德国法兰克福大学Grininger Martin团队报道了化学酶法合成氟化聚酮。相关研究成果于2022年7月25日发表于国际顶尖学术期刊《自然—化学》。

用氟对聚酮进行改性为开发新药物提供了一条有前途的途径。近年来，虽然用于在复杂分子中选择性掺入氟的合成化学方法有所改进，但用于在天然化合物中生物合成掺入氟的方法仍然很少。

该文中，研究人员报告了一种在生物合成过程中将氟引入复杂聚酮的策略。研究人员将聚酮合酶的天然酰基转移酶结构域与后生动物I型脂肪酸合酶的进化相关但具有底物耐受性的结构域相交换，该结构域充当选择延长单元的看门人。由此产生的聚酮合酶/脂肪酸合酶杂交可以利用氟丙二酰辅酶A和氟甲基丙二酰辅酶A进行聚酮链延伸，在聚酮支架中引入氟或氟甲基单元。

研究人员证明了该方法在化学酶法合成含氟12和14元大环内酯，以及大环内酯类抗生素YC-17和甲氧霉素的含氟衍生物方面的可行性。将氟引入药物分子可以改变其生物反应，包括调节生物利用度、药代动力学和选择性。现在，已经设计了一种混合聚酮/脂肪酸合成酶多酶，以在聚酮生物合成过程中结合含氟前体，该方法提供了获得含氟天然化合物的新的化学酶途径。

附：英文原文

Title: Chemoenzymatic synthesis of fluorinated polyketides

Author: Rittner, Alexander, Joppe, Mirko, Schmidt, Jennifer J., Mayer, Lara Maria, Reiners, Simon, Heid, Elia, Herzberg, Dietmar, Sherman, David H., Grininger, Martin

Issue&Volume: 2022-07-25

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. The introduction of fluorine into a drug molecule can alter the biological responses to it, including modulating bioavailability, pharmacokinetics and selectivity. Now, a hybrid polyketide/fatty acid synthase multienzyme has been designed to incorporate fluorinated precursors during polyketide biosynthesis in an approach that provides new chemoenzymatic access to fluorinated natural compounds.

DOI: 10.1038/s41557-022-00996-z

Source: https://www.nature.com/articles/s41557-022-00996-z