Total Synthesis Facilitates In Vitro Reconstitution of the C–S Bond-Forming P450 in Griseoviridin Biosynthesis,Journal of the American Chemical Society

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Total Synthesis Facilitates In Vitro Reconstitution of the C–S Bond-Forming P450 in Griseoviridin Biosynthesis
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2024-07-23 , DOI: 10.1021/jacs.4c06080
Carter N Stout _{1,

2} , Hans Renata ₁

Affiliation

Griseoviridin is a group A streptogramin natural product from Streptomyces with broad-spectrum antibacterial activity. A hybrid polyketide-nonribosomal peptide, it comprises a 23-membered macrocycle, an embedded oxazole motif, and a macrolactone with a unique ene-thiol linkage. Recent analysis of the griseoviridin biosynthetic gene cluster implicated SgvP, a cytochrome P450 monooxygenase, in late-stage installation of the critical C–S bond. While genetic and crystallographic experiments provided indirect evidence to support this hypothesis, the exact function of SgvP has never been confirmed biochemically. Herein, we report a convergent total synthesis of pre-griseoviridin, the putative substrate of P450 SgvP and precursor to griseoviridin. Our strategy features concise and rapid assembly of two fragments joined via sequential peptide coupling and Stille macrocyclization. Access to pre-griseoviridin then enabled in vitro validation of SgvP as the C–S bond-forming P450 during griseoviridin biosynthesis, culminating in a nine-step chemoenzymatic synthesis of griseoviridin.

中文翻译：

全合成促进灰绿素生物合成中 C-S 键形成 P450 的体外重建

Griseoviridin 是一种来自链霉菌的 A 族链霉素天然产物，具有广谱抗菌活性。它是一种杂合聚酮化合物-非核糖体肽，包含 23 元大环、嵌入的恶唑基序和具有独特烯-硫醇键的大环内酯。最近对灰绿素生物合成基因簇的分析表明，SgvP（一种细胞色素 P450 单加氧酶）参与了关键 C-S 键的后期安装。虽然遗传和晶体学实验提供了间接证据来支持这一假设，但 SgvP 的确切功能从未得到生化证实。在此，我们报告了前灰绿素的聚合全合成，前灰绿素是 P450 SgvP 的推定底物，也是灰绿素的前体。我们的策略的特点是通过连续肽偶联和 Stille 大环化连接的两个片段的简洁和快速组装。然后，利用预灰绿素，可以在体外验证 SgvP 在灰绿素生物合成过程中作为 C-S 键形成 P450，最终实现灰绿素的九步化学酶合成。

更新日期：2024-07-23

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