Abstract
5-Lipoxygenase (5-LO) plays an essential role in the biosynthesis of leukotrienes (LTs), proinflammatory mediators, which are mainly released from myeloid cells. Whereas LTB4 is a potent chemotactic and chemokinetic agent for leukocytes, the cysteinyl (cys) LTs C4, D4 and E4 cause vascular permeability and smooth muscle contraction. In view of these properties, LT synthesis inhibitors have been hypothesised to possess therapeutic potential for the treatment of asthma, allergic disorders and other inflammatory diseases. The expression of 5-LO in mammals is tightly regulated. Enzymatic activity in vitro can be modulated by calcium, ATP, phosphatidylcholine and lipid hydroperoxide; nevertheless activation of cellular 5-LO in response to external stimuli is rather incompletely understood. Intensive research revealed that on cell stimulation, 5-LO redistributes to the nuclear membrane where it colocalises with 5-lipoxygenase-activating protein and cytosolic phospholipase A2. Accumulating data suggest that phosphorylation of 5-LO by p38 MAPK-regulated MAPKAP-kinases and extracellular signal-regulated kinases 1 / 2 regulates cellular 5-LO activity and influences redistribution of the enzyme in the cell. In addition, the cellular redox tone regulates 5-LO product formation, and 5-LO reactions may be influenced by cellular proteins physically interacting with 5-LO. This review highlights the determinants of cellular 5-LO activity and summarises the molecular pharmacology of 5-LO.
Keywords: 5-lipoxygenase-activating protein, leukotriene, arachidonic acid, polymorphonuclear leukocytes
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