State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic & Developmental Sciences, and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
Department of Molecular Biology, Shanghai Jikaixing Biotech Inc., Shanghai, 200131, China.
Nat Commun. 2023 Mar 10;14(1):1319. doi: 10.1038/s41467-023-36989-w.
Assembly-line polyketide synthases (PKSs) are molecular factories that produce diverse metabolites with wide-ranging biological activities. PKSs usually work by constructing and modifying the polyketide backbone successively. Here, we present the cryo-EM structure of CalA3, a chain release PKS module without an ACP domain, and its structures with amidation or hydrolysis products. The domain organization reveals a unique "∞"-shaped dimeric architecture with five connected domains. The catalytic region tightly contacts the structural region, resulting in two stabilized chambers with nearly perfect symmetry while the N-terminal docking domain is flexible. The structures of the ketosynthase (KS) domain illustrate how the conserved key residues that canonically catalyze C-C bond formation can be tweaked to mediate C-N bond formation, revealing the engineering adaptability of assembly-line polyketide synthases for the production of novel pharmaceutical agents.
装配线聚酮合酶（PKSs）是分子工厂，能够产生具有广泛生物活性的各种代谢物。PKSs 通常通过连续构建和修饰聚酮主链来发挥作用。在这里，我们展示了 CalA3 的冷冻电镜结构，这是一个没有 ACP 结构域的链释放 PKS 模块，以及其与酰胺化或水解产物的结构。该结构域组织揭示了一种独特的“∞”形二聚体架构，由五个连接的结构域组成。催化区域与结构区域紧密接触，导致两个稳定的腔室具有几乎完美的对称性，而 N 端对接结构域是灵活的。酮合酶（KS）结构域的结构阐明了如何调整保守的关键残基，以经典地催化 C-C 键形成，从而介导 C-N 键形成，揭示了装配线聚酮合酶在生产新型药物方面的工程适应性。
