Journal
BIOCHEMICAL JOURNAL
Volume 393, Issue -, Pages 211-218Publisher
PORTLAND PRESS LTD
DOI: 10.1042/BJ20060669
Keywords
arachidonic acid (AA); 5-lipoxygenase-activating protein (FLAP); leukotriene (LT); 5-hpoxygenase (5-LO); polymorphonuclear cells (PMN); prostaglandin B2 (PGB2)
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FLAP (5-lipoxygenase-activating protein) is a nuclear transmembrane protein involved in the biosynthesis of LTs (leukotrienes) and other 5-LO (5-lipoxygenase) products. However, little is known about its mechanism of action. In the present study, using cross-linkers, we demonstrate that FLAP is present as a monomer and a homodimer in human PMN (polymorphonuclear cells). The functional relevance of the FLAP dinner in LT biosynthesis was assessed in different experimental settings. First, the 5-LO substrate AA (arachidonic acid) concomitantly disrupted the FLAP dimer (at >= 10 mu M) and inhibited LT biosynthesis. Secondly, using Sf9 cells expressing active and inactive FLAP mutants and 5-LO, we observed that the FLAP mutants capable Of Supporting 5-LO product biosynthesis also form the FLAP dimer, whereas inactive FLAP mutants do not. Finally, we showed that FLAP inhibitors such as MK-0591 which block LT biosynthesis in human PMN, disrupt the FLAP dimer in PMN membranes with a similar IC50. The present study demonstrates that LT biosynthesis in intact cells not only requires the presence of FLAP but its further organization into a FLAP homodimer.
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