A combined experimental and modelling approach for the Weimberg pathway optimisation

Lu Shen, Martha Kohlhaas, Junichi Enoki, Roland Meier, Bernhard Schönenberger, Roland Wohlgemuth, Robert Kourist, Felix Niemeyer, David van Niekerk, Christopher Bräsen, Jochen Niemeyer (), Jacky Snoep () and Bettina Siebers ()
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Lu Shen: University of Duisburg-Essen
Martha Kohlhaas: University of Duisburg-Essen
Junichi Enoki: Ruhr-University Bochum
Roland Meier: Member of Merck Group, Sigma-Aldrich
Bernhard Schönenberger: Member of Merck Group, Sigma-Aldrich
Roland Wohlgemuth: Member of Merck Group, Sigma-Aldrich
Robert Kourist: Ruhr-University Bochum
Felix Niemeyer: University of Duisburg-Essen
David van Niekerk: University of Stellenbosch
Christopher Bräsen: University of Duisburg-Essen
Jochen Niemeyer: University of Duisburg-Essen
Jacky Snoep: University of Stellenbosch
Bettina Siebers: University of Duisburg-Essen

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: Abstract The oxidative Weimberg pathway for the five-step pentose degradation to α-ketoglutarate is a key route for sustainable bioconversion of lignocellulosic biomass to added-value products and biofuels. The oxidative pathway from Caulobacter crescentus has been employed in in-vivo metabolic engineering with intact cells and in in-vitro enzyme cascades. The performance of such engineering approaches is often hampered by systems complexity, caused by non-linear kinetics and allosteric regulatory mechanisms. Here we report an iterative approach to construct and validate a quantitative model for the Weimberg pathway. Two sensitive points in pathway performance have been identified as follows: (1) product inhibition of the dehydrogenases (particularly in the absence of an efficient NAD+ recycling mechanism) and (2) balancing the activities of the dehydratases. The resulting model is utilized to design enzyme cascades for optimized conversion and to analyse pathway performance in C. cresensus cell-free extracts.

Date: 2020
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DOI: 10.1038/s41467-020-14830-y

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