Potential inhibitors of S-adenosylmethionine-dependent methyltransferases. 5. Role of the asymmetric sulfonium pole in the enzymatic binding of S-adenosyl-L-methionine.
The configuration at the asymmetric sulfonium pole of S-adenosyl-L-methionine (SAM) necessary for optimal enzymatic binding and methyl donation has been elucidated in this study. For the transmethylations catalyzed by catechol O-methyltransferase, phenylethanolamine N-methyltransferase, histamine N-methyltransferase, and hydroxyindole O-methyltransferase, it was demonstrated that only the natural (-) enantiomer of SAM was active as a methyl donor. The corresponding (+)-SAM, which was prepared by enzymatic resolution of synthetic (+/-)-SAM, was shown to be inactive as a methyl donor in these enzymatic reactions. The (+)-SAM was found, however, to be a potent inhibitor of each of these enzyme-catalyzed transmethylations. These results suggest that the (+) enantiomer offers a nonproductive configuration for the methyl-transfer reaction itself; however, this configuration fails to hamper enzymatic binding. These results are discussed relative to the geometric requirements necessary for the methyl-transfer reaction and the requirements for enzymatic binding.
D000818:Animals; D001665:Binding Sites; D002417:Cattle; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D008780:Methyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008968:Molecular Conformation; D011485:Protein Binding; D051381:Rats; D012436:S-Adenosylmethionine / Q000378:metabolism* / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013452:Sulfonium Compounds
D013452:Sulfonium Compounds; D012436:S-Adenosylmethionine; D008780:Methyltransferases