Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Nat Prod Rep. 2024 Aug 14;41(8):1219-1234. doi: 10.1039/d3np00060e.
Covering: up to the end of 2023Type I modular polyketide synthases construct polyketide natural products in an assembly line-like fashion, where the growing polyketide chain attached to an acyl carrier protein is passed from catalytic domain to catalytic domain. These enzymes have immense potential in drug development since they can be engineered to produce non-natural polyketides by strategically adding, exchanging, and deleting individual catalytic domains. In practice, however, this approach frequently results in complete failures or dramatically reduced product yields. A comprehensive understanding of modular polyketide synthase architecture is expected to resolve these issues. We summarize the three-dimensional structures and the proposed mechanisms of three full-length modular polyketide synthases, Lsd14, DEBS module 1, and PikAIII. We also describe the advantages and limitations of using X-ray crystallography, cryo-electron microscopy, and AlphaFold2 to study intact type I polyketide synthases.
截至 2023 年底 I 型模块化聚酮合酶以类似于装配线的方式构建聚酮天然产物，其中附着在酰基辅酶 A 上的不断增长的聚酮链从一个催化结构域传递到另一个催化结构域。由于这些酶可以通过策略性地添加、交换和删除单个催化结构域来产生非天然聚酮，因此它们在药物开发方面具有巨大的潜力。然而，实际上，这种方法经常导致完全失败或产品产量大幅降低。对模块化聚酮合酶结构的全面了解有望解决这些问题。我们总结了全长模块化聚酮合酶 LSD14、DEBS 模块 1 和 PikAIII 的三维结构和提出的机制。我们还描述了使用 X 射线晶体学、冷冻电镜和 AlphaFold2 研究完整的 I 型聚酮合酶的优势和局限性。
