Department of Hematology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, 430071, Wuhan, People's Republic of China.
Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (Ministry of Education), Wuhan University, 430071, Wuhan, People's Republic of China.
Nat Commun. 2023 Feb 4;14(1):612. doi: 10.1038/s41467-023-36213-9.
Modular polyketide synthase (PKS) is an ingenious core machine that catalyzes abundant polyketides in nature. Exploring interactions among modules in PKS is very important for understanding the overall biosynthetic process and for engineering PKS assembly-lines. Here, we show that intermodular recognition between the enoylreductase domain ER inside module 1/2 and the ketosynthase domain KS inside module 3 is required for the cross-module enoylreduction in azalomycin F (AZL) biosynthesis. We also show that KS of module 4 acts as a gatekeeper facilitating cross-module enoylreduction. Additionally, evidence is provided that module 3 and module 6 in the AZL PKS are evolutionarily homologous, which makes evolution-oriented PKS engineering possible. These results reveal intermodular recognition, furthering understanding of the mechanism of the PKS assembly-line, thus providing different insights into PKS engineering. This also reveals that gene duplication/conversion and subsequent combinations may be a neofunctionalization process in modular PKS assembly-lines, hence providing a different case for supporting the investigation of modular PKS evolution.
模块化聚酮合酶（PKS）是一种巧妙的核心机器，能够在自然界中催化大量的聚酮类化合物。探索 PKS 中模块之间的相互作用对于理解整体生物合成过程和工程 PKS 装配线非常重要。在这里，我们表明，在阿扎霉素 F（AZL）生物合成中，跨模块烯酰还原需要模块 1/2 中的烯酰还原酶结构域 ER 和模块 3 中的酮合酶结构域 KS 之间的模块间识别。我们还表明，模块 4 的 KS 充当了一个门控因子，促进了跨模块烯酰还原。此外，还提供了证据表明，AZL PKS 中的模块 3 和模块 6 在进化上是同源的，这使得基于进化的 PKS 工程成为可能。这些结果揭示了模块间的识别，进一步了解了 PKS 装配线的机制，从而为 PKS 工程提供了不同的见解。这也表明基因复制/转换和随后的组合可能是模块化 PKS 装配线中的一个新功能化过程，因此为支持模块化 PKS 进化的研究提供了一个不同的案例。
