Structure−Activity Study of New Inhibitors of Human Betaine-Homocysteine S-Methyltransferase

Abstract

Betaine-homocysteine S-methyltransferase (BHMT) catalyzes the transfer of a methyl group from betaine to L-homocysteine, yielding dimethylglycine and L-methionine. In this study, we prepared a new series of BHMT inhibitors. The inhibitors were designed to mimic the hypothetical transition state of BHMT substrates and consisted of analogues with NH, N(CH 3 ), or N(CH 3 ) 2 groups separated from the homocysteine sulfur atom by a methylene, ethylene, or a propylene spacer. Only the inhibitor with the N(CH 3 ) moiety and ethylene spacer gave moderate inhibition. This result led us to prepare two inhibitors lacking a nitrogen atom in the S-linked alkyl chain: (RS,RS)-5-(3-amino-3-carboxypropylthio)-3-methylpentanoic acid and (RS)-5-(3-amino-3-carboxypropylthio)-3,3-dimethylpentanoic acid. Both of these compounds were highly potent inhibitors of BHMT. The finding that BHMT does not tolerate a true betaine mimic within these inhibitors, especially the nitrogen atom, is surprising and evokes questions about putative conformational changes of BHMT upon the binding of the substrates/products and inhibitors.

Synthesis and Biological Applications of Phosphinates and Derivatives

“…Thus, BHMT is considered as a potential target to restore osmotic balance during unwanted diuresis. In the past, Jiráček et al described several selective and potent inhibitors of BHMT, belonging to phosphinic pseudopeptides [158] and S-alkyl derivatives of homocysteine [159,160]. Among the compounds tested, three of them 235-237 incorporating an S-alkyl homocysteine were detected as potent inhibitors (Fig.…”

A simplified characterization of S-adenosyl-l-methionine-consuming enzymes with 1-Step EZ-MTase: a universal and straightforward coupled-assay for in vitro and in vivo setting

“…SDMT catalyzes a two-step methylation process leading to a key metabolite: betaine. Trimethylglycine is an effective methyl donor involved in the biosynthesis of l -methionine from l -homocysteine; 56 furthermore, under extreme conditions ( e.g. high salt concentrations or low temperatures), this molecule stabilizes proteins acting as an osmoprotectant.…”

Trifluoroselenomethionine: A New Unnatural Amino Acid

“…The solution was heated to reflux for 24 h. The cooled reaction mixture was filtered and then concentrated in vacuo. The residue was purified by flash chromatography with EtOAc and hexane (1:4) to give the known title compound as a colorless solid (1.5 g, 88 %); 1 H NMR (CDCl 3 , 400 MHz): δ =1.45 (s, 9 H), 1.46 (s, 9 H), 2.21–2.41 (m, 2 H), 3.43–3.58 (m, 2 H), 4.43 (m, 1 H), 5.13 ppm (s, 1 H).…”