Inhibition of a plant sesquiterpene cyclase by mevinolin

Urs Vögeli; Joseph Chappell

doi:10.1016/0003-9861(91)90178-L

Inhibition of a plant sesquiterpene cyclase by mevinolin

Urs Vögeli, Joseph Chappell

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8 Scopus citations

Abstract

The specificity of mevinolin as an inhibitor of sterol and sesquiterpene metabolism in tobacco cell suspension cultures was examined. Exogenous mevinolin inhibited [¹⁴C]acetate, but not [³H]mevalonate incorporation into free sterols. In contrast, mevinolin inhibited the incorporation of both [¹⁴C]acetate and [³H]mevalonate into capsidiol, an extracellular sesquiterpene. Microsomal 3-hydroxy-3-methylglutaryl Coenzyme A reductase was inhibited greater than 90% by 3 μm mevinolin, while squalene synthetase was insensitive to even 600 μm mevinolin. Sesquiterpene cyclase, the first branch point enzyme specific for sesquiterpene biosynthesis, was inhibited in a dose-dependent manner by mevinolin with a 50% reduction in activity at 100 μm. Kinetic analysis indicated that the mechanism for inhibition was complex with mevinolin acting as both a competitive and noncompetitive inhibitor. The results suggest that the mevinolin inhibition of [³H]mevalonate incorporation into extracellular sesquiterpenes can, in part, be attributed to a secondary, but specific, site of inhibition, the sesquiterpene cyclase.

Original language	English
Pages (from-to)	157-162
Number of pages	6
Journal	Archives of Biochemistry and Biophysics
Volume	288
Issue number	1
DOIs	https://doi.org/10.1016/0003-9861(91)90178-L
State	Published - Jul 1991

Bibliographical note

Funding Information:
’ Supported by the Kentucky Agricultural Experiment Station, a co-operative grant from the USDA, and NSF Grant DCB-8806273. This is journal paper 90-3-153 of the Kentucky Agricultural Experiment Station. ’ Current address: Dr. R. Maag Ltd., Agrochemicals, CH-8157 Diels-dorf, Switzerland. 3 Abbreviations used: HMGR, 3-hydroxy-3-methylglutaryl Coenzyme A reductase; DTT, dithiothreitol; FPP, farnesyl diphosphate; DMSO, dimethyl sulfoxide; BSA, bovine serum albumin.

ASJC Scopus subject areas

Biophysics
Biochemistry
Molecular Biology

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10.1016/0003-9861(91)90178-L

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title = "Inhibition of a plant sesquiterpene cyclase by mevinolin",

abstract = "The specificity of mevinolin as an inhibitor of sterol and sesquiterpene metabolism in tobacco cell suspension cultures was examined. Exogenous mevinolin inhibited [14C]acetate, but not [3H]mevalonate incorporation into free sterols. In contrast, mevinolin inhibited the incorporation of both [14C]acetate and [3H]mevalonate into capsidiol, an extracellular sesquiterpene. Microsomal 3-hydroxy-3-methylglutaryl Coenzyme A reductase was inhibited greater than 90% by 3 μm mevinolin, while squalene synthetase was insensitive to even 600 μm mevinolin. Sesquiterpene cyclase, the first branch point enzyme specific for sesquiterpene biosynthesis, was inhibited in a dose-dependent manner by mevinolin with a 50% reduction in activity at 100 μm. Kinetic analysis indicated that the mechanism for inhibition was complex with mevinolin acting as both a competitive and noncompetitive inhibitor. The results suggest that the mevinolin inhibition of [3H]mevalonate incorporation into extracellular sesquiterpenes can, in part, be attributed to a secondary, but specific, site of inhibition, the sesquiterpene cyclase.",

author = "Urs V{\"o}geli and Joseph Chappell",

note = "Funding Information: {\textquoteright} Supported by the Kentucky Agricultural Experiment Station, a co-operative grant from the USDA, and NSF Grant DCB-8806273. This is journal paper 90-3-153 of the Kentucky Agricultural Experiment Station. {\textquoteright} Current address: Dr. R. Maag Ltd., Agrochemicals, CH-8157 Diels-dorf, Switzerland. 3 Abbreviations used: HMGR, 3-hydroxy-3-methylglutaryl Coenzyme A reductase; DTT, dithiothreitol; FPP, farnesyl diphosphate; DMSO, dimethyl sulfoxide; BSA, bovine serum albumin.",

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N1 - Funding Information: ’ Supported by the Kentucky Agricultural Experiment Station, a co-operative grant from the USDA, and NSF Grant DCB-8806273. This is journal paper 90-3-153 of the Kentucky Agricultural Experiment Station. ’ Current address: Dr. R. Maag Ltd., Agrochemicals, CH-8157 Diels-dorf, Switzerland. 3 Abbreviations used: HMGR, 3-hydroxy-3-methylglutaryl Coenzyme A reductase; DTT, dithiothreitol; FPP, farnesyl diphosphate; DMSO, dimethyl sulfoxide; BSA, bovine serum albumin.

PY - 1991/7

Y1 - 1991/7

N2 - The specificity of mevinolin as an inhibitor of sterol and sesquiterpene metabolism in tobacco cell suspension cultures was examined. Exogenous mevinolin inhibited [14C]acetate, but not [3H]mevalonate incorporation into free sterols. In contrast, mevinolin inhibited the incorporation of both [14C]acetate and [3H]mevalonate into capsidiol, an extracellular sesquiterpene. Microsomal 3-hydroxy-3-methylglutaryl Coenzyme A reductase was inhibited greater than 90% by 3 μm mevinolin, while squalene synthetase was insensitive to even 600 μm mevinolin. Sesquiterpene cyclase, the first branch point enzyme specific for sesquiterpene biosynthesis, was inhibited in a dose-dependent manner by mevinolin with a 50% reduction in activity at 100 μm. Kinetic analysis indicated that the mechanism for inhibition was complex with mevinolin acting as both a competitive and noncompetitive inhibitor. The results suggest that the mevinolin inhibition of [3H]mevalonate incorporation into extracellular sesquiterpenes can, in part, be attributed to a secondary, but specific, site of inhibition, the sesquiterpene cyclase.

AB - The specificity of mevinolin as an inhibitor of sterol and sesquiterpene metabolism in tobacco cell suspension cultures was examined. Exogenous mevinolin inhibited [14C]acetate, but not [3H]mevalonate incorporation into free sterols. In contrast, mevinolin inhibited the incorporation of both [14C]acetate and [3H]mevalonate into capsidiol, an extracellular sesquiterpene. Microsomal 3-hydroxy-3-methylglutaryl Coenzyme A reductase was inhibited greater than 90% by 3 μm mevinolin, while squalene synthetase was insensitive to even 600 μm mevinolin. Sesquiterpene cyclase, the first branch point enzyme specific for sesquiterpene biosynthesis, was inhibited in a dose-dependent manner by mevinolin with a 50% reduction in activity at 100 μm. Kinetic analysis indicated that the mechanism for inhibition was complex with mevinolin acting as both a competitive and noncompetitive inhibitor. The results suggest that the mevinolin inhibition of [3H]mevalonate incorporation into extracellular sesquiterpenes can, in part, be attributed to a secondary, but specific, site of inhibition, the sesquiterpene cyclase.

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Inhibition of a plant sesquiterpene cyclase by mevinolin

Abstract

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