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Kinetic compartmentalization by unnatural reaction for itaconate production

Author

Listed:
  • Dae-yeol Ye

    (Pohang University of Science and Technology)

  • Myung Hyun Noh

    (Pohang University of Science and Technology)

  • Jo Hyun Moon

    (Pohang University of Science and Technology)

  • Alfonsina Milito

    (Campus UAB)

  • Minsun Kim

    (Pohang University of Science and Technology)

  • Jeong Wook Lee

    (Pohang University of Science and Technology
    Pohang University of Science and Technology)

  • Jae-Seong Yang

    (Campus UAB)

  • Gyoo Yeol Jung

    (Pohang University of Science and Technology
    Pohang University of Science and Technology)

Abstract

Physical compartmentalization of metabolism using membranous organelles in eukaryotes is helpful for chemical biosynthesis to ensure the availability of substrates from competitive metabolic reactions. Bacterial hosts lack such a membranous system, which is one of the major limitations for efficient metabolic engineering. Here, we employ kinetic compartmentalization with the introduction of an unnatural enzymatic reaction by an engineered enzyme as an alternative strategy to enable substrate availability from competitive reactions through kinetic isolation of metabolic pathways. As a proof of concept, we kinetically isolate the itaconate synthetic pathway from the tricarboxylic acid cycle in Escherichia coli, which is natively separated by mitochondrial membranes in Aspergillus terreus. Specifically, 2-methylcitrate dehydratase is engineered to alternatively catalyze citrate and kinetically secure cis-aconitate for efficient production using a high-throughput screening system. Itaconate production can be significantly improved with kinetic compartmentalization and its strategy has the potential to be widely applicable.

Suggested Citation

  • Dae-yeol Ye & Myung Hyun Noh & Jo Hyun Moon & Alfonsina Milito & Minsun Kim & Jeong Wook Lee & Jae-Seong Yang & Gyoo Yeol Jung, 2022. "Kinetic compartmentalization by unnatural reaction for itaconate production," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33033-1
    DOI: 10.1038/s41467-022-33033-1
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    References listed on IDEAS

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    1. Austin G. Rottinghaus & Aura Ferreiro & Skye R. S. Fishbein & Gautam Dantas & Tae Seok Moon, 2022. "Genetically stable CRISPR-based kill switches for engineered microbes," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    2. Jina Yang & Sang Woo Seo & Sungho Jang & So-I Shin & Chae Hyun Lim & Tae-Young Roh & Gyoo Yeol Jung, 2013. "Synthetic RNA devices to expedite the evolution of metabolite-producing microbes," Nature Communications, Nature, vol. 4(1), pages 1-7, June.
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    4. Gordon Rix & Ella J. Watkins-Dulaney & Patrick J. Almhjell & Christina E. Boville & Frances H. Arnold & Chang C. Liu, 2020. "Scalable continuous evolution for the generation of diverse enzyme variants encompassing promiscuous activities," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
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