Remodeling isoprene pyrophosphate metabolism for promoting terpenoids bioproduction
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Published version
Author(s)
Type
Journal Article
Abstract
Terpenoids are the largest family of natural products. They are made from the building block isoprene pyrophosphate (IPP), and their bioproduction using engineered cell factories has received a great deal of attention. To date, the insufficient metabolic supply of IPP remains a great challenge for the efficient synthesis of terpenoids. In this work, we discover that the imbalanced metabolic flux distribution between the central metabolism and the IPP supply hinders IPP accumulation in Bacillus subtilis (B. subtilis). Therefore, we remodel the IPP metabolism using a series of genetically encoded two-input-multi-output (TIMO) circuits that are responsive to pyruvate or/and malonyl-CoA, resulting in an IPP pool that is significantly increased by up to four-fold. As a proof-of-concept validation, we design an IPP metabolism remodeling strategy to improve the production of three valuable terpenoids, including menaquinone-7 (MK-7, 4.1-fold), lycopene (9-fold), and β-carotene (0.9-fold). In particular, the titer of MK-7 in a 50-L bioreactor reached 1549.6 mg∙L−1, representing the highest titer reported so far. Thus, we propose a TIMO genetic circuits-assisted IPP metabolism remodeling framework that can be generally used for the synergistic fine-tuning of complicated metabolic modules to achieve the efficient bioproduction of terpenoids.
Date Issued
2023-09
Date Acceptance
2023-03-21
Citation
Engineering, 2023, 28, pp.166-178
ISSN
2095-8099
Publisher
Elsevier
Start Page
166
End Page
178
Journal / Book Title
Engineering
Volume
28
Copyright Statement
© 2023 THE AUTHORS. Published by Elsevier LTD on behalf of Chinese Academy of Engineering and Higher Education Press Limited Company.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Identifier
https://www.sciencedirect.com/science/article/pii/S2095809923002771?via%3Dihub
Subjects
ACETYL-COA
Bacillus subtilis
BACILLUS-SUBTILIS
BIOSYNTHESIS
Engineering
Engineering, Multidisciplinary
EXPRESSION
Genetic circuits
Isoprene pyrophosphate
MODEL
PATHWAY
REPRESSOR
SACCHAROMYCES-CEREVISIAE
Science & Technology
SYNTHETIC BIOLOGY
Technology
Terpenoids
Publication Status
Published
Date Publish Online
2023-07-25