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=Volume 12 - 2024

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. Analogues of SAM with a reporter group in place of the S-methyl group are widely used to study these processes. However, many of these analogues are chemical 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 SAM carboxylic group. SAM‑PH is significantly more stable than SAM; retains functional activity in methyltransferase WBSCR27, associated with Williams-Beuren syndrome WBSCR27, and сatechol O methyltransferase reactions. Rac-SAM‑PH was synthesized chemically, while (R,S) SAM‑PH and its analogues were prepared enzymatically either from H‑phosphinic analogues of methionine (Met-PH), or H‑phosphinic analogue of S adenosyl L homocysteine (SAH‑PH), using methionine adenosyltransferase 2A or halide methyltransferases, respectively. SAH‑PH undergo glycoside bond cleavage in the presence of methylthioadenosine nucleosidase like natural SAH. Thus SAM‑PH and its analogues are a promising new tool for investigating methyltransferases and incorporating reporter groups into their substrates.