American Chemical Society
jm8015798_si_001.pdf (586.83 kB)

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

Download (586.83 kB)
journal contribution
posted on 2009-06-25, 00:00 authored by Václav Vaněk, Miloš Buděšínský, Petra Kabeleová, Miloslav Šanda, Milan Kožíšek, Ivona Hančlová, Jana Mládková, Jiří Brynda, Ivan Rosenberg, Markos Koutmos, Timothy A. Garrow, Jiří Jiráček
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-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.