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.

• MeSH
• betain-homocystein-S-methyltransferasa antagonisté a inhibitory   MeSH
• homocystein analogy a deriváty   chemická syntéza   chemie   farmakologie   MeSH
• inhibitory enzymů chemická syntéza   chemie   farmakologie   MeSH
• kyseliny pentanové chemická syntéza   chemie   farmakologie   MeSH
• lidé MeSH
• molekulární struktura MeSH
• racionální návrh léčiv MeSH
• stereoizomerie MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• 5-(3-amino-3-carboxypropylthio)-3-methylpentanoic acid MeSH Prohlížeč
• 5-(3-amino-3-carboxypropylthio)-3,3-dimethylpentanoic acid MeSH Prohlížeč
• betain-homocystein-S-methyltransferasa MeSH
• homocystein MeSH
• inhibitory enzymů MeSH
• kyseliny pentanové MeSH

A series of S-alkylated derivatives of homocysteine were synthesized and characterized as inhibitors of human recombinant betaine-homocysteine S-methyltransferase (BHMT). Some of these compounds inhibit BHMT with IC50 values in the nanomolar range. BHMT is very sensitive to the structure of substituents on the sulfur atom of homocysteine. The S-carboxybutyl and S-carboxypentyl derivatives make the most potent inhibitors, and an additional sulfur atom in the alkyl chain is well tolerated. The respective (R,S)-5-(3-amino-3-carboxy-propylsulfanyl)-pentanoic, (R,S)-6-(3-amino-3-carboxy-propylsulfanyl)-hexanoic, and (R,S)-2-amino-4-(2-carboxymethylsulfanyl-ethylsulfanyl)-butyric acids are very potent inhibitors and are the strongest ever reported. We determined that (R,S)-5-(3-amino-3-carboxy-propylsulfanyl)-pentanoic acid displays competitive inhibition with respect to betaine binding with a Kappi of 12 nM. Some of these compounds are currently being tested in mice to study the influence of BHMT on the metabolism of sulfur amino acids in vivo.

• MeSH
• betain-homocystein-S-methyltransferasa antagonisté a inhibitory   chemie   MeSH
• butyráty chemická syntéza   chemie   MeSH
• homocystein analogy a deriváty   chemická syntéza   chemie   MeSH
• kapronáty chemická syntéza   chemie   MeSH
• kyseliny pentanové chemická syntéza   chemie   MeSH
• lidé MeSH
• stereoizomerie MeSH
• sulfidy chemická syntéza   chemie   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• 2-amino-4-(2-carboxymethylsulfanylethylsulfanyl)butyric acid MeSH Prohlížeč
• 5-(3-amino-3-carboxypropylsulfanyl)pentanoic acid MeSH Prohlížeč
• 6-(3-amino-3-carboxypropylsulfanyl)hexanoic acid MeSH Prohlížeč
• betain-homocystein-S-methyltransferasa MeSH
• BHMT protein, human MeSH Prohlížeč
• butyráty MeSH
• homocystein MeSH
• kapronáty MeSH
• kyseliny pentanové MeSH
• sulfidy MeSH