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.
Wu
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Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, Wayne State University, Detroit, Michigan 48202.
Woster
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PM
D012437:Adenosylmethionine Decarboxylase / Q000037:antagonists & inhibitors*; D001665:Binding Sites; D003517:Cyclopentanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003839:Deoxyadenosines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004926:Escherichia coli / Q000201:enzymology; D007700:Kinetics; D015394:Molecular Structure
D003517:Cyclopentanes; D003839:Deoxyadenosines; C076204:S-(5'-deoxy-5'-adenosyl)-1-ammonio-4-(methylsulfonio)-2-cyclopentene; D012437:Adenosylmethionine Decarboxylase