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Mechanism of the inhibition of cholesterol biosynthesis by 6-fluoromevalonate.

Authors
  • Nave, J F
  • d'Orchymont, H
  • Ducep, J B
  • Piriou, F
  • Jung, M J
Type
Published Article
Journal
The Biochemical journal
Publication Date
Apr 01, 1985
Volume
227
Issue
1
Pages
247–254
Identifiers
PMID: 2986604
Source
Medline
License
Unknown

Abstract

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.

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