Using chemobiosynthesis and synthetic mini-polyketide synthases to produce pharmaceutical intermediates in Escherichia coli.

Kosan Biosciences Inc., Hayward, California 94545, USA.
Applied and Environmental Microbiology (Impact Factor: 3.95). 08/2010; 76(15):5221-7. DOI: 10.1128/AEM.02961-09
Source: PubMed

ABSTRACT Recombinant microbial whole-cell biocatalysis is a valuable approach for producing enantiomerically pure intermediates for the synthesis of complex molecules. Here, we describe a method to produce polyketide intermediates possessing multiple stereogenic centers by combining chemobiosynthesis and engineered mini-polyketide synthases (PKSs). Chemobiosynthesis allows the introduction of unnatural moieties, while a library of synthetic bimodular PKSs expressed from codon-optimized genes permits the introduction of a variety of ketide units. To validate the approach, intermediates for the synthesis of trans-9,10-dehydroepothilone D were generated. The designer molecules obtained have the potential to greatly reduce the manufacturing cost of epothilone analogues, thus facilitating their commercial development as therapeutic agents.

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