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A photo-switchable yeast isocitrate dehydrogenase to control metabolic flux through the citric acid cycle

Haoqi Chen, Lianne Mulder, Hein J. Wijma, Ronja Wabeke, Jose Pedro Vila Cha Losa, Mattia Rovetta, Tijn Caspar de Leeuw, Andreas Millias-Argeitis, View ORCID ProfileMatthias Heinemann
doi: https://doi.org/10.1101/2021.05.25.445643
Haoqi Chen
1Molecular Systems Biology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands
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Lianne Mulder
1Molecular Systems Biology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands
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Hein J. Wijma
2Biocatalysis and Biotransformation, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands
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Ronja Wabeke
1Molecular Systems Biology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands
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Jose Pedro Vila Cha Losa
1Molecular Systems Biology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands
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Mattia Rovetta
1Molecular Systems Biology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands
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Tijn Caspar de Leeuw
1Molecular Systems Biology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands
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Andreas Millias-Argeitis
1Molecular Systems Biology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands
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Matthias Heinemann
1Molecular Systems Biology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands
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  • ORCID record for Matthias Heinemann
  • For correspondence: m.heinemann@rug.nl
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Abstract

For various research questions in metabolism, it is highly desirable to have means available, with which the flux through specific pathways can be perturbed dynamically, in a reversible manner, and at a timescale that is consistent with the fast turnover rates of metabolism. Optogenetics, in principle, offers such possibility. Here, we developed an initial version of a photo-switchable isocitrate dehydrogenase (IDH) aimed at controlling the metabolic flux through the citric acid cycle in budding yeast. By inserting a protein-based light switch (LOV2) into computationally identified active/regulatory-coupled sites of IDH and by using in vivo screening in Saccharomyces cerevisiae, we obtained a number of IDH enzymes whose activity can be switched by light. Subsequent in-vivo characterization and optimization resulted in an initial version of photo-switchable (PS) IDH. While further improvements of the enzyme are necessary, our study demonstrates the efficacy of the overall approach from computational design, via in vivo screening and characterization. It also represents one of the first few examples, where optogenetics were used to control the activity of a metabolic enzyme.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted May 25, 2021.
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A photo-switchable yeast isocitrate dehydrogenase to control metabolic flux through the citric acid cycle
Haoqi Chen, Lianne Mulder, Hein J. Wijma, Ronja Wabeke, Jose Pedro Vila Cha Losa, Mattia Rovetta, Tijn Caspar de Leeuw, Andreas Millias-Argeitis, Matthias Heinemann
bioRxiv 2021.05.25.445643; doi: https://doi.org/10.1101/2021.05.25.445643
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A photo-switchable yeast isocitrate dehydrogenase to control metabolic flux through the citric acid cycle
Haoqi Chen, Lianne Mulder, Hein J. Wijma, Ronja Wabeke, Jose Pedro Vila Cha Losa, Mattia Rovetta, Tijn Caspar de Leeuw, Andreas Millias-Argeitis, Matthias Heinemann
bioRxiv 2021.05.25.445643; doi: https://doi.org/10.1101/2021.05.25.445643

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