Covalent binding Cyclooxygenases

Irreversible inhibitors combine or destroy a functional group on the enzyme so that it is no longer active. They often act by covalently modifying the enzyme. Thus a new enzyme needs to be synthesized. Examples of irreversible inhibitors include acetylsal-icyclic acid, which irreversibly inhibits cyclooxygenase in prostaglandin synthesis. Organophosphates (e.g., malathion, 8.10) irreversibly inhibit acetylcholinesterase. Suicide inhibitors (mechanism-based inactivators) are a special class of irreversible inhibitors. They are relatively unreactive until they bind to the active site of the enzyme, and then they inactivate the enzyme. 

Irreversible (covalent) inhibition The drug again binds to the active site of the enzyme and then covalently reacts with it, so that the active site becomes irreversibly blocked. Example Inhibition of cyclooxygenase by acetylsalicylic acid. 

NSAID-Assodated Ulcer. NSAIDs inhibit the production of prostaglandins, prostacyclins, and thromboxanes from arachidonic acid by covalently modifying the enzyme cyclooxygenase (COX) and irreversibly inhibiting the ability of arachidonic acid to bind to the active site on the enzyme. Chronic administration of NSAIDs has been linked to ulcer disease, although there is no evidence that they are the direct cause of ulcer formation. In patients already diagnosed with ulcer disease, chronic administration of NSAIDs was associated with a fourfold increase in the risk of ul-... 

El and ET cannot bind fatty acid and thus neither can catalyze the cyclooxygenase reaction. For aspirin, conversion of El to El is accompanied by covalent modification of the protein, making the transition irreversible. 

Since platelets have no DNA, they are unable to synthesise new COX once aspirin has irreversibly inhibited the enzyme. Other NSAlDs cyclooxygenase inhibitors such as ibuprofen, diclofenac, and indomethacin act similarly to aspirin in that they bind to COX but they do not covalently modify the enzjtme and thus do not irreversibly inhibit the platelet function (Fig. 14.11). NSAID analgesics can be chemically classified as shown in Table 14.2. Ibuprofen was the first of these compounds to be marketed and it was followed by a number of other compounds such as naproxen and ketoprofen, which are more potent than ibuprofen. 

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