Mechanism of the inhibition of cholesterol biosynthesis by 6-fluoromevalonate.
6-Fluoromevalonate blocks the incorporation of mevalonic acid, but not that of isopentenyl pyrophosphate, into non-saponifiable lipids in a rat liver multienzyme system. With 3H-labelled 6-fluoromevalonate, it was found that 6-fluoromevalonate is converted to its phospho and pyrophospho derivatives in this system. The kinetics of the two kinases were studied. 6-Fluoromevalonate 5-pyrophosphate is a potent competitive inhibitor of pyrophosphomevalonate decarboxylase (Ki 37 nM). In the multienzyme assay for cholesterol biosynthesis, there is accumulation of mevalonate 5-phosphate and mevalonate 5-pyrophosphate in the presence of 5 microM-6-fluoromevalonate, and 6-fluoromevalonate 5-pyrophosphate is more effective than 6-fluoromevalonate in inhibiting cholesterol biosynthesis. We suggest therefore that 6-fluoromevalonate blocks cholesterol biosynthesis at the level of pyrophosphomevalonate decarboxylase after being pyrophosphorylated.
Nave
J F
JF
d'Orchymont
H
H
Ducep
J B
JB
Piriou
F
F
Jung
M J
MJ
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D002262:Carboxy-Lyases / Q000037:antagonists & inhibitors; D002784:Cholesterol / Q000096:biosynthesis*; D002855:Chromatography, Thin Layer; D045782:Hemiterpenes; D066298:In Vitro Techniques; D007700:Kinetics; D008055:Lipids / Q000096:biosynthesis; D008099:Liver / Q000378:metabolism*; D008798:Mevalonic Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D009943:Organophosphorus Compounds / Q000378:metabolism; D010770:Phosphotransferases / Q000037:antagonists & inhibitors; D017853:Phosphotransferases (Alcohol Group Acceptor); D017856:Phosphotransferases (Phosphate Group Acceptor); D051381:Rats; D011919:Rats, Inbred Strains
D000924:Anticholesteremic Agents; D045782:Hemiterpenes; D008055:Lipids; D009943:Organophosphorus Compounds; C045174:6-fluoromevalonolactone; C004809:isopentenyl pyrophosphate; C045175:6-fluoromevalonate-5-pyrophosphate; D002784:Cholesterol; D010770:Phosphotransferases; D017853:Phosphotransferases (Alcohol Group Acceptor); C021796:mevalonate kinase; D017856:Phosphotransferases (Phosphate Group Acceptor); C022371:phosphomevalonate kinase; D002262:Carboxy-Lyases; C022503:pyrophosphomevalonate decarboxylase; D008798:Mevalonic Acid