Potential inhibitors of S-adenosylmethionine-dependent methyltransferases. 5. Role of the asymmetric sulfonium pole in the enzymic binding of S-adenosyl-L-methionine

Abstract

The configuration at the asymmetric sulfonium pole of S-adenosyl-L-methionine (SAM) necessary for optimal enzymatic binding and methyl donation was elucidated in this study. For the transmethylations catalyzed by catechol O-methyltransferase [rat liver], phenylethanolamine N-methyltransferase [bovine adrenal medulla], histamine N-methyltransferase [guinea pig brain] and hydroxyindole O-methyltransferase [bovine pineal gland], 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 inactive as a methyl donor in these enzymatic reactions. The (+)-SAM was a potent inhibitor of each of these enzyme-catalyzed transmethylations. The (+) enantiomer probably offers a nonproductive configuration for the methyl-transfer reaction, 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.