Irreversible inhibition of human S-adenosylmethionine decarboxylase by the pure diastereomeric forms of S-(5'-deoxy-5'-adenosyl)-1-ammonio-4- methylsulfonio-2-cyclopentene (AdoMac).
The S-adenosylmethionine (AdoMet) analogue AdoMac [S-(5'-deoxy-5'-adenosyl)-1-ammonio-4-methylsulfonio-2-cyclopen ten e], an enzyme-activated, irreversible inhibitor of the Escherchia coli form of S-adenosylmethionine decarboxylase (AdoMet-DC), also acts as a potent inhibitor of the human form of the enzyme. This analogue has been resolved recently into its four possible diastereomeric forms, and each pure diastereomer has now been evaluated as an inhibitor of human AdoMet-DC. As was the case for the bacterial enzyme, kinetic analysis revealed that the four pure diastereomeric forms of AdoMac differentially inhibit human S-adenosylmethionine decarboxylase (K(i) values ranging between 11 and 63 microM). Although the human and bacterial forms of the enzyme each discriminated between the four diastereomers of AdoMac, each form appeared to bind optimally to a distinctly different diastereomer of the inhibitor. These data suggest that the active sites of human and bacterial AdoMet-DC are distinctly different, and that it may be possible to design inhibitors that are specific for a given form of the enzyme.
Wu
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YQ
Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, Wayne State University, Detroit, MI 48202, USA.
Woster
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PM
D012437:Adenosylmethionine Decarboxylase / Q000037:antagonists & inhibitors*; D001665:Binding Sites; D003517:Cyclopentanes / Q000494:pharmacology*; D003839:Deoxyadenosines / Q000494:pharmacology*; D004789:Enzyme Activation; D004926:Escherichia coli / Q000201:enzymology; D006801:Humans; D007700:Kinetics; D008968:Molecular Conformation; D013237:Stereoisomerism
D003517:Cyclopentanes; D003839:Deoxyadenosines; C076204:S-(5'-deoxy-5'-adenosyl)-1-ammonio-4-(methylsulfonio)-2-cyclopentene; D012437:Adenosylmethionine Decarboxylase