天然物から抗生物質を生産する新しい生合成法を開発(A New Biosynthesis Method Has Been Developed to Produce Antibiotics from Natural Substances)

2022-08-03 フランクフルト大学

<関連情報>

• https://aktuelles.uni-frankfurt.de/englisch/a-new-biosynthesis-method-has-been-developed-to-produce-antibiotics-from-natural-substances/
• https://www.nature.com/articles/s41557-022-00996-z

化学酵素を用いたフッ素化ポリケチドの合成 Chemoenzymatic synthesis of fluorinated polyketides

Alexander Rittner,Mirko Joppe,Jennifer J. Schmidt,Lara Maria Mayer,Simon Reiners,Elia Heid,Dietmar Herzberg,David H. Sherman & Martin Grininger
Nature Chemistry  Published:25 July 2022
DOI:https://doi.org/10.1038/s41557-022-00996-z

Abstract

Modification of polyketides with fluorine offers a promising approach to develop new pharmaceuticals. While synthetic chemical methods for site-selective incorporation of fluorine in complex molecules have improved in recent years, approaches for the biosynthetic incorporation of fluorine in natural compounds are still rare. Here, we report a strategy to introduce fluorine into complex polyketides during biosynthesis. We exchanged the native acyltransferase domain of a polyketide synthase, which acts as the gatekeeper for the selection of extender units, with an evolutionarily related but substrate tolerant domain from metazoan type I fatty acid synthase. The resulting polyketide-synthase/fatty-acid-synthase hybrid can utilize fluoromalonyl coenzyme A and fluoromethylmalonyl coenzyme A for polyketide chain extension, introducing fluorine or fluoro-methyl units in polyketide scaffolds. We demonstrate the feasibility of our approach in the chemoenzymatic synthesis of fluorinated 12- and 14-membered macrolactones and fluorinated derivatives of the macrolide antibiotics YC-17 and methymycin.