Cited by 104Fungal and yeast genetics researchMicrobial Metabolic Engineering and BioproductionBiofuel production and bioconversion

An internal deletion in MTH1 enables growth on glucose of pyruvate-decarboxylase negative, non-fermentative Saccharomyces cerevisiae

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Oud, Bart, Flores, Carmen-Lisset, Gancedo, Carlos, Zhang, Xiuying, Trueheart, Joshua, Daran, Jean-Marc, Pronk, Jack T, van Maris, Antonius JA·2012·Microbial Cell Factories

Abstract

Background: Pyruvate-decarboxylase negative (Pdc-) strains of Saccharomyces cerevisiae combine the robustness and high glycolytic capacity of this yeast with the absence of alcoholic fermentation. This makes Pdc- S. cerevisiae an interesting platform for efficient conversion of glucose towards pyruvate-derived products without formation of ethanol as a by-product. However, Pdc- strains cannot grow on high glucose concentrations and require C 2-compounds (ethanol or acetate) for growth under conditions with low glucose concentrations, which hitherto has limited application in industry. Results: Genetic analysis of a Pdc- strain previously evolved to overcome these deficiencies revealed a 225bp in-frame internal deletion in MTH1, encoding a transcriptional regulator involved in glucose sensing. This internal deletion contains a phosphorylation site required for degradation, thereby hypothetically resulting in increased stability of the protein. Reverse engineering of this alternative MTH1 allele into a non-evolved Pdc- strain enabled growth on 20 g l-1 glucose and 0.3% (v/v) ethanol at a maximum specific growth rate (0.24 h-1) similar to that of the evolved Pdc- strain (0.23 h-1). Furthermore, the reverse engineered Pdc- strain grew on glucose as sole carbon source, albeit at a lower specific growth rate (0.10 h-1) than the evolved strain (0.20 h-1). The observation that overexpression of the wild-type MTH1 allele also restored growth of Pdc- S. cerevisiae on glucose is consistent with the hypothesis that the internal deletion results in decreased degradation of Mth1. Reduced degradation of Mth1 has been shown to result in deregulation of hexose transport. In Pdc- strains, reduced glucose uptake may prevent intracellular accumulation of pyruvate and/or redox problems, while release of glucose repression due to the MTH1 internal deletion may contribute to alleviation of the C 2-compound auxotrophy. Conclusions: In this study we have discovered and characterised a mutation in MTH1 enabling Pdc- strains to grow on glucose as the sole carbon source. This successful example of reverse engineering not only increases the understanding of the glucose tolerance of evolved Pdc- S. cerevisiae, but also allows introduction of this portable genetic element into various industrial yeast strains, thereby simplifying metabolic engineering strategies.

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Authors
Oud, B., Flores, C.-L., Gancedo, C., Zhang, X., Trueheart, J., Daran, J.-M., Pronk, J. T., & van Maris, A. J.
Affiliations
  • Delft University of Technology (NL)
  • Instituto de Investigaciones Biomédicas Sols-Morreale (ES)
Venue
Microbial Cell Factories
Published
2012-09-15
Volume
11
Issue
1
Pages
131-131
ISSN
1475-2859 (ISSN-L)
OpenAlex
W2127470474
Cited by
104
References
61
Citations by year
2026: 2 · 2025: 3 · 2024: 5 · 2023: 2 · 2022: 5 · 2021: 24 · 2020: 9 · 2019: 4 · 2018: 7 · 2017: 8 · 2016: 11 · 2015: 7 · 2014: 10 · 2013: 6
FWCI
2.96
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Microbial Cell Factories (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • Research Repository (Delft University of Technology) (submittedVersion, other-oa)
  • Data Archiving and Networked Services (DANS) (submittedVersion, cc-by)
Funders
Ministerio de Ciencia e Innovación
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Microbial Metabolic Engineering and Bioproduction
  • Physical Sciences › Engineering › Biomedical Engineering › Biofuel production and bioconversion
Keywords
MTH1, Saccharomyces cerevisiae, glucose tolerance, glucose detection, transcription factors, protein stability, phosphorylation sites, reverse engineering, glucose repression, ethanol tolerance, glucose uptake, hexose transport, metabolic engineering
MeSH terms
Alleles, Amino Acid Sequence, Fermentation, Glucose, Molecular Sequence Data, Mutation, Pyruvate Decarboxylase, Saccharomyces cerevisiae, Sequence Alignment, Saccharomyces cerevisiae Proteins, Adaptor Proteins, Signal Transducing, Metabolic Engineering

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