Engineering controllable alteration of malonyl-CoA levels to enhance polyketide production
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ABSTRACT: Heterologous expression of polyketide synthase (PKS) genes in Escherichia coli has enabled the production of various valuable natural and synthetic products. However, the limited availability of malonyl-CoA (M-CoA) in E. coli remains a significant impediment to high-titer polyketide production. In this study, 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 significantly 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 improves E. coli as a host for polyketide biosynthesis and advances understanding of M-CoA metabolism in microbial systems.
INSTRUMENT(S): Orbitrap Exploris 480
ORGANISM(S): Escherichia Coli
SUBMITTER:
Christopher Petzold
LAB HEAD: Christopher J.
PROVIDER: PXD060741 | Pride | 2025-02-13
REPOSITORIES: Pride
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