Cyclo-oxygenase isoenzymes. Structural basis for selective inhibition of cyclo-oxygenases by anti-inflammatory agents.
Cyclo-oxygenase (prostaglandin endoperoxide synthase) is the enzyme which metabolizes the conversion of arachidonic acid to prostaglandin. It exists in at least two isoforms: the constitutive (cyclo-oxygenase-1) and the inducible (cyclo-oxygenase-2) which is controlled by a number of factors, including cytokines and intracellular messengers. These enzymes are the therapeutic targets of non-steroidal anti-inflammatory drugs such as aspirin and ibuprofen. The cyclo-oxygenase active site is a long, hydrophobic, channel where the substrate arachidonic acid gains access to the active site. Cyclo-oxygenase-2 differs form cyclo-oxygenase-1 in certain key characteristics, particularly important is the valine/leucine substitution at position 523 that creates a defect in the inner shell of the cyclo-oxygenase-2 enzyme channel leaving a side pocket by which drugs selective for cyclo-oxygenase-2 gain access. Although cyclo-oxygenase-1 seems to be expressed in physiological conditions and cyclo-oxygenase-2 in inflammatory conditions, it is not yet possible to identify all their different roles. Cyclo-oxygenase-2 may be expressed constitutively, whereas the generation of prostaglandin by cyclo-oxygenase-2 may replace that by cyclo-oxygenase-1 in some situations (or vice-versa). Both cyclo-oxygenase isoenzymes contribute to mucosal defence and the inhibition of the two isoforms contributes to the pathogenesis of non-steroidal anti-inflammatory drug-induced gastric damage.
Fiorucci
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University of Perugia, Italy. fiorucci@unipg.it
Antonelli
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D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects*; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000009:adverse effects*; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis / Q000378:metabolism*; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000378:metabolism*; D013276:Stomach Ulcer / Q000139:chemically induced* / Q000201:enzymology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases