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Metabolic engineering strategies to enable microbial utilization of C1 feedstocks


One-carbon (C1) substrates are preferred feedstocks for the biomanufacturing industry and have recently gained attention owing to their natural abundance, low production cost and availability as industrial by-products. However, native pathways to utilize these substrates are absent in most biotechnologically relevant microorganisms. Recent advances in synthetic biology, genome engineering and laboratory evolution are enabling the first steps towards the creation of synthetic C1-utilizing microorganisms. Here, we briefly review the native metabolism of methane, methanol, CO2, CO and formate, and how these C1-utilizing pathways can be engineered into heterologous hosts. In addition, this review analyses the potential, the challenges and the perspectives of C1-based biomanufacturing.

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Fig. 1: C1-based biomanufacturing.
Fig. 2: Examples of successful approaches to enable C1 substrate utilization in E. coli.
Fig. 3: Methanol- and methane-utilization pathways in native organisms.
Fig. 4: Typical metabolic engineering strategy applied to construction of synthetic methylotrophic E. coli.
Fig. 5: Natural CO2 fixation pathways.
Fig. 6: Engineered CO2 utilization in E. coli and P. pastoris.


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W.J. is supported by Monash University under a Monash Graduate Scholarship (MGS), a Monash International Tuition Scholarship (MITS), and a Graduate Research International Travel Award (GRITA). R.L.-A. and H.P. received funding from the Biotechnology and Biological Sciences Research Council (BBSRC; BB/R01602X/1). R.L.-A. received funding from UK research and Innovation (19-ERACoBioTech- 33 SyCoLim BB/T011408/1), the BBSRC (BB/T013176/1), the British Council 527429894, and the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (DEUSBIO - 949080). D.H-V. is supported by Erasmus+ (E MADRID03 – UK LONDON015). R.L.-A.: Newton Advanced Fellowship (NAF\R1\201187). In addition, the authors thank A. Graham for improving the figures.

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Jiang, W., Hernández Villamor, D., Peng, H. et al. Metabolic engineering strategies to enable microbial utilization of C1 feedstocks. Nat Chem Biol 17, 845–855 (2021).

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