Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 52, Issue 12, Pages 3652-3665Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm8015798
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Funding
- NIH Research Grant [R01TWO052501]
- National Institutes of Health [DK52501]
- Research Project of the Academy of Sciences of the Czech Republic [Z40550506]
- Ministry of Education, Youth and Sports of the Czech Republic [LC060777]
- Research Centre for Chemical Genetics [M0508]
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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(CH3) or N(CH3)(2) groups separated from the homocysteine sulfur atom by a methylene, ethylene, or a propylene spacer. Only the inhibitor with the N(CH3) 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-aniino-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 chances of BHMT upon the binding of the substrates/products and inhibitors.
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