Open AccessUsing Chemobiosynthesis and Synthetic Mini-Polyketide Synthases To Produce Pharmaceutical Intermediates in Escherichia coli
Author(s) -
Hugo G. Menzella,
John R. Carney,
Yong Li,
Daniel V. Santi
Publication year - 2010
Publication title -
applied and environmental microbiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.552
H-Index - 324
eISSN - 1070-6291
pISSN - 0099-2240
DOI - 10.1128/aem.02961-09
Subject(s) - polyketide , biocatalysis , synthetic biology , stereocenter , polyketide synthase , combinatorial chemistry , escherichia coli , stereochemistry , computational biology , chemistry , biosynthesis , biology , biochemistry , enantioselective synthesis , gene , catalysis , reaction mechanism
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 oftrans -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.