title: Double-headed sulfur-linked amino acids as first inhibitors for betaine-homocysteine S-methyltransferase 2.
abstract: 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.
authors: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo nám. 2, 166 10 Prague 6, Czech Republic.
authors: Jana
authors: J
authors: Mládková
authors: Václav
authors: V
authors: Vaněk
authors: Miloš
authors: M
authors: Buděšínský
authors: Tomáš
authors: T
authors: Elbert
authors: Zuzana
authors: Z
authors: Demianová
authors: Timothy A
authors: TA
authors: Garrow
authors: Jiří
authors: J
authors: Jiráček
mesh_terms: D050940:Betaine-Homocysteine S-Methyltransferase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D057075:Enzyme Assays; D006710:Homocysteine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D006801:Humans; D007700:Kinetics; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013440:Sulfides / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: C576047:5-thia-2,11-diamino-8-methyldodecanedioic acid; C494551:BHMT2 protein, human; D011994:Recombinant Proteins; D013440:Sulfides; D006710:Homocysteine; D050940:Betaine-Homocysteine S-Methyltransferase