Structure-activity study of new inhibitors of human betaine-homocysteine S-methyltransferase.

Article Details


Vanek V, Budesinsky M, Kabeleova P, Sanda M, Kozisek M, Hanclova I, Mladkova J, Brynda J, Rosenberg I, Koutmos M, Garrow TA, Jiracek J

Structure-activity study of new inhibitors of human betaine-homocysteine S-methyltransferase.

J Med Chem. 2009 Jun 25;52(12):3652-65. doi: 10.1021/jm8015798.

PubMed ID
19534555 [ View in PubMed

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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
S-(D-Carboxybutyl)-L-HomocysteineBetaine--homocysteine S-methyltransferase 1Kd (nM)280N/AN/ADetails
S-(D-Carboxybutyl)-L-HomocysteineBetaine--homocysteine S-methyltransferase 1IC 50 (nM)138N/AN/ADetails
S-(D-Carboxybutyl)-L-HomocysteineBetaine--homocysteine S-methyltransferase 1Ki (nM)12N/AN/ADetails