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

Paper ID Volume ID Publish Year Pages File Format Full-Text
31528 44807 2015 10 PDF Available
Title
Regulating malonyl-CoA metabolism via synthetic antisense RNAs for enhanced biosynthesis of natural products
Abstract

•Development of antisense RNA tools with high interference efficiency up to 80%.•Conditional down-regulation of fatty acid biosynthesis.•4.5-fold increase in intracellular malonyl-CoA concentration.•Application of the asRNA tool in improvement of natural products production.•A versatile strategy for manipulating essential genes in metabolic engineering.

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.

Keywords
Antisense RNA; Malonyl-CoA; Fatty acid biosynthesis; 4-hydroxycoumarin; Resveratrol; Naringenin
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Regulating malonyl-CoA metabolism via synthetic antisense RNAs for enhanced biosynthesis of natural products
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Publisher
Database: Elsevier - ScienceDirect
Journal: Metabolic Engineering - Volume 29, May 2015, Pages 217–226
Authors
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Subjects
Physical Sciences and Engineering Chemical Engineering Bioengineering
Get Full-Text Now
Don't Miss Today's Special Offer
Price was $35.95
You save - $31
Price after discount Only $4.95
100% Money Back Guarantee
Full-text PDF Download
Online Support
Any Questions? feel free to contact us