Chemoenzymatic synthesis of fluorinated polyketides

Area of Science:

• Biochemistry
• Synthetic Biology
• Medicinal Chemistry

Background:

• Fluorine incorporation into polyketides is a key strategy for developing novel pharmaceuticals.
• Biosynthetic methods for introducing fluorine into natural products are limited.
• Acyltransferase domains in polyketide synthases control extender unit selection.

Purpose of the Study:

• To develop a biosynthetic strategy for site-selective fluorine incorporation into complex polyketides.
• To engineer a hybrid enzyme capable of utilizing fluorinated extender units.
• To demonstrate the production of novel fluorinated polyketides and macrolide antibiotics.

Main Methods:

• Engineered a hybrid polyketide synthase (PKS) by replacing its native acyltransferase (AT) domain with a substrate-tolerant AT domain from a metazoan type I fatty acid synthase (FAS).
• Utilized the engineered PKS/FAS hybrid enzyme to incorporate fluoromalonyl coenzyme A and fluoromethylmalonyl coenzyme A into polyketide chains.
• Performed chemoenzymatic synthesis of fluorinated macrolactones and derivatives of macrolide antibiotics YC-17 and methymycin.

Main Results:

• The PKS/FAS hybrid enzyme successfully utilized fluorinated extender units for polyketide chain extension.
• Introduced fluorine or fluoro-methyl units into polyketide scaffolds.
• Synthesized fluorinated 12- and 14-membered macrolactones and fluorinated YC-17 and methymycin derivatives.

Conclusions:

• The developed chemoenzymatic strategy enables the biosynthetic incorporation of fluorine into complex polyketides.
• This approach provides a powerful tool for generating novel fluorinated natural products with potential pharmaceutical applications.
• The engineered hybrid enzyme expands the scope of polyketide biosynthesis for drug discovery.