PT  - JOURNAL ARTICLE
AU  - S. Sirirungruang
AU  - O. Ad
AU  - T. M. Privalsky
AU  - S. Ramesh
AU  - J. L. Sax
AU  - H. Dong
AU  - E. E. K. Baidoo
AU  - B. Amer
AU  - C. Khosla
AU  - M. C. Y. Chang
TI  - Engineering site-selective incorporation of fluorine into natural product analogs
AID  - 10.1101/2021.08.09.455754
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.08.09.455754
4099  - http://biorxiv.org/content/early/2021/08/10/2021.08.09.455754.short
4100  - http://biorxiv.org/content/early/2021/08/10/2021.08.09.455754.full
AB  - While bioactive compounds are commonly derived both by human design as well as from living organisms, man-made and natural products typically display very different structural characteristics. As such, a longstanding goal in the discovery of new molecular function is to develop approaches to incorporate the advantageous elements of both groups of molecules, thereby expanding the molecular space accessible for this purpose. In this work, we report the engineering a fluorine-selective enzyme that can complement mutated acyltransferase (AT) domains of a modular polyketide synthase, which are the main determinants of the identity and location of substituents on polyketides, to produce different fluorinated regioisomers of the erythromycin precursor in vitro. We further show that by engineering cell uptake of fluorinated building blocks, we can control fluorine selectivity in vivo to produce selectively fluorinated polyketides using engineered E. coli. These results demonstrate that it is possible to introduce fluorine, a key synthetic design element for drug development, selectively into the scaffold of a complex natural product and produce these analogs by microbial fermentation.Competing Interest StatementThe authors have declared no competing interest.