5-lipoxygenase-activating protein

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
Identifiers
Symbols  ; FLAP
External IDs ChEMBL: GeneCards:
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)
RefSeq (protein)
Location (UCSC)
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]

Contents

  • Function 1
  • Clinical significance 2
  • Inhibitors 3
  • References 4
  • Further reading 5
  • External links 6

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.[1]

Clinical significance

Gene polymorphisms in FLAP are suspected of playing a role in Alzheimer's disease.[5] 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.[1]

Inhibitors

References

  1. ^ a b c  
  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.  
  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.  
  4. ^ Peters-Golden M, Brock TG (2003). "5-lipoxygenase and FLAP". Prostaglandins Leukot Essent Fatty Acids 69 (2-3): 99–109.  
  5. ^ 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.  
  6. ^ 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.  

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.  
  • 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.  
  • 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.  
  • 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.  
  • Wang Q (2005). "Molecular genetics of coronary artery disease.". Current Opinion in Cardiology 20 (3): 182–8.  
  • McGeachie M, Ramoni RL, Mychaleckyj JC, et al. (2009). "Integrative predictive model of coronary artery calcification in atherosclerosis.". Circulation 120 (24): 2448–54.  
  • 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.  
  • 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.  
  • 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.  
  • 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.  
  • 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.  
  • 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.  
  • Matarin M, Brown WM, Dena H, et al. (2009). "Candidate gene polymorphisms for ischemic stroke.". Stroke 40 (11): 3436–42.  
  • 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.  
  • 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.  
  • 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.  
  • Vickers PJ (1995). "5-Lipoxygenase-activating protein (FLAP).". J Lipid Mediat Cell Signal 12 (2-3): 185–94.  
  • 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).  
  • Steinhilber D (1994). "5-Lipoxygenase: enzyme expression and regulation of activity.". Pharm Acta Helv 69 (1): 3–14.  
  • 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.  

External links