Synergistic substrate cofeeding stimulates reductive metabolism

Nature Metabolism
Junyoung O ParkGregory Stephanopoulos

Abstract

Advanced bioproduct synthesis via reductive metabolism requires coordinating carbons, ATP and reducing agents, which are generated with varying efficiencies depending on metabolic pathways. Substrate mixtures with direct access to multiple pathways may optimally satisfy these biosynthetic requirements. However, native regulation favouring preferential use precludes cells from co-metabolizing multiple substrates. Here we explore mixed substrate metabolism and tailor pathway usage to synergistically stimulate carbon reduction. By controlled cofeeding of superior ATP and NADPH generators as 'dopant' substrates to cells primarily using inferior substrates, we circumvent catabolite repression and drive synergy in two divergent organisms. Glucose doping in Moorella thermoacetica stimulates CO2 reduction (2.3 g gCDW-1 h-1) into acetate by augmenting ATP synthesis via pyruvate kinase. Gluconate doping in Yarrowia lipolytica accelerates acetate-driven lipogenesis (0.046 g gCDW-1 h-1) by obligatory NADPH synthesis through the pentose cycle. Together, synergistic cofeeding produces CO2-derived lipids with 38% energy yield and demonstrates the potential to convert CO2 into advanced bioproducts. This work advances the systems-level control ...Continue Reading

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Citations

Jan 7, 2020·Biotechnology and Bioengineering·Erju TangQipeng Yuan
Aug 28, 2020·Frontiers in Bioengineering and Biotechnology·Isabel BatorLars M Blank
Apr 16, 2020·Frontiers in Bioengineering and Biotechnology·James K HeffernanEsteban Marcellin
Feb 6, 2021·Critical Reviews in Biotechnology·Hui LiuLiming Liu
Dec 5, 2020·Nature Communications·Jingbo LiGregory Stephanopoulos
Sep 13, 2019·Current Opinion in Biotechnology·Nian LiuGregory Stephanopoulos
Dec 7, 2019·Accounts of Chemical Research·Edward V LaBelleHarold D May
Sep 15, 2020·Joule·Sevcan Erşan, Junyoung O Park

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