Auxin-mediated protein depletion for metabolic engineering in terpene-producing yeast

Zeyu Lu, Bingyin Peng (), Birgitta E. Ebert, Geoff Dumsday and Claudia E. Vickers ()
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Zeyu Lu: the University of Queensland
Bingyin Peng: the University of Queensland
Birgitta E. Ebert: the University of Queensland
Geoff Dumsday: CSIRO Manufacturing
Claudia E. Vickers: the University of Queensland

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract In metabolic engineering, loss-of-function experiments are used to understand and optimise metabolism. A conditional gene inactivation tool is required when gene deletion is lethal or detrimental to growth. Here, we exploit auxin-inducible protein degradation as a metabolic engineering approach in yeast. We demonstrate its effectiveness using terpenoid production. First, we target an essential prenyl-pyrophosphate metabolism protein, farnesyl pyrophosphate synthase (Erg20p). Degradation successfully redirects metabolic flux toward monoterpene (C10) production. Second, depleting hexokinase-2, a key protein in glucose signalling transduction, lifts glucose repression and boosts production of sesquiterpene (C15) nerolidol to 3.5 g L−1 in flask cultivation. Third, depleting acetyl-CoA carboxylase (Acc1p), another essential protein, delivers growth arrest without diminishing production capacity in nerolidol-producing yeast, providing a strategy to decouple growth and production. These studies demonstrate auxin-mediated protein degradation as an advanced tool for metabolic engineering. It also has potential for broader metabolic perturbation studies to better understand metabolism.

Date: 2021
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DOI: 10.1038/s41467-021-21313-1

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