5-lipoxygenase-activating protein FLAP

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]. 

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. 

As part of the response to leukocyte cell activation, cysteinyl leukotrienes are generated de novo from arachidonic acid liberated from cell membrane phospholipid by cytosolic phospholipase A2 (Fig. 3.8). In concert with 5-lipoxygenase-activating protein (FLAP), the enzyme 5-lipoxygenase (5-LO) converts arachidonic... 

Fig. 4.17. Hypothetical mechanism of 5-lipoxygenase activation by calcium, ATP and 5-lipoxygenase-activating protein (FLAP) in intact cells. Based on results reviewed in ref. 93.

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