TY - JOUR
T1 - Double-headed sulfur-linked amino acids as first inhibitors for betaine-homocysteine S -methyltransferase 2
AU - Mládková, Jana
AU - Vaněk, Václav
AU - Buděšínský, Miloš
AU - Elbert, Tomáš
AU - Demianová, Zuzana
AU - Garrow, Timothy A.
AU - Jiráček, Jiří
PY - 2012/8/9
Y1 - 2012/8/9
N2 - 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.
AB - 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.
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U2 - 10.1021/jm300571h
DO - 10.1021/jm300571h
M3 - Article
C2 - 22775318
AN - SCOPUS:84864929477
VL - 55
SP - 6822
EP - 6831
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 15
ER -