Interaction of DNA Methyltransferase Dnmt3a with Phosphorus Analogues of <i>S</i>-Adenosylmethionine and <i>S</i>-Adenosylhomocysteine

Abstract

Enzymatic methylatransferase reactions are of crucial importance for cellular metabolism, and S-adenosyl-L-methionine is the main donor of the methyl group. DNA, RNA, proteins, and low-molecular-weight compounds are the substrates of methyltransferases. In mammals, methylation of the C5 position of cytosine residues in CpG sequences in DNA is performed de novo by DNA methyltransferase Dnmt3a. “Methylation pattern” is one of the factors determining the epigenetic regulation of gene expression. In the present work, we investigated the interaction of phosphonous and phosphonic analogues of S-adenosyl-L-methionine and S-adenosyl-L-homocysteine with the catalytic domain of Dnmt3a. The phosphonous and phosphonic analogs of S-adenosyl-L-methionine were shown to be substrates of Dnmt3a, and the efficiency of the methylation was only two times less than that of natural S-adenosyl-L-methionine. Both phosphorus-containing analogs of S- adenosyl-L-homocysteine, a natural methyltransferase inhibitor, exhibited similar inhibitory activity against Dnmt3a and were approximately four times less active than S-adenosyl-L-homocysteine. The activities of the phosphonous and phosphonic analogs turned out to be close that was quite unexpected, since the geometry and charge of the phosphorus-containing groups differ significantly. The possibilities of using phosphorus-containing analogs of S- adenosyl-L- methionine and S-adenosyl-L-homocysteine as promising tools for the investigation of methyltransferases are discussed.