Document Detail


Double-headed sulfur-linked amino acids as first inhibitors for betaine-homocysteine S-methyltransferase 2.
MedLine Citation:
PMID:  22775318     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Jana Mládková; Václav Vaněk; Miloš Buděšínský; Tomáš Elbert; Zuzana Demianová; Timothy A Garrow; Jiří Jiráček
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-07-18
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  55     ISSN:  1520-4804     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2012 Aug 
Date Detail:
Created Date:  2012-08-09     Completed Date:  2012-11-05     Revised Date:  2012-12-18    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  6822-31     Citation Subset:  IM    
Affiliation:
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.
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MeSH Terms
Descriptor/Qualifier:
Betaine-Homocysteine S-Methyltransferase / antagonists & inhibitors*,  chemistry
Enzyme Assays
Homocysteine / analogs & derivatives*,  chemical synthesis,  chemistry
Humans
Kinetics
Recombinant Proteins / antagonists & inhibitors
Stereoisomerism
Structure-Activity Relationship
Sulfides / chemical synthesis*,  chemistry
Chemical
Reg. No./Substance:
0/5-thia-2,11-diamino-8-methyldodecanedioic acid; 0/BHMT2 protein, human; 0/Recombinant Proteins; 0/Sulfides; 454-28-4/Homocysteine; EC 2.1.1.5/Betaine-Homocysteine S-Methyltransferase
Comments/Corrections
Erratum In:
J Med Chem. 2012 Oct 25;55(20):8974

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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