S-(5'-deoxy-5'-adenosyl)-1-ammonio-4-(methylsulfonio)-2-cyclopentene: A potent, enzyme-activated irreversible inhibitor of S-adenosylmethionine decarboxylase.

The compound S-(5'-deoxy-5'-adenosyl)-1-ammonio-4-(methylsulfonio)-2- cyclopentene (AdoMac) was prepared and evaluated as an irreversible inhibitor of S-adenosylmethionine decarboxylase (AdoMet-DC). AdoMac was shown to inhibit AdoMet-DC in a time-dependent manner with a KI of 18.3 microM and a kinact of 0.133 min-1. In addition, AdoMet-DC activity could not be restored following extensive dialysis of the enzyme-inhibitor complex, and the enzyme was protected from irreversible inactivation by the known competitive inhibitor methylglyoxal bis(guanylhydrazone). HPLC analysis of the enzymatic reaction products revealed a time-dependent decrease in the peak coeluting with AdoMac, and a corresponding increase in the peak coeluting with (methylthio)adenosine (MTA), a byproduct of the irreversible binding of AdoMac to the enzyme. Thus, AdoMac appears to function as an enzyme-activated, irreversible inhibitor of AdoMet-DC.