Structure-activity study of new inhibitors of human betaine-homocysteine S-methyltransferase.
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.
Vanek
Václav
V
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.
Budesínský
Milos
M
Kabeleová
Petra
P
Sanda
Miloslav
M
Kozísek
Milan
M
Hanclová
Ivona
I
Mládková
Jana
J
Brynda
Jirí
J
Rosenberg
Ivan
I
Koutmos
Markos
M
Garrow
Timothy A
TA
Jirácek
Jirí
J
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
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