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Title: Engineering controllable alteration of malonyl-CoA levels to enhance polyketide production
Abstract Heterologous expression of polyketide synthase (PKS) genes inEscherichia colihas enabled the production of various valuable natural and synthetic products. However, the limited availability of malonyl-CoA (M-CoA) inE. coliremains a substantial impediment to high-titer polyketide production. Here we address this limitation by disrupting the native M-CoA biosynthetic pathway and introducing an orthogonal pathway comprising a malonate transporter and M-CoA ligase, enabling efficient M-CoA biosynthesis under malonate supplementation. This approach substantially increases M-CoA levels, enhancing fatty acid and polyketide titers while reducing the promiscuous activity of PKSs toward undesired acyl-CoA substrates. Subsequent adaptive laboratory evolution of these strains provides insights into M-CoA regulation and identifies mutations that further boost M-CoA and polyketide production. This strategy improvesE. colias a host for polyketide biosynthesis and advances understanding of M-CoA metabolism in microbial systems.  more » « less
Award ID(s):
2036849
PAR ID:
10637344
Author(s) / Creator(s):
; ; ; ; ; ; ; ; ; ;
Publisher / Repository:
Nature Chemical Biology
Date Published:
Journal Name:
Nature Chemical Biology
Volume:
21
Issue:
8
ISSN:
1552-4450
Page Range / eLocation ID:
1214 to 1225
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
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