Adaptive laboratory evolution of tolerance to dicarboxylic acids in Saccharomyces cerevisiae

Rui Pereira, Yongjun Wei, Elsayed Tharwat Tolba Mohamed, Mohammad Radi, Carl Malina, Markus J. Herrgård, Adam M. Feist, Jens Nielsen, Yun Chen*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

Improving the growth phenotypes of microbes in high product concentrations is an essential design objective in the development of robust cell factories. However, the limited knowledge regarding tolerance mechanisms makes rational design of such traits complicated. Here, adaptive laboratory evolution was used to explore the tolerance mechanisms that Saccharomyces cerevisiae can evolve in the presence of inhibiting concentrations of three dicarboxylic acids: glutaric acid, adipic acid and pimelic acid. Whole-genome sequencing of tolerant mutants enabled the discovery of the genetic changes behind tolerance and most mutations could be linked to the up-regulation of multidrug resistance transporters. The amplification of QDR3, in particular, was shown to confer tolerance not only to the three dicarboxylic acids investigated, but also towards muconic acid and glutaconic acid. In addition to increased acid tolerance, QDR3 overexpression also improved the production of muconic acid in the context of a strain engineered for producing this compound.
Original languageEnglish
JournalMetabolic Engineering
Volume56
Pages (from-to)130-141
Number of pages12
ISSN1096-7176
DOIs
Publication statusPublished - 2019

Keywords

  • Adaptive laboratory evolution
  • Dicarboxylic acid
  • Multidrug resistance transporter

Cite this

Pereira, Rui ; Wei, Yongjun ; Mohamed, Elsayed Tharwat Tolba ; Radi, Mohammad ; Malina, Carl ; Herrgård, Markus J. ; Feist, Adam M. ; Nielsen, Jens ; Chen, Yun. / Adaptive laboratory evolution of tolerance to dicarboxylic acids in Saccharomyces cerevisiae. In: Metabolic Engineering. 2019 ; Vol. 56. pp. 130-141.
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abstract = "Improving the growth phenotypes of microbes in high product concentrations is an essential design objective in the development of robust cell factories. However, the limited knowledge regarding tolerance mechanisms makes rational design of such traits complicated. Here, adaptive laboratory evolution was used to explore the tolerance mechanisms that Saccharomyces cerevisiae can evolve in the presence of inhibiting concentrations of three dicarboxylic acids: glutaric acid, adipic acid and pimelic acid. Whole-genome sequencing of tolerant mutants enabled the discovery of the genetic changes behind tolerance and most mutations could be linked to the up-regulation of multidrug resistance transporters. The amplification of QDR3, in particular, was shown to confer tolerance not only to the three dicarboxylic acids investigated, but also towards muconic acid and glutaconic acid. In addition to increased acid tolerance, QDR3 overexpression also improved the production of muconic acid in the context of a strain engineered for producing this compound.",
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Adaptive laboratory evolution of tolerance to dicarboxylic acids in Saccharomyces cerevisiae. / Pereira, Rui; Wei, Yongjun; Mohamed, Elsayed Tharwat Tolba; Radi, Mohammad; Malina, Carl; Herrgård, Markus J.; Feist, Adam M.; Nielsen, Jens; Chen, Yun.

In: Metabolic Engineering, Vol. 56, 2019, p. 130-141.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Adaptive laboratory evolution of tolerance to dicarboxylic acids in Saccharomyces cerevisiae

AU - Pereira, Rui

AU - Wei, Yongjun

AU - Mohamed, Elsayed Tharwat Tolba

AU - Radi, Mohammad

AU - Malina, Carl

AU - Herrgård, Markus J.

AU - Feist, Adam M.

AU - Nielsen, Jens

AU - Chen, Yun

PY - 2019

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N2 - Improving the growth phenotypes of microbes in high product concentrations is an essential design objective in the development of robust cell factories. However, the limited knowledge regarding tolerance mechanisms makes rational design of such traits complicated. Here, adaptive laboratory evolution was used to explore the tolerance mechanisms that Saccharomyces cerevisiae can evolve in the presence of inhibiting concentrations of three dicarboxylic acids: glutaric acid, adipic acid and pimelic acid. Whole-genome sequencing of tolerant mutants enabled the discovery of the genetic changes behind tolerance and most mutations could be linked to the up-regulation of multidrug resistance transporters. The amplification of QDR3, in particular, was shown to confer tolerance not only to the three dicarboxylic acids investigated, but also towards muconic acid and glutaconic acid. In addition to increased acid tolerance, QDR3 overexpression also improved the production of muconic acid in the context of a strain engineered for producing this compound.

AB - Improving the growth phenotypes of microbes in high product concentrations is an essential design objective in the development of robust cell factories. However, the limited knowledge regarding tolerance mechanisms makes rational design of such traits complicated. Here, adaptive laboratory evolution was used to explore the tolerance mechanisms that Saccharomyces cerevisiae can evolve in the presence of inhibiting concentrations of three dicarboxylic acids: glutaric acid, adipic acid and pimelic acid. Whole-genome sequencing of tolerant mutants enabled the discovery of the genetic changes behind tolerance and most mutations could be linked to the up-regulation of multidrug resistance transporters. The amplification of QDR3, in particular, was shown to confer tolerance not only to the three dicarboxylic acids investigated, but also towards muconic acid and glutaconic acid. In addition to increased acid tolerance, QDR3 overexpression also improved the production of muconic acid in the context of a strain engineered for producing this compound.

KW - Adaptive laboratory evolution

KW - Dicarboxylic acid

KW - Multidrug resistance transporter

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