Engineering site-selective incorporation of fluorine into polyketides

Sasilada Sirirungruang, Omer Ad, Thomas M. Privalsky, Swetha Ramesh, Joel L. Sax, Hongjun Dong, Edward E.K. Baidoo, Bashar Amer, Chaitan Khosla, Michelle C.Y. Chang

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

Although natural products and synthetic small molecules both serve important medicinal functions, their structures and chemical properties are relatively distinct. To expand the molecular diversity available for drug discovery, one strategy is to blend the effective attributes of synthetic and natural molecules. A key feature found in synthetic compounds that is rare in nature is the use of fluorine to tune drug behavior. We now report a method to site-selectively incorporate fluorine into complex structures to produce regioselectively fluorinated full-length polyketides. We engineered a fluorine-selective trans-acyltransferase to produce site-selectively fluorinated erythromycin precursors in vitro. We further demonstrated that these analogs could be produced in vivo in Escherichia coli on engineering of the fluorinated extender unit pool. By using engineered microbes, elaborate fluorinated compounds can be produced by fermentation, offering the potential for expanding the identification and development of bioactive fluorinated small molecules. [Figure not available: see fulltext.]

Original languageEnglish (US)
Pages (from-to)886-893
Number of pages8
JournalNature Chemical Biology
Volume18
Issue number8
DOIs
StatePublished - Aug 2022
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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