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ACS Synth Biol. 2018 Apr 20;7(4):995-1003. doi: 10.1021/acssynbio.7b00439. Epub 2018 Apr 5.

An Orthogonal and pH-Tunable Sensor-Selector for Muconic Acid Biosynthesis in Yeast.

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Novo Nordisk Foundation Center for Biosustainability , Technical University of Denmark , 2800 Kgs. Lyngby , Denmark.
Joint BioEnergy Institute , Emeryville , California 94608 , United States.
Biological Systems and Engineering Division , Lawrence Berkeley National Laboratory , Berkeley , California 94720 , United States.
Department of Chemical and Biomolecular Engineering & Department of Bioengineering , University of California , Berkeley , California 94720 , United States.


Microbes offer enormous potential for production of industrially relevant chemicals and therapeutics, yet the rapid identification of high-producing microbes from large genetic libraries is a major bottleneck in modern cell factory development. Here, we develop and apply a synthetic selection system in Saccharomyces cerevisiae that couples the concentration of muconic acid, a plastic precursor, to cell fitness by using the prokaryotic transcriptional regulator BenM driving an antibiotic resistance gene. We show that the sensor-selector does not affect production nor fitness, and find that tuning pH of the cultivation medium limits the rise of nonproducing cheaters. We apply the sensor-selector to selectively enrich for best-producing variants out of a large library of muconic acid production strains, and identify an isolate that produces more than 2 g/L muconic acid in a bioreactor. We expect that this sensor-selector can aid the development of other synthetic selection systems based on allosteric transcription factors.


biosensor; evolution; metabolic engineering; sustainability; transcriptional activator; yeast


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