Structure−Activity Study of New Inhibitors of Human Betaine-Homocysteine S-Methyltransferase
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- 作者：Vclav Vank ; Milo Budnsk ; Petra Kabeleov ; Miloslav anda ; Milan Koek ; Ivona Hanlov ; Jana Mldkov ; Ji Brynda ; Ivan Rosenberg ; Markos Koutmos ; Timothy A. Garrow ; Ji Jirek
- 刊名：Journal of Medicinal Chemistry
- 出版年：2009
- 出版时间：June 25, 2009
- 年：2009
- 卷：52
- 期：12
- 页码：3652-3665
- 全文大小：281K
- 年卷期：v.52,no.12(June 25, 2009)
- ISSN：1520-4804
文摘
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.