Farnesol as a Regulator of HMG-CoA Reductase Degradation: Characterization and Role of Farnesyl Pyrophosphatase

We have recently reported that the isoprenoid compound farnesol accelerates degradation of the cholesterologenic enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, when added to cultured cells. We have thus proposed that farnesol is a required nonsterol regulator of this degradation e...

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Published inArchives of biochemistry and biophysics Vol. 345; no. 1; pp. 1 - 9
Main Authors Meigs, Thomas E., Simoni, Robert D.
Format Journal Article
LanguageEnglish
Published United States Elsevier Inc 01.09.1997
Subjects
Animals
beta-Galactosidase - genetics
CHO Cells
Cricetinae
Edetic Acid - pharmacology
Enzyme Inhibitors - pharmacology
farnesol
Farnesol - pharmacology
FPPase
HMG-CoA reductase
Hydroxymethylglutaryl CoA Reductases - chemistry
Hydroxymethylglutaryl CoA Reductases - metabolism
Magnesium - pharmacology
Mevalonic Acid - pharmacology
Organophosphonates - pharmacology
Phosphinic Acids - pharmacology
protein degradation
Pyrophosphatases - metabolism
Recombinant Fusion Proteins - metabolism
farnesol
HMG-CoA reductase
FPPase
protein degradation
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Summary:We have recently reported that the isoprenoid compound farnesol accelerates degradation of the cholesterologenic enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, when added to cultured cells. We have thus proposed that farnesol is a required nonsterol regulator of this degradation event (T. E. Meigs, D. S. Roseman, and R. D. Simoni, 1996,J. Biol. Chem.271, 7916–7922). In this report, we have studied the enzyme farnesyl pyrophosphatase (FPPase) in Chinese hamster ovary cells. We demonstrate that FPPase activity increases under conditions of increased metabolic flow through the isoprenoid pathway. Also, we show that a nonhydrolyzable analog of farnesyl pyrophosphate, an isoprenoid (phosphinylmethyl)phosphonate, inhibits FPPasein vitro,and when added to cells this inhibitor blocks the mevalonate-dependent, sterol-induced degradation of HMG-CoA reductase. Furthermore, exogenous farnesol overcomes the effect of this inhibitor. These results suggest an isoprenoid-mediated regulatory mechanism governing intracellular farnesol production and support the hypothesis that farnesol is a nonsterol regulator of reductase degradation.
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ISSN:0003-9861
1096-0384
DOI:10.1006/abbi.1997.0200