Using chemobiosynthesis and synthetic mini-polyketide synthases to produce pharmaceutical intermediates in Escherichia coli.
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.
Menzella
Hugo G
HG
Kosan Biosciences Inc., Hayward, California 94545, USA. hugomenzella@gmail.com
Carney
John R
JR
Li
Yong
Y
Santi
Daniel V
DV
D000900:Anti-Bacterial Agents / Q000378:metabolism*; D053898:Biosynthetic Pathways / Q000235:genetics; D001709:Biotechnology / Q000191:economics / Q000379:methods*; D004926:Escherichia coli / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism*; D007218:Industrial Microbiology / Q000379:methods*; D018942:Macrolides / Q000378:metabolism*; D015394:Molecular Structure; D048630:Polyketide Synthases / Q000235:genetics / Q000378:metabolism*
D000900:Anti-Bacterial Agents; D018942:Macrolides; D048630:Polyketide Synthases