title: Structure-activity study of new inhibitors of human betaine-homocysteine S-methyltransferase.
abstract: Betaine-homocysteine S-methyltransferase (BHMT) catalyzes the transfer of a methyl group from betaine to l-homocysteine, yielding dimethylglycine and l-methionine. In this study, we prepared a new series of BHMT inhibitors. The inhibitors were designed to mimic the hypothetical transition state of BHMT substrates and consisted of analogues with NH, N(CH(3)), or N(CH(3))(2) groups separated from the homocysteine sulfur atom by a methylene, ethylene, or a propylene spacer. Only the inhibitor with the N(CH(3)) moiety and ethylene spacer gave moderate inhibition. This result led us to prepare two inhibitors lacking a nitrogen atom in the S-linked alkyl chain: (RS,RS)-5-(3-amino-3-carboxypropylthio)-3-methylpentanoic acid and (RS)-5-(3-amino-3-carboxypropylthio)-3,3-dimethylpentanoic acid. Both of these compounds were highly potent inhibitors of BHMT. The finding that BHMT does not tolerate a true betaine mimic within these inhibitors, especially the nitrogen atom, is surprising and evokes questions about putative conformational changes of BHMT upon the binding of the substrates/products and inhibitors.
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo nam. 2, 166 10 Prague 6, Czech Republic.
authors.forename: Václav
authors.initials: V
authors.lastname: Vanek
authors.forename: Milos
authors.initials: M
authors.lastname: Budesínský
authors.forename: Petra
authors.initials: P
authors.lastname: Kabeleová
authors.forename: Miloslav
authors.initials: M
authors.lastname: Sanda
authors.forename: Milan
authors.initials: M
authors.lastname: Kozísek
authors.forename: Ivona
authors.initials: I
authors.lastname: Hanclová
authors.forename: Jana
authors.initials: J
authors.lastname: Mládková
authors.forename: Jirí
authors.initials: J
authors.lastname: Brynda
authors.forename: Ivan
authors.initials: I
authors.lastname: Rosenberg
authors.forename: Markos
authors.initials: M
authors.lastname: Koutmos
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Garrow
authors.forename: Jirí
authors.initials: J
authors.lastname: Jirácek
mesh_terms: D050940:Betaine-Homocysteine S-Methyltransferase / Q000037:antagonists & inhibitors*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006710:Homocysteine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D015394:Molecular Structure; D010421:Pentanoic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C541934:5-(3-amino-3-carboxypropylthio)-3,3-dimethylpentanoic acid; C541933:5-(3-amino-3-carboxypropylthio)-3-methylpentanoic acid; D004791:Enzyme Inhibitors; D010421:Pentanoic Acids; D006710:Homocysteine; D050940:Betaine-Homocysteine S-Methyltransferase