Kinetic compartmentalization by unnatural reaction for itaconate production

Dae-yeol Ye, Myung Hyun Noh, Jo Hyun Moon, Alfonsina Milito, Minsun Kim, Jeong Wook Lee, Jae-Seong Yang () and Gyoo Yeol Jung ()
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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
Jae-Seong Yang: Campus UAB
Gyoo Yeol Jung: Pohang University of Science and Technology

Nature Communications, 2022, vol. 13, issue 1, 1-10

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-33033-1

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