5-lipoxygenase activating protein

同

FLAP

WordNet

1. any of a large group of nitrogenous organic compounds that are essential constituents of living cells; consist of polymers of amino acids; essential in the diet of animals for growth and for repair of tissues; can be obtained from meat and eggs and milk and legumes; "a diet high in protein"
2. causing motion or action or change (同)actuating

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/06/01 22:27:05」(JST)

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Arachidonate 5-lipoxygenase-activating protein
Crystallographic structure of the inhibitor-bound human 5-lipoxygenase-activating protein.
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 • arachidonate 5-lipoxygenase activity • glutathione transferase activity • leukotriene-C4 synthase activity • glutathione peroxidase activity • protein binding • enzyme activator activity • enzyme binding • protein homodimerization activity • protein heterodimerization activity • protein N-terminus binding • arachidonic acid binding Cellular component • nuclear envelope • endoplasmic reticulum • endoplasmic reticulum membrane • cytosol • integral to membrane • nuclear membrane Biological process • leukotriene production involved in inflammatory response • positive regulation of acute inflammatory response • leukotriene metabolic process • glutathione biosynthetic process • arachidonic acid metabolic process • leukotriene biosynthetic process • lipoxygenase pathway • 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_009663
RefSeq (protein)	NP_001191335	NP_033793
Location (UCSC)	Chr 13: 31.31 – 31.34 Mb	Chr 5: 149.27 – 149.29 Mb
PubMed search	[1]	[2]

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.

Function

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

Clinical significance

Gene polymorphisms in FLAP are suspected of playing a role in Alzheimer's disease. 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.

Inhibitors

• AM-679

References

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. 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.". Eur. J. Hum. Genet. 17 (11): 1448–53. doi:10.1038/ejhg.2009.71. PMC 2986684. PMID 19417766. 
• Wang Q (2005). "Molecular genetics of coronary artery disease.". Curr. Opin. Cardiol. 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. 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)

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

• 1. 喘息の治療において5-リポキシゲナーゼ経路に影響する薬剤 agents affecting the 5 lipoxygenase pathway in the treatment of asthma
• 2. 心血管疾患の危険因子の概要 overview of the possible risk factors for cardiovascular disease
• 3. 12歳未満の小児における慢性喘息：持続性喘息の治療およびコントロール薬 asthma in children younger than 12 years treatment of persistent asthma with controller medications
• 4. 肥満細胞：表面受容体とシグナル伝達 mast cells surface receptors and signal transduction
• 5. 肥満細胞由来のメディエーター mast cell derived mediators

English Journal

• 4,5-Diarylisoxazol-3-carboxylic acids: A new class of leukotriene biosynthesis inhibitors potentially targeting 5-lipoxygenase-activating protein (FLAP).

• Banoglu E1, Çelikoğlu E2, Völker S3, Olgaç A2, Gerstmeier J4, Garscha U4, Çalışkan B2, Schubert US5, Carotti A6, Macchiarulo A6, Werz O3.
• European journal of medicinal chemistry.Eur J Med Chem.2016 May 4;113:1-10. doi: 10.1016/j.ejmech.2016.02.027. Epub 2016 Feb 15.
• In this article, we report novel leukotriene (LT) biosynthesis inhibitors that may target 5-lipoxygenase-activating protein (FLAP) based on the previously identified isoxazole derivative (8). The design and synthesis was directed towards a subset of 4,5-diaryl-isoxazole-3-carboxylic acid derivatives
• PMID 26922224

• 5-Lipoxygenase-activating protein rescues activity of 5-lipoxygenase mutations that delay nuclear membrane association and disrupt product formation.

• Gerstmeier J1, Newcomer ME1, Dennhardt S1, Romp E1, Fischer J1, Werz O1, Garscha U2.
• FASEB journal : official publication of the Federation of American Societies for Experimental Biology.FASEB J.2016 Feb 3. pii: fj.201500210R. [Epub ahead of print]
• Leukotrienes (LTs) are proinflammatory lipid mediators formed from arachidonic acid in a 2-step reaction catalyzed by 5-lipoxygenase (5-LOX) requiring the formation of 5-HPETE (5(S)-hydroperoxyeicosatetraenoic acid) and its subsequent transformation to LTA4. 5-LOX is thought to receive arachidonic a
• PMID 26842853

• Polypharmacology of Small-Molecule Modulators of the 5-Lipoxygenase Activating Protein (FLAP) Observed via a High-throughput Lipidomics Platform.

• Song J1, Liu X2, Zhu J2, Tootoonchi M2, Keith JM2, Meduna SP2, Dvorak CA2, Eccles W2, Krawczuk PJ2, Blevitt JM1, Wu J1, Rao NL2, Lebsack AD2, Milla ME3.
• Journal of biomolecular screening.J Biomol Screen.2016 Feb;21(2):127-35. doi: 10.1177/1087057115607815. Epub 2015 Oct 6.
• Leukotrienes (LTs) and related species are proinflammatory lipid mediators derived from arachidonic acid (AA) that have pathological roles in autoimmune and inflammatory conditions, cardiovascular diseases, and cancer. 5-Lipoxygenase activating protein (FLAP) plays a critical accessory role in the c
• PMID 26442913

Japanese Journal

• Preliminary assessment of differential expression of candidate genes associated with atherosclerosis

• Genes & genetic systems 88(3), 199-209, 2013-06-25
• NAID 10031194259

• Validation of the Association Between the Gene Encoding 5-Lipoxygenase-Activating Protein and Myocardial Infarction in a Japanese Population

• Circulation Journal 69(9), 1029-1034, 2005-08-20
• NAID 110002703834

• Phosphodiesterase 4D and 5-lipoxygenase activating protein in ischemic stroke

• Ann Neurol 58, 351-361, 2005
• NAID 30008839780

Related Links

• ALOX5AP arachidonate 5-lipoxygenase-activating protein ...

This gene encodes a protein which, with 5-lipoxygenase, is required for leukotriene synthesis. Leukotrienes are arachidonic acid metabolites which have been implicated in various types of inflammatory responses ...

• 5-Lipoxygenase–Activating Protein - Circulation Research

Gene array analyses identified the 5-lipoxygenase–activating protein (FLAP) among the most upregulated genes in both the aorta and adipose tissue of dnTGFβRII transgenic ApoE −/ − mice compared with their ApoE ...

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★リンクテーブル★

リンク元	「FLAP」
関連記事	「lipoxygenase」

「FLAP」

　　[★]

• 5-lipoxygenase activating protein, 5-LOX-activating protein, 5-LOXAP, LOX5AP

関

lipoxygenase activating protein

「lipoxygenase」

　　[★] リポキシゲナーゼ, 不飽和脂肪酸酸化酵素, LOX