Isoprenoid Alcohols Restore Protein Isoprenylation in a Time-Dependent Manner Independent of Protein Synthesis

Susan E. Ownby, Raymond Hohl

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Mevalonic acid derivatives are required for the isoprenylation of a variety of growth-regulating proteins. Treatment of NIH3T3 cells with lovastatin (LOV), an HMG-CoA reductase inhibitor, depletes cells of these derivatives and impairs isoprenylation of RAS and RAS-related proteins. In LOV-treated cells, farnesol (FOH) and geranylgeraniol (GGOH) restore RAS and Rapl isoprenylation, respectively. In this study, we further characterize the manner in which these isoprenoid alcohols are utilized for protein isoprenylation. Over a 48-h time span, FOH is unable to maintain RAS isoprenylation in the continuing presence of LOV, whereas GGOH is able to maintain Rap1 isoprenylation in the presence of LOV at all times tested. When cells are pretreated with LOV, the ability of both FOH and GGOH to restore protein isoprenylation is time dependent; as the LOV pretreatment time increases, the time required for FOH and GGOH to restore isoprenylation also increases. Despite this time dependence, the ability of FOH and GGOH to restore protein isoprenylation is not dependent on new protein synthesis and does not require alcohol dehydrogenase. These data support the existence of and further characterize the isoprenoid shunt, a novel metabolic pathway that utilizes FOH and GGOH for protein isoprenylation. The enzymes of the isoprenoid shunt are constitutively expressed, their activity may be modulated by isoprenoid depletion, and they are differentially regulated.

Original languageEnglish (US)
Pages (from-to)751-759
Number of pages9
JournalLipids
Volume38
Issue number7
DOIs
StatePublished - Jul 1 2003

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Protein Prenylation
Prenylation
Lovastatin
Terpenes
Alcohols
Proteins
Farnesol
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Mevalonic Acid
Derivatives
Alcohol Dehydrogenase
Metabolic Networks and Pathways
Cells
Enzymes
Growth

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Organic Chemistry
  • Cell Biology

Cite this

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abstract = "Mevalonic acid derivatives are required for the isoprenylation of a variety of growth-regulating proteins. Treatment of NIH3T3 cells with lovastatin (LOV), an HMG-CoA reductase inhibitor, depletes cells of these derivatives and impairs isoprenylation of RAS and RAS-related proteins. In LOV-treated cells, farnesol (FOH) and geranylgeraniol (GGOH) restore RAS and Rapl isoprenylation, respectively. In this study, we further characterize the manner in which these isoprenoid alcohols are utilized for protein isoprenylation. Over a 48-h time span, FOH is unable to maintain RAS isoprenylation in the continuing presence of LOV, whereas GGOH is able to maintain Rap1 isoprenylation in the presence of LOV at all times tested. When cells are pretreated with LOV, the ability of both FOH and GGOH to restore protein isoprenylation is time dependent; as the LOV pretreatment time increases, the time required for FOH and GGOH to restore isoprenylation also increases. Despite this time dependence, the ability of FOH and GGOH to restore protein isoprenylation is not dependent on new protein synthesis and does not require alcohol dehydrogenase. These data support the existence of and further characterize the isoprenoid shunt, a novel metabolic pathway that utilizes FOH and GGOH for protein isoprenylation. The enzymes of the isoprenoid shunt are constitutively expressed, their activity may be modulated by isoprenoid depletion, and they are differentially regulated.",
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Isoprenoid Alcohols Restore Protein Isoprenylation in a Time-Dependent Manner Independent of Protein Synthesis. / Ownby, Susan E.; Hohl, Raymond.

In: Lipids, Vol. 38, No. 7, 01.07.2003, p. 751-759.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Isoprenoid Alcohols Restore Protein Isoprenylation in a Time-Dependent Manner Independent of Protein Synthesis

AU - Ownby, Susan E.

AU - Hohl, Raymond

PY - 2003/7/1

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N2 - Mevalonic acid derivatives are required for the isoprenylation of a variety of growth-regulating proteins. Treatment of NIH3T3 cells with lovastatin (LOV), an HMG-CoA reductase inhibitor, depletes cells of these derivatives and impairs isoprenylation of RAS and RAS-related proteins. In LOV-treated cells, farnesol (FOH) and geranylgeraniol (GGOH) restore RAS and Rapl isoprenylation, respectively. In this study, we further characterize the manner in which these isoprenoid alcohols are utilized for protein isoprenylation. Over a 48-h time span, FOH is unable to maintain RAS isoprenylation in the continuing presence of LOV, whereas GGOH is able to maintain Rap1 isoprenylation in the presence of LOV at all times tested. When cells are pretreated with LOV, the ability of both FOH and GGOH to restore protein isoprenylation is time dependent; as the LOV pretreatment time increases, the time required for FOH and GGOH to restore isoprenylation also increases. Despite this time dependence, the ability of FOH and GGOH to restore protein isoprenylation is not dependent on new protein synthesis and does not require alcohol dehydrogenase. These data support the existence of and further characterize the isoprenoid shunt, a novel metabolic pathway that utilizes FOH and GGOH for protein isoprenylation. The enzymes of the isoprenoid shunt are constitutively expressed, their activity may be modulated by isoprenoid depletion, and they are differentially regulated.

AB - Mevalonic acid derivatives are required for the isoprenylation of a variety of growth-regulating proteins. Treatment of NIH3T3 cells with lovastatin (LOV), an HMG-CoA reductase inhibitor, depletes cells of these derivatives and impairs isoprenylation of RAS and RAS-related proteins. In LOV-treated cells, farnesol (FOH) and geranylgeraniol (GGOH) restore RAS and Rapl isoprenylation, respectively. In this study, we further characterize the manner in which these isoprenoid alcohols are utilized for protein isoprenylation. Over a 48-h time span, FOH is unable to maintain RAS isoprenylation in the continuing presence of LOV, whereas GGOH is able to maintain Rap1 isoprenylation in the presence of LOV at all times tested. When cells are pretreated with LOV, the ability of both FOH and GGOH to restore protein isoprenylation is time dependent; as the LOV pretreatment time increases, the time required for FOH and GGOH to restore isoprenylation also increases. Despite this time dependence, the ability of FOH and GGOH to restore protein isoprenylation is not dependent on new protein synthesis and does not require alcohol dehydrogenase. These data support the existence of and further characterize the isoprenoid shunt, a novel metabolic pathway that utilizes FOH and GGOH for protein isoprenylation. The enzymes of the isoprenoid shunt are constitutively expressed, their activity may be modulated by isoprenoid depletion, and they are differentially regulated.

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