5-lipoxygenase-activating protein

Arachidonate 5-lipoxygenase-activating protein
Crystallographic structure of the inhibitor-bound human 5-lipoxygenase-activating protein.[1]
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 2Q7M​, 2Q7R​
Identifiers
Symbols	ALOX5AP ; FLAP
External IDs	OMIM: 603700 MGI: 107505 HomoloGene: 1231 ChEMBL: 4550 GeneCards: ALOX5AP Gene
Gene ontology Molecular function • glutathione transferase activity • leukotriene-C4 synthase activity • glutathione peroxidase activity • protein binding • enzyme activator activity • protein N-terminus binding • arachidonic acid binding Cellular component • nuclear envelope • endoplasmic reticulum • endoplasmic reticulum membrane • membrane • integral component of membrane • nuclear membrane Biological process • leukotriene metabolic process • arachidonic acid metabolic process • leukotriene biosynthetic process • lipoxygenase pathway • positive regulation of catalytic activity • small molecule metabolic process • protein homotrimerization • cellular response to calcium ion • lipoxin metabolic process Sources: Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	241	11690
Ensembl	ENSG00000132965	ENSMUSG00000060063
UniProt	P20292	P30355
RefSeq (mRNA)	NM_001204406	NM_001308462
RefSeq (protein)	NP_001191335	NP_001295391
Location (UCSC)	Chr 13: 30.71 – 30.76 Mb	Chr 5: 149.27 – 149.29 Mb
PubMed search

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.^[2][3]

Function

FLAP is necessary for the activation of 5-lipoxygenase and therefore for the production of leukotrienes.^[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]

Inhibitors

• AM-679^[7]

References

1. 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. doi:10.1126/science.1144346. PMID 17600184.
2. 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)". J. Biol. Chem. 266 (13): 8511–6. PMID 1673682.
3. 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.
4. Peters-Golden M, Brock TG (2003). "5-lipoxygenase and FLAP". Prostaglandins Leukot Essent Fatty Acids 69 (2-3): 99–109. doi:10.1016/S0952-3278(03)00070-X. PMID 12895592.
5. PDB: 2q7r​;Ferguson, A. D.; McKeever, B. M.; Xu, S.; Wisniewski, D.; Miller, D. K.; Yamin, T.-T.; Spencer, R. H.; Chu, L.; Ujjainwalla, F.; Cunningham, B. R.; Evans, J. F.; Becker, J. W. (2007). "Crystal Structure of Inhibitor-Bound Human 5-Lipoxygenase-Activating Protein". Science 317 (5837): 510–512. doi:10.1126/science.1144346. ISSN 0036-8075. PMID 17600184.
6. Manev H, Manev R (2006). "5-Lipoxygenase (ALOX5) and FLAP (ALOX5AP) gene polymorphisms as factors in vascular pathology and Alzheimer's disease". Med Hypotheses 66 (3): 501–3. doi:10.1016/j.mehy.2005.09.031. PMID 16278051.
7. Musiyenko, A.; Correa, L.; Stock, N.; Hutchinson, J. H.; Lorrain, D. S.; Bain, G.; Evans, J. F.; Barik, S. (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.

Further reading

• Bevan S, Lorenz MW, Sitzer M, Markus HS (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; et al. (2009). "Association of genetic variants with chronic kidney disease in Japanese individuals with type 2 diabetes mellitus.". Int. J. Mol. Med. 23 (4): 529–37. doi:10.3892/ijmm_00000161. PMID 19288030.
• He YL, Zhu M, Jin XP, Zhou YL (2009). "[Relationship of polymorphism of SG13S114A/T in ALOX5AP gene with atherosclerotic cerebral infarction]". Zhejiang Da Xue Xue Bao Yi Xue Ban 38 (6): 630–3. PMID 20014490.
• Quarta G, Stanzione R, Evangelista A; et al. (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 (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; et al. (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 (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; et al. (2009). "Leukotriene pathway polymorphisms are associated with altered cysteinyl leukotriene production in children with acute asthma.". Prostaglandins Leukot. Essent. Fatty Acids 81 (1): 9–15. doi:10.1016/j.plefa.2009.05.022. PMID 19524426.
• Zintzaras E, Rodopoulou P, Sakellaridis N (2009). "Variants of the arachidonate 5-lipoxygenase-activating protein (ALOX5AP) gene and risk of stroke: a HuGE gene-disease association review and meta-analysis.". Am. J. Epidemiol. 169 (5): 523–32. doi:10.1093/aje/kwn368. PMID 19126581.
• van der Net JB, Janssens AC, Defesche JC; et al. (2009). "Usefulness of genetic polymorphisms and conventional risk factors to predict coronary heart disease in patients with familial hypercholesterolemia.". Am. J. Cardiol. 103 (3): 375–80. doi:10.1016/j.amjcard.2008.09.093. PMID 19166692.
• Liu J, Sun K, Bai Y; et al. (2009). "Association of three-gene interaction among MTHFR, ALOX5AP and NOTCH3 with thrombotic stroke: a multicenter case-control study.". Hum. Genet. 125 (5-6): 649–56. doi:10.1007/s00439-009-0659-0. PMID 19373490.
• Zhao J, Quyyumi AA, Patel R; et al. (2009). "Sex-specific association of depression and a haplotype in leukotriene A4 hydrolase gene.". Psychosom Med 71 (7): 691–6. doi:10.1097/PSY.0b013e3181b05c57. PMC 3113512. PMID 19622707.
• Matarin M, Brown WM, Dena H; et al. (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; et al. (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; et al. (2009). "Distinct parts of leukotriene C(4) synthase interact with 5-lipoxygenase and 5-lipoxygenase activating protein.". Biochem. Biophys. Res. Commun. 381 (4): 518–22. doi:10.1016/j.bbrc.2009.02.074. PMID 19233132.
• Drenos F, Talmud PJ, Casas JP; et al. (2009). "Integrated associations of genotypes with multiple blood biomarkers linked to coronary heart disease risk.". Hum. Mol. Genet. 18 (12): 2305–16. doi:10.1093/hmg/ddp159. PMC 2685759. PMID 19336475.
• Vickers PJ (1995). "5-Lipoxygenase-activating protein (FLAP).". J Lipid Mediat Cell Signal 12 (2-3): 185–94. doi:10.1016/0929-7855(95)00018-L. PMID 8777565.
• Via M, De Giacomo A, Corvol H; et al. (2010). "The role of LTA4H and ALOX5AP genes in the risk for asthma in Latinos.". Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 40 (4): HASH(0x2d4c020). doi:10.1111/j.1365-2222.2009.03438.x. PMC 2866051. PMID 20067482.
• Steinhilber D (1994). "5-Lipoxygenase: enzyme expression and regulation of activity.". Pharm Acta Helv 69 (1): 3–14. doi:10.1016/0031-6865(94)90024-8. PMID 7938075.
• Oosterveer DM, Versmissen J, Yazdanpanah M; et al. (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 US National Library of Medicine Medical Subject Headings (MeSH)