AUTHOR=Rudenko Alexander Yu , Mariasina Sofia S. , Bolikhova Anastasiia K. , Nikulin Maxim V. , Ozhiganov Ratislav M. , Vasil’ev Vasiliy G. , Ikhalaynen Yuri A. , Khandazhinskaya Anastasia L. , Khomutov Maxim A. , Sergiev Peter V. , Khomutov Alex R. , Polshakov Vladimir I. TITLE=Organophosphorus S-adenosyl-L-methionine mimetics: synthesis, stability, and substrate properties JOURNAL=Frontiers in Chemistry VOLUME=12 YEAR=2024 URL=https://www.frontiersin.org/journals/chemistry/articles/10.3389/fchem.2024.1448747 DOI=10.3389/fchem.2024.1448747 ISSN=2296-2646 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-P_H, which contains an H-phosphinic group (-P(O)(H)OH) instead of the SAM carboxylic group. SAM-P_H 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-P_H was synthesized chemically, while (R,S)-SAM-P_H and its analogs were prepared enzymatically either from H-phosphinic analogs of methionine (Met-P_H) or H-phosphinic analog of S-adenosyl-l-homocysteine (SAH-P_H) using methionine adenosyltransferase 2A or halide methyltransferases, respectively. SAH-P_H undergoes glycoside bond cleavage in the presence of methylthioadenosine nucleosidase like natural SAH. Thus, SAM-P_H and its analogs are promising new tools for investigating methyltransferases and incorporating reporter groups into their substrates.