Regulating malonyl-CoA metabolism via synthetic antisense RNAs for enhanced biosynthesis of natural products

Authors
Yang, Yaping
Lin, Yuheng
Li, Lingyun
Linhardt, Robert J.
Yan, Yajun
ORCID
https://orcid.org/0000-0003-2219-5833
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Other Contributors
Issue Date
2015-05-01
Keywords
Biology , Chemistry and chemical biology , Chemical and biological engineering , Biomedical engineering
Degree
Terms of Use
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Full Citation
Regulating malonyl-CoA metabolism via synthetic antisense RNAs for enhanced biosynthesis of natural products, Y. Yang, Y. Lin, L. Li, R. J. Linhardt, Y. Yan, Metabolic Engineering, 29: 217–226, 2015.
Abstract
Malonyl-CoA is the building block for fatty acid biosynthesis and also a precursor to various pharmaceutically and industrially valuable molecules, such as polyketides and biopolymers. However, intracellular malonyl-CoA is usually maintained at low levels, which poses great challenges to efficient microbial production of malonyl-CoA derived molecules. Inactivation of the malonyl-CoA consumption pathway to increase its intracellular availability is not applicable, since it is usually lethal to microorganisms. In this work, we employ synthetic antisense RNAs (asRNAs) to conditionally down-regulate fatty acid biosynthesis and achieve malonyl-CoA enrichment in Escherichia coli. The optimized asRNA constructs with a loop-stem structure exhibit high interference efficiency up to 80%, leading to a 4.5-fold increase in intracellular malonyl-CoA concentration when fabD gene expression is inhibited. Strikingly, this strategy allows the improved production of natural products 4-hydroxycoumarin, resveratrol, and naringenin by 2.53-, 1.70-, and 1.53-fold in E. coli, respectively. In addition, down-regulation of other fab genes including fabH, fabB, and fabF also leads to remarkable increases in 4-hydroxycoumarin production. This study demonstrates a novel strategy to enhance intracellular malonyl-CoA and indicates the effectiveness of asRNA as a powerful tool for use in metabolic engineering.
Description
Metabolic Engineering, 29: 217–226
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Department
The Linhardt Research Labs.
The Shirley Ann Jackson, Ph.D. Center for Biotechnology and Interdisciplinary Studies (CBIS)
Publisher
Relationships
The Linhardt Research Labs Online Collection
Rensselaer Polytechnic Institute, Troy, NY
Metabolic Engineering
https://harc.rpi.edu/
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https://login.libproxy.rpi.edu/login?url=https://doi.org/10.1016/j.ymben.2015.03.018