Double-headed sulfur-linked amino acids as first inhibitors for betaine-homocysteine S -methyltransferase 2

Jana Mládková, Václav Vaněk, Miloš Buděšínský, Tomáš Elbert, Zuzana Demianová, Timothy A. Garrow, Jiří Jiráček

Research output: Contribution to journalArticlepeer-review


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 (Kiapp ∼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.

Original languageEnglish (US)
Pages (from-to)6822-6831
Number of pages10
JournalJournal of Medicinal Chemistry
Issue number15
StatePublished - Aug 9 2012

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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