5-lipoxygenase-activating protein

Fe-TPAA Fe(III)-tris[N-(2-pyridylmethyl)-2-aminoethyl] amine Fe-TPEN Fe(II)-tetrakis-N,N,N, N -(2-pyridyl methyl-2-aminoethyl)amine FFA Free fatty acids FGF Fibroblast growth factor FID Flame ionization detector FITC Fluorescein isothiocyanate FKBP FK506-binding protein FLAP 5-lipoxygenase-activating protein... 

Kedda MA, Worsley P, Shi J, Phelps S, Duffy D, Thompson PJ. (2005) Polymorphisms in the 5-lipoxygenase activating protein (ALOX5AP) gene are not associated with asthma in an Australian population. Clin Exp Allergy. 35, 332-338. 

Ben-Asher E, Lancet D. (2004) 5-Lipoxygenase activating protein (ALOX5AP) association with cardiovascular infarction and stroke. Isr Med Assoc J. 6, 318-319. 

Finally there has been a growing interest in the development of selective leukotriene inhibitors. Bay Y 1015 (R-(-)-2-cycloheptyl-N-methylsulfonyl-(4-(2-quinolinyl-methoxy) phenyl)-acetamide) is a quinoline-type 5-lipoxygenase-activating protein inhibitor which was effective in inhibiting inflammation in a dextran sulfate model of mouse colitis [112]. Whether these compounds can also exert their anti-inflammatory action through inhibition of endothelial cell activation needs to be established. 

Helgadottir A, Manolescu A, Thorleifsson G, et al. The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke. Nat Genet. Mar 2004 36(3) 233-239. 

Lipoxygenase-activating protein (FLAP) is also involved in the process by which AA is converted to LTA4 and a number of interesting inhibitors have been described (Section 5.2). 

Lipoxygenase activating protein (FLAP) 82 Liposomal gene delivery 1507 Liposomal parenteral dmgs 1370... 

Low concentrations of calcium ion (1-2 pM) are required for maximal activity of purified 5-LO, but the major role of calcium appears to be that of increasing lipophilicity of 5-LO through a C-2-like domain in order to translocate to the nuclear envelope. ATP has a stimulatory effect on 5-LO at 20 nM and lipid hydroperoxides are important to initiate the 5-LO catalytic cycle since they readily form Fe(III) from inactive 5-LO with Fe(II) by the pseudoperoxidase mechanism. Microsomal membranes as well as phosphatidylcholine vesicles can stimulate purified 5-LO activity since 5-LO performs the oxidation of AA at the interface between the membrane and cytosol in a manner similar to that of cPLAja. Calcium ions increase the association of 5-LO with phosphatidylcholine vesicles that likely recapitulate events within the cell where 5-LO becomes associated with the nuclear membrane which is rich in phosphatidylcholine [25]. At the nuclear membrane AA is thought to be presented by a protein which has been termed 5-lipoxygenase activating protein (FLAP) [24]. In cells, such as the neutrophil and mast cells where 5-LO is found in the cytosol, 5-LO is catalytically active only when bound to a membrane, typically the nuclear membrane. In fact, in some cells 5-LO is found to be constitutively associated with the nuclear membrane, likely a result of a process of cellular activation while 5-LO is found in the alveolar macrophage within the nucleus itself [25]. 

Evans, J. 1998. 5-Lipoxygenase and 5-lipoxygenase-activating protein. In Five-Lipoxygenase Products in Asthma. J.M. Drazen, editor. New York Marcel Dekker, pp. 11-32. 

The leukotrienes occur in a variety of inflammatory cells that are abundant in asthma, including eosinophils, mast cells, and macrophages. They are derived from arachidonic acid via a branch of the common pathway to the prostacyclins and thromboxanes. Arachidonic acid itself is produced by the action of phospholipase A2 on cell walls. Unlike the prostacyclins and thromboxanes, excess arachidonic acid does not activate the pathway. Instead, the first step in the conversion of arachidonic acid to produce the leukotrienes is controlled by an activating protein, 5-lipoxygenase-activating protein, which... 

Pouliot M, McDonald PP, Borgeat P, McColl SR Granulocyte/macrophage colony-stimulating factor stimulates the expression of the 5-lipoxygenase-activating protein (FLAP) in human neutrophils. J Exp Med 1994 179 1225-1232. 

Fig. 4. Regulatory targets for leukotriene (LT) inhibition. AA, arachidonic acid FLAP, 5-lipoxygenase activating protein 5-HPETE, 5-hydroperoxyeicosatetraenoic acid.

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