Inhibition of 3-hydroxy-3-methylglutaryl coenzyme A synthase by antibiotic 1233A and other beta-lactones.
3-Hydroxy-3-methylglutaryl CoA synthase was shown to be inhibited in a time-dependent, irreversible manner by compounds containing the substituted beta-lactone functionality found in the natural product 1233A. The rate of inactivation (kinact) was found to approach the rate of catalysis (kcat). The inactivation was irreversible over several hours. A related compound lacking the hydroxymethyl substituent on the beta-lactone ring is a reversible inhibitor and is competitive with respect to acetylCoA. The results are consistent with beta-lactone ring opening by the active site Cys to form an enzyme bound thioester.
Mayer
R J
RJ
Department of Medicinal Chemistry, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406.
Louis-Flamberg
P
P
Elliott
J D
JD
Fisher
M
M
Leber
J
J
D000085:Acetates / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular; D002460:Cell Line; D002792:Cholestyramine Resin / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology*; D006801:Humans; D006904:Hydroxymethylglutaryl-CoA Synthase / Q000037:antagonists & inhibitors*; D007700:Kinetics; D007783:Lactones / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008113:Liver Neoplasms; D008148:Lovastatin / Q000494:pharmacology; D015394:Molecular Structure; D007652:Oxo-Acid-Lyases / Q000037:antagonists & inhibitors*; D051381:Rats; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D000085:Acetates; D000900:Anti-Bacterial Agents; D005231:Fatty Acids, Unsaturated; D007783:Lactones; D002792:Cholestyramine Resin; C054282:antibiotic 1233A; D008148:Lovastatin; D006904:Hydroxymethylglutaryl-CoA Synthase; D007652:Oxo-Acid-Lyases