5-lipoxygenase-activating protein

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. 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.

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. 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
• MK-886
• Veliflapon (BAY X1005)

References

References

1. (May 1991). "Gene characterization and promoter analysis of the human 5-lipoxygenase-activating protein (FLAP)". The Journal of Biological Chemistry.
2. (February 1999). "Cytogenetic and radiation hybrid mapping of human arachidonate 5-lipoxygenase-activating protein (ALOX5AP) to chromosome 13q12". Genomics.
3. (2003). "5-lipoxygenase and FLAP". Prostaglandins, Leukotrienes, and Essential Fatty Acids.
4. (2015). "Lipid mediators in the resolution of inflammation". Cold Spring Harbor Perspectives in Biology.
5. (July 2007). "Crystal structure of inhibitor-bound human 5-lipoxygenase-activating protein". Science.
6. (2007-06-01). "Association of ALOX5AP with ischemic stroke: a population-based case-control study". Human Genetics.
7. (February 2008). "What's all the FLAP about?: 5-lipoxygenase-activating protein inhibitors for inflammatory diseases". Trends in Pharmacological Sciences.
8. (November 2009). "A novel 5-lipoxygenase-activating protein inhibitor, AM679, reduces inflammation in the respiratory syncytial virus-infected mouse eye". Clinical and Vaccine Immunology.
9. (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.