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Pathway and organelle engineering for production of useful chemicals in yeast

  • Author(s): Grewal, Parbir
  • Advisor(s): Dueber, John E
  • Clark, Douglas S
  • et al.
Abstract

Researchers in the field of metabolic engineering aim to develop processes to produce

useful chemicals, sustainably and responsibly, using biotechnology. These processes are

often designed to replace products derived from fossil fuels, which are unsustainable and

contribute to climate change, or plant-based products, which compete with food

production for scarce land and are subject to supply uncertainty due to weather, crop

disease, and climate change. Here, we present two research projects in metabolic

engineering. First, we demonstrate microbial production of the red food dye betanin by

engineering the betalain biosynthesis pathway into yeast. Betanin is currently

manufactured through extraction from red beets specifically grown for dye production.

We achieved betanin production levels of 17 mg/L, which is equivalent to the amount of

betanin found in 10 g/L of beet extract. With further production improvements, this

bioprocess may become cost-competitive with agricultural production and is likely to

lead to a purer product. We also demonstrate the synthesis of a suite of non-natural

betalain dyes achieved through feeding of diverse amines to a yeast production host,

including several which have never been reported. In the second research project, we

discover that an enzyme that limits production levels of a drug family is toxic to the yeast

production host. This enzyme, norcoclaurine synthase, is critical to the production of

benzylisoquinoline alkaloids, an important family of medicines that are extracted from

plants like the opium poppy. We devised a novel subcellular compartmentalization

strategy, sequestering norcoclaurine synthase in the peroxisome to alleviate cytotoxicity

while maintaining access to the enzyme’s substrates. By targeting norcoclaurine synthase

for organellar compartmentalization, we achieved improved cell growth, final titer, and

culture productivity. These projects highlight the potential of engineering complex plant

pathways into microbial hosts for economical and sustainable chemical production.

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