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Biotechnology and Bioengineering

Volume 100, Issue 2
Article

Redirection of flux through the FPP branch‐point in Saccharomyces cerevisiae by down‐regulating squalene synthase

Eric M. Paradise

Department of Chemical Engineering, University of California, Berkeley, California 94720

California Institute for Quantitative Biomedical Research (QB3), University of California, Berkeley, California 94720

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James Kirby

California Institute for Quantitative Biomedical Research (QB3), University of California, Berkeley, California 94720

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Rossana Chan

California Institute for Quantitative Biomedical Research (QB3), University of California, Berkeley, California 94720

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Jay D. Keasling

Corresponding Author

E-mail address:keasling@berkeley.edu

Department of Chemical Engineering, University of California, Berkeley, California 94720

California Institute for Quantitative Biomedical Research (QB3), University of California, Berkeley, California 94720

Department of Bioengineering, University of California, Berkeley, California 94720

Synthetic Biology Department, Physical Bioscience Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720

Berkeley Center for Synthetic Biology, University of California, 717 Potter Street, Building 977, Mail Code 3224, Berkeley, California 94720‐3224; telephone: 510‐495‐2620; fax: 510‐495‐2630

Berkeley Center for Synthetic Biology, University of California, 717 Potter Street, Building 977, Mail Code 3224, Berkeley, California 94720‐3224; telephone: 510‐495‐2620; fax: 510‐495‐2630.
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First published: 03 January 2008
https://doi.org/10.1002/bit.21766
Cited by: 73

Abstract

Saccharomyces cerevisiae utilizes several regulatory mechanisms to maintain tight control over the intracellular level of farnesyl diphosphate (FPP), the central precursor to nearly all yeast isoprenoid products. High‐level production of non‐native isoprenoid products requires that FPP flux be diverted from production of sterols to the heterologous metabolic reactions. To do so, expression of the gene encoding squalene synthase (ERG9), the first committed step in sterol biosynthesis, was down‐regulated by replacing its native promoter with the methionine‐repressible MET3 promoter. The intracellular levels of FPP were then assayed by expressing the gene encoding amorphadiene synthase (ADS) and converting the FPP to amorphadiene. Under certain culture conditions amorphadiene production increased fivefold upon ERG9 repression. With increasing flux to amorphadiene, squalene and ergosterol production each decreased. The levels of these three metabolites were dependent not only upon the level of ERG9 repression, but also the timing of its repression relative to the induction of ADS and genes responsible for enhancing flux to FPP. Biotechnol. Bioeng. 2008;99: 371–378. © 2007 Wiley Periodicals, Inc.

Number of times cited: 73

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