membrane endoplasmic reticulum membrane membrane nuclear envelope endoplasmic reticulum nucleus Biological process cellular response to calcium ion leukotriene metabolic process positive regulation of catalytic activity protein homotrimerization lipoxygenase pathway leukotriene biosynthetic process lipoxin metabolic process cellular oxidant detoxification lipoxin biosynthetic process Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 241 11690 Ensembl n/a ENSMUSG00000060063 UniProt P20292 P30355 RefSeq (mRNA) NM_001204406 NM_001629 NM_009663 NM_001308462 RefSeq (protein) NP_001191335 NP_001620 NP_001295391 NP_033793 Location (UCSC) n/a Chr 5: 149.2 – 149.22 Mb PubMed search [2] [3]
Wikidata
View/Edit Human View/Edit Mouse

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. ^{[4] [5]}

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. ^{[6] [7]} 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. ^[8]

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. ^[9] 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. ^{[8] [10]}

Inhibitors

• AM-679 ^[11]
• MK-886 ^[12]
• Veliflapon (BAY X1005)

References

1. GRCm38: Ensembl release 89: ENSMUSG00000060063 – Ensembl, May 2017
2. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
3. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. 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. doi: 10.1016/S0021-9258(18)93004-8 . PMID   1673682.
5. 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. PMID   10036194.
6. 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. PMID   12895592.
7. 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. PMC   4315926 . PMID   25359497.
8. PDB: 2q7r ​;Ferguson AD, McKeever BM, Xu S, Wisniewski D, Miller DK, Yamin TT, Spencer RH, Chu L, Ujjainwalla F, Cunningham BR, Evans JF, Becker JW (July 2007). "Crystal structure of inhibitor-bound human 5-lipoxygenase-activating protein". Science. 317 (5837): 510–2. Bibcode:2007Sci...317..510F. doi: 10.1126/science.1144346 . PMID   17600184. S2CID   31544959.
9. 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. 121 (5): 601–607. doi:10.1007/s00439-007-0338-y. ISSN   1432-1203. PMID   17387518. S2CID   20183625.
10. 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.
11. Musiyenko A, Correa L, Stock N, Hutchinson JH, Lorrain DS, Bain G, Evans JF, Barik S (November 2009). "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. doi:10.1128/CVI.00220-09. PMC   2772391 . PMID   19759251.
12. 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. doi:10.1139/y89-073. ISSN   0008-4212. PMID   2548691.

Further reading

• 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. 40 (3): 696–701. doi: 10.1161/STROKEAHA.108.525733 . PMID   19131661.
• 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 . PMID   19288030.
• 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. doi:10.3785/j.issn.1008-9292.2009.06.013. PMID   20014490.
• Quarta G, Stanzione R, Evangelista A, Zanda B, Di Angelantonio E, Marchitti S, Di Castro S, Di Vavo M, Volpe M, Rubattu S (November 2009). "Phosphodiesterase 4D and 5-lipoxygenase activating protein genes and risk of ischemic stroke in Sardinians". European Journal of Human Genetics. 17 (11): 1448–53. doi:10.1038/ejhg.2009.71. PMC   2986684 . PMID   19417766.
• Wang Q (May 2005). "Molecular genetics of coronary artery disease". Current Opinion in Cardiology. 20 (3): 182–8. doi:10.1097/01.hco.0000160373.77190.f1. PMC   1579824 . PMID   15861005.
• 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 (December 2009). "Integrative predictive model of coronary artery calcification in atherosclerosis". Circulation. 120 (24): 2448–54. doi:10.1161/CIRCULATIONAHA.109.865501. PMC   2810344 . PMID   19948975.
• 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. PMID   19450127.
• 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. PMID   19524426.
• 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 . PMID   19126581.
• 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. PMID   19166692.
• 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. PMID   19373490. S2CID   21475249.
• Zhao J, Quyyumi AA, Patel R, Zafari AM, Veledar E, Onufrak S, Shallenberger LH, Jones L, Vaccarino V (September 2009). "Sex-specific association of depression and a haplotype in leukotriene A4 hydrolase gene". Psychosomatic Medicine. 71 (7): 691–6. doi:10.1097/PSY.0b013e3181b05c57. PMC   3113512 . PMID   19622707.
• 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 (November 2009). "Candidate gene polymorphisms for ischemic stroke". Stroke. 40 (11): 3436–42. doi:10.1161/STROKEAHA.109.558015. PMC   2784015 . PMID   19729601.
• 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. PMID   19596330.
• 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. PMID   19233132.
• Drenos F, Talmud PJ, Casas JP, Smeeth L, Palmen J, Humphries SE, Hingorani AD (June 2009). "Integrated associations of genotypes with multiple blood biomarkers linked to coronary heart disease risk". Human Molecular Genetics. 18 (12): 2305–16. doi:10.1093/hmg/ddp159. PMC   2685759 . PMID   19336475.
• Vickers PJ (October 1995). "5-Lipoxygenase-activating protein (FLAP)". Journal of Lipid Mediators and Cell Signalling. 12 (2–3): 185–94. doi:10.1016/0929-7855(95)00018-L. PMID   8777565.
• 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 (April 2010). "The role of LTA4H and ALOX5AP genes in the risk for asthma in Latinos". Clinical and Experimental Allergy. 40 (4): 582–9. doi:10.1111/j.1365-2222.2009.03438.x. PMC   2866051 . PMID   20067482.
• 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. PMID   7938075.
• 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. PMID   19361804.

External links

• 5-lipoxygenase-activating+protein at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Human ALOX5AP genome location and ALOX5AP gene details page in the UCSC Genome Browser .