Inducible Synthetic Growth Regulation Using the ClpXP Proteasome Enhances cis,cis-Muconic Acid and Glycolic Acid Yields in Saccharomyces cerevisiae

Natalia Kakko, Anssi Rantasalo, Tino Koponen, Virve Vidgren, Matti Kannisto, Natalia Maiorova, Heli Nygren, Dominik Mojzita, Merja Penttilä, Paula Jouhten (Corresponding Author)

Research output: Contribution to journalArticleScientificpeer-review

1 Citation (Scopus)

Abstract

Engineered microbial cells can produce sustainable chemistry, but the production competes for resources with growth. Inducible synthetic control over the resource use would enable fast accumulation of sufficient biomass and then divert the resources to production. We developed inducible synthetic resource-use control overSaccharomyces cerevisiae by expressing a bacterial ClpXP proteasome from an inducible promoter. By individually targeting growth-essential metabolic enzymes Aro1, Hom3, and Acc1 to the ClpXP proteasome, cell growth could be efficiently repressed during cultivation. The ClpXP proteasome was specific to the target proteins, and there was no reduction in the targets when ClpXP was not induced. The inducible growth repression improved product yields from glucose (cis,cis-muconic acid) and per biomass (cis,cis-muconic acid and glycolic acid). The inducible ClpXP proteasome tackles uncertainties in strain optimization by enabling model-guided repression of competing, growth-essential, and metabolic enzymes. Most importantly, it allows improving production without compromising biomass accumulation when uninduced; therefore, it is expected to mitigate strain stability and low productivity challenges.
Original languageEnglish
Pages (from-to)1021-1033
JournalACS Synthetic Biology
Volume12
Issue number4
DOIs
Publication statusPublished - 21 Apr 2023
MoE publication typeA1 Journal article-refereed

Funding

Paula Jouhten acknowledges funding from the Academy of Finland (decision numbers 310514, 314125, 335783, 352410, and 352412). Natalia Kakko and Merja Penttilä acknowledge funding from the Jenny and Antti Wihuri Foundation (for the Center for Young Synbio Scientists).

Keywords

  • cis,cis-muconic acid
  • ClpXP proteasome
  • glycolic acid
  • Saccharomyces cerevisiae
  • synthetic regulation
  • Metabolic Engineering
  • Saccharomyces cerevisiae/metabolism
  • Proteasome Endopeptidase Complex/genetics
  • Saccharomyces cerevisiae Proteins/genetics

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