Double-headed sulfur-linked amino acids as first inhibitors for betaine-homocysteine S-methyltransferase 2
| Autor: | Zuzana Demianová, Václav Vaněk, Jana Mládková, Timothy A. Garrow, Jiří Jiráček, Tomáš Elbert, Miloš Buděšínský |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Methyltransferase
Homocysteine Betaine—homocysteine S-methyltransferase chemistry.chemical_element Sulfides Copurification law.invention chemistry.chemical_compound Structure-Activity Relationship law Drug Discovery Humans Enzyme Assays chemistry.chemical_classification Stereoisomerism Sulfur Recombinant Proteins Amino acid Kinetics chemistry Biochemistry Betaine-Homocysteine S-Methyltransferase Recombinant DNA Molecular Medicine Methyl group |
| Zdroj: | Journal of medicinal chemistry. 55(15) |
| ISSN: | 1520-4804 |
| Popis: | Betaine-homocysteine S-methyltransferase 2 (BHMT-2) catalyzes the transfer of a methyl group from S-methylmethionine to l-homocysteine, yielding two molecules of l-methionine. It is one of three homocysteine methyltransferases in mammals, but its overall contribution to homocysteine remethylation and sulfur amino acid homeostasis is not known. Moreover, recombinant BHMT-2 is highly unstable, which has slowed research on its structural and catalytic properties. In this study, we have prepared the first series of BHMT-2 inhibitors to be described, and we have tested them with human recombinant BHMT-2 that has been stabilized by copurification with human recombinant BHMT. Among the compounds synthesized, (2S,8RS,11RS)-5-thia-2,11-diamino-8-methyldodecanedioic acid (11) was the most potent (K(i)(app) ∼77 nM) and selective inhibitor of BHMT-2. Compound 11 only weakly inhibited human BHMT (IC(50) about 77 μM). This compound (11) may be useful in future in vivo studies to probe the physiological significance of BHMT-2 in sulfur amino acid metabolism. |
| Databáze: | OpenAIRE |
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