S-alkylated homocysteine derivatives: new inhibitors of human betaine-homocysteine S-methyltransferase
Language English Country United States Media print
Document type Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
Grant support
R03 TW006858
FIC NIH HHS - United States
DK52501
NIDDK NIH HHS - United States
R01 TW0052501
FIC NIH HHS - United States
R29 DK052501
NIDDK NIH HHS - United States
R01 DK052501
NIDDK NIH HHS - United States
PubMed
16789755
PubMed Central
PMC2622432
DOI
10.1021/jm050885v
Knihovny.cz E-resources
- MeSH
- Betaine-Homocysteine S-Methyltransferase antagonists & inhibitors chemistry MeSH
- Butyrates chemical synthesis chemistry MeSH
- Homocysteine analogs & derivatives chemical synthesis chemistry MeSH
- Caproates chemical synthesis chemistry MeSH
- Pentanoic Acids chemical synthesis chemistry MeSH
- Humans MeSH
- Stereoisomerism MeSH
- Sulfides chemical synthesis chemistry MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
- Names of Substances
- 2-amino-4-(2-carboxymethylsulfanylethylsulfanyl)butyric acid MeSH Browser
- 5-(3-amino-3-carboxypropylsulfanyl)pentanoic acid MeSH Browser
- 6-(3-amino-3-carboxypropylsulfanyl)hexanoic acid MeSH Browser
- Betaine-Homocysteine S-Methyltransferase MeSH
- BHMT protein, human MeSH Browser
- Butyrates MeSH
- Homocysteine MeSH
- Caproates MeSH
- Pentanoic Acids MeSH
- Sulfides 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.
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Structure-activity study of new inhibitors of human betaine-homocysteine S-methyltransferase