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김동혁

Kim, Donghyuk
Systems Biology and Machine Learning Lab.
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Unlocking the biosynthesis of sesquiterpenoids from methane via the methylerythritol phosphate pathway in methanotrophic bacteria, using alpha-humulene as a model compound

Author(s)
Anh Duc NguyenKim, DonghyukLee, Eun Yeol
Issued Date
2020-09
DOI
10.1016/j.ymben.2020.04.011
URI
https://scholarworks.unist.ac.kr/handle/201301/48296
Fulltext
https://www.sciencedirect.com/science/article/pii/S1096717620300823
Citation
METABOLIC ENGINEERING, v.61, pp.69 - 78
Abstract
Isoprenoids are an abundant and diverse class of natural products with various applications in the pharmaceutical, cosmetics and biofuel industries. A methanotroph-based biorefinery is an attractive scenario for the production of a variety of value-added compounds from methane, because methane is a promising alternative feedstock for industrial biomanufacturing. In this study, we metabolically engineered Methylotuvimicrobium alcaliphilum 20Z for de novo synthesis of a sesquiterpenoid from methane, using alpha-humulene as a model compound, via optimization of the native methylerythritol phosphate (MEP) pathway. Expression of codon-optimized alpha-humulene synthase from Zingiber zerumbet in M. alcaliphilum 20Z resulted in an initial yield of 0.04 mg/g dry cell weight. Overexpressing key enzymes (IspA, IspG, and Dxs) for debottlenecking of the MEP pathway increased alpha-humulene production 5.2-fold compared with the initial strain. Subsequently, redirecting the carbon flux through the Embden-Meyerhof-Parnas pathway resulted in an additional 3-fold increase in alpha-humulene production. Additionally, a genome-scale model using flux scanning based on enforced objective flux method was used to identify potential overexpression targets to increase flux towards isoprenoid production. Several target reactions from cofactor synthesis pathways were probed and evaluated for their effects on alpha-humulene synthesis, resulting in alpha-humulene yield up to 0.75 mg/g DCW with 18.8-fold enhancement from initial yield. This study first demonstrates production of a sesquiterpenoid from methane using methanotrophs as the biocatalyst and proposes potential strategies to enhance production of sesquiterpenoid and related isoprenoid products in engineered methanotrophic bacteria.
Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
ISSN
1096-7176
Keyword (Author)
Methanotrophic bacteriaMethylerythritol phosphate pathwayMetabolic engineeringSesquiterpenoidalpha-humuleneGenome-scale model
Keyword
SYNTHETIC BIOLOGYESCHERICHIA-COLICODON USAGEPRECURSORSYNTHASECONVERSIONMEVALONATE PATHWAY

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