模块化聚酮合酶还原区的结构。
Structure of a modular polyketide synthase reducing region.
机构信息
Life Sciences Institute, University of Michigan, Ann Arbor MI 48109, USA; Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109, USA.
Life Sciences Institute, University of Michigan, Ann Arbor MI 48109, USA.
出版信息
Structure. 2023 Sep 7;31(9):1109-1120.e3. doi: 10.1016/j.str.2023.05.019. Epub 2023 Jun 21.
The chemical scaffolds of numerous therapeutics are polyketide natural products, many formed by bacterial modular polyketide synthases (PKS). The large and flexible dimeric PKS modules have distinct extension and reducing regions. Structures are known for all individual enzyme domains and several extension regions. Here, we report the structure of the full reducing region from a modular PKS, the ketoreductase (KR), dehydratase (DH), and enoylreductase (ER) domains of module 5 of the juvenimicin PKS. The modular PKS-reducing region has a different architecture than the homologous fatty acid synthase (FAS) and iterative PKS systems in its arrangement of domains and dimer interface. The structure reveals a critical role for linker peptides in the domain interfaces, leading to discovery of key differences in KR domains dependent on module composition. Finally, our studies provide insight into the mechanism underlying modular PKS intermediate shuttling by carrier protein (ACP) domains.
许多治疗药物的化学支架都是聚酮天然产物，其中许多是由细菌模块化聚酮合酶（PKS）形成的。大型且灵活的二聚体 PKS 模块具有不同的延伸和还原区域。已知所有单个酶结构域和几个延伸区域的结构。在这里，我们报告了来自模块化 PKS 的完整还原区域的结构，该 PKS 是 juvenimicin PKS 模块 5 的酮还原酶（KR）、脱水酶（DH）和烯酰还原酶（ER）结构域。模块化 PKS 还原区域在其结构域排列和二聚体界面方面与同源脂肪酸合酶（FAS）和迭代 PKS 系统具有不同的结构。该结构揭示了连接肽在结构域界面中的关键作用，导致发现 KR 结构域依赖于模块组成的关键差异。最后，我们的研究为载脂蛋白（ACP）结构域介导的模块化 PKS 中间穿梭的机制提供了深入的了解。
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