Precursor-Directed Biosynthesis of Epothilone in Escherichia coli

Engineered biosynthetic pathways provide a powerful method for generating complex molecules. Precursor-directed biosynthesis, which combines chemical synthesis and enzymatic transformations, allows non-native starting materials to be incorporated into biosynthetic pathways. Using this approach, we a...

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Bibliographic Details
Published in:Journal of the American Chemical Society 2004-06, Vol.126 (24), p.7436-7437
Main Authors: BODDY, Christopher N., HOTTA, Kinya, TSE, Martha Lovato, WATTS, R. Edward, KHOSLA, Chaitan
Format: Article
Language:English
Subjects:
Antibiotics, Antineoplastic - analysis
Antibiotics, Antineoplastic - biosynthesis
Antineoplastic agents
Biological and medical sciences
Epothilones - analysis
Epothilones - biosynthesis
Epothilones - genetics
Escherichia coli - genetics
Escherichia coli - metabolism
General aspects
Medical sciences
Molecular Structure
Multienzyme Complexes - biosynthesis
Multienzyme Complexes - genetics
Pharmacology. Drug treatments
Protein Precursors - physiology
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Summary:Engineered biosynthetic pathways provide a powerful method for generating complex molecules. Precursor-directed biosynthesis, which combines chemical synthesis and enzymatic transformations, allows non-native starting materials to be incorporated into biosynthetic pathways. Using this approach, we achieved the production of the anticancer agent epothilone C in Escherichia coli. An E. coli strain was engineered to express the last three modules of the epothilone biosynthetic pathway (epoD-M6, epoE, and epoF) and the substrate required to complement the biosynthetic enzymes was obtained by chemical synthesis. Under high-density cell culture conditions, the E. coli strain processed exogenously fed synthetic substrate into epothilone C at levels comparable to the native host (1 mg/L) and at higher levels than other heterologous hosts. Importantly, this precursor-directed approach will allow chemical modifications to be introduced into the polyketide backbone and may ultimately provide access to epothilone analogues with improved pharmacological properties in quantities sufficient for clinical development.
ISSN:0002-7863
1520-5126
DOI:10.1021/ja048108s