5-lipoxygenase: cellular biology and molecular pharmacology.
5-lipoxygenase (5-LO) plays an essential role in the biosynthesis of leukotrienes, proinflammatory mediators which are mainly released from myeloid cells. Whereas LTB(4) is a potent chemotactic and chemokinetic agent for a variety of leukocytes, the cysteinyl-leukotrienes C, D(4) and E(4) cause vascular permeability and smooth muscle contraction. In view of these properties, leukotriene synthesis inhibitors have been hypothesized to possess therapeutic potential for the treatment of asthma, allergic disorders and other inflammatory diseases. Whereas cysteinyl-leukotriene receptor antagonists possess potential for antileukotriene therapy in asthma, results from clinical trials with leukotriene synthesis inhibitors were less encouraging. The expression of 5-LO in mammals is tightly regulated. Enzymatic activity in vitro can be modulated by calcium, ATP, phosphatidylcholine and lipid hydroperoxides; 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 colocalizes with 5-lipoxygenase-activating protein and cytosolic phospholipase A(2). In addition, various cellular proteins interacting with 5-LO have been identified. It was suggested that enzyme phosphorylation could influence redistribution and cellular activity of 5-LO and that the cellular redox tone regulates 5-LO product formation. This review highlights the determinants of cellular 5-LO activity and summarizes the molecular pharmacology of 5-LO.
Werz
Oliver
O
Institute of Pharmaceutical Chemistry, University of Frankfurt, D-60439 Frankfurt, Germany. o.werz@pharmchem.uni-frankfurt.de
D058927:5-Lipoxygenase-Activating Proteins; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics / Q000502:physiology*; D002118:Calcium / Q000502:physiology; D002352:Carrier Proteins / Q000502:physiology; D006801:Humans; D015289:Leukotrienes / Q000096:biosynthesis; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008565:Membrane Proteins / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D010766:Phosphorylation; D048051:p38 Mitogen-Activated Protein Kinases
D058927:5-Lipoxygenase-Activating Proteins; C548592:ALOX5AP protein, human; D002352:Carrier Proteins; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D008565:Membrane Proteins; D001094:Arachidonate 5-Lipoxygenase; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D002118:Calcium