10.1021/jm8015798
The research focuses on the structure-activity study of new inhibitors for human betaine-homocysteine S-methyltransferase (BHMT), an enzyme that catalyzes the transfer of a methyl group from betaine to L-homocysteine, producing dimethylglycine and L-methionine. The purpose of the study was to design and synthesize a series of BHMT inhibitors that mimic the hypothetical transition state of BHMT substrates, with the aim of developing potent and selective inhibitors to better understand the enzyme's role in sulfur metabolism, osmolytic balance, and other physiological functions. The researchers synthesized and tested various compounds, including analogues with NH, N(CH3), or N(CH3)2 groups separated by different spacers from the homocysteine sulfur atom. They found that only certain inhibitors, particularly those without a nitrogen atom in the S-linked alkyl chain, such as (RS,RS)-5-(3-amino-3-carboxypropylthio)-3-methylpentanoic acid and (RS)5-(3-amino-3-carboxypropylthio)-3,3-dimethylpentanoic acid, showed high potency in inhibiting BHMT. The study concluded that BHMT does not tolerate certain betaine mimics, especially the presence of a nitrogen atom, in these inhibitors, which was surprising and suggests potential conformational changes of BHMT upon binding of substrates/products and inhibitors. The chemicals used in the process included various organic compounds, such as gamma-aminobutyrolactone, 3-mercaptopropionic acid, diethyl acetamidomalonate, and a range of other alkylating agents and protected amino acids, as well as reagents for synthesis and deprotection steps.
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