Smith Emily R, Al-Smadi Dua H, Dai Yitao, Khin Manead, Burdette Joanna E, Duggan Brendan M, La Clair James J, Eustáquio Alessandra S, Burkart Michael D
Department of Chemistry and Biochemistry, University of California 9500 Gilman Drive, La Jolla San Diego California 92093 USA
Department of Pharmaceutical Sciences, Retzky College of Pharmacy, University of Illinois Chicago Chicago IL 60607 USA
RSC Chem Biol. 2025 May 8. doi: 10.1039/d5cb00068h.
Well-recognized for the ability to modulate spliceosome activity, the pladienolide family of polyketide natural products has been the recent subject of intense synthetic and bioactivity studies. However, our understanding of their biosynthesis remains incomplete. Here, we report the biosynthetic gene cluster of FD-895 from A-9561 and explore the installation of a key methylation important for metabolite stability. We demonstrate the and application of an -methyltransferase for regioselective methylation of pladienolide B at the C21 position, a post-synthase modification critical for compound stability. These findings provide a crucial next step in developing systems to engineer this important family of splicing modulatory anti-tumor agents.
聚酮类天然产物普拉地内酯家族以其调节剪接体活性的能力而闻名，最近一直是深入的合成和生物活性研究的主题。然而，我们对其生物合成的理解仍不完整。在这里，我们报告了来自A-9561的FD-895的生物合成基因簇，并探索了对代谢物稳定性至关重要的关键甲基化的引入。我们展示了一种S-腺苷甲硫氨酸（SAM）-甲基转移酶对普拉地内酯B在C21位进行区域选择性甲基化的功能和应用，这是一种对化合物稳定性至关重要的合成后修饰。这些发现为开发工程化这个重要的剪接调节抗肿瘤药物家族的系统提供了关键的下一步。
