Organophosphorus S-adenosyl-L-methionine mimetics: synthesis, stability, and substrate properties

Abstract

S-Adenosyl-l-methionine (SAM)-mediated methylation of biomolecules controls their function and regulates numerous vital intracellular processes. Analogs of SAM with a reporter group in place of the S-methyl group are widely used to study these processes. However, many of these analogs are chemically unstable that largely limits their practical application. We have developed a new compound, SAM-PH, which contains an H-phosphinic group (-P(O)(H)OH) instead of the SAM carboxylic group. SAM-PH is significantly more stable than SAM, retains functional activity in catechol-O-methyltransferase and methyltransferase WBSCR27 reactions. The last is associated with Williams–Beuren syndrome. Rac-SAM-PH was synthesized chemically, while (R,S)-SAM-PH and its analogs were prepared enzymatically either from H-phosphinic analogs of methionine (Met-PH) or H-phosphinic analog of S-adenosyl-l-homocysteine (SAH-PH) using methionine adenosyltransferase 2A or halide methyltransferases, respectively. SAH-PH undergoes glycoside bond cleavage in the presence of methylthioadenosine nucleosidase like natural SAH. Thus, SAM-PH and its analogs are promising new tools for investigating methyltransferases and incorporating reporter groups into their substrates.