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

MENZELLA H.G. (CORRESPONDING); CARNEY J.; LI Y.; SANTI D.

APPLIED AND ENVIRONMENTAL MICROBIOLOGY

AMER SOC MICROBIOLOGY

Año: 2010 vol. 76 p. 5221 - 5227

0099-2240

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 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.