期刊
CELL CHEMICAL BIOLOGY
卷 25, 期 7, 页码 833-+出版社
CELL PRESS
DOI: 10.1016/j.chembiol.2018.04.009
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资金
- DOE Office of Science User Facility [DE-AC02-05CH11231]
- Max Planck Society
- LOEWE program (Landes-Offensive zur Entwicklung wissenschaftlich-okonomischer Exzellenz) of the state of Hessen
The incorporation of different extender units generates structural diversity in polyketides. There is significant interest in engineering substrate specificity of polyketide synthases (PKSs) to change their chemical structure. Efforts to change extender unit selectivity are hindered by the lack of simple screening methods and easily available atypical extender units. Here, we present a chemo-biosynthetic strategy that employs biocatalytic proofreading and allows access to a large variety of extender units. First, saturated acids are chemically coupled to free coenzyme A (CoA). The corresponding acyl-CoAs are then converted to alkylmalonyl-CoAs in a one-pot'' reaction through the combined action of an acyl-CoA oxidase and enoyl-CoA carboxylase/reductase. We synthesized six different extender units and used them in in vitro competition screens to investigate active site residues conferring extender unit selectivity. Our results show the importance of an uncharacterized glutamine in extender unit selectivity and open the possibility for comprehensive studies on extender incorporation in PKSs.
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