Total Biosynthesis of the Tubulin-Binding Alkaloid Colchicine,Journal of the American Chemical Society

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Total Biosynthesis of the Tubulin-Binding Alkaloid Colchicine
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2021-11-15 , DOI: 10.1021/jacs.1c08659
Ryan S Nett _{1,

2} , Elizabeth S Sattely _{1,

2}

Affiliation

Colchicine (1) is a bioactive plant alkaloid from Colchicum and Gloriosa species that is used as a pharmaceutical treatment for inflammatory diseases, including gouty arthritis and familial Mediterranean fever. The activity of this alkaloid is attributed to its ability to bind tubulin dimers and inhibit microtubule assembly, which not only promotes anti-inflammatory effects, but also makes colchicine a potent mitotic poison. The biochemical origins of colchicine biosynthesis have been investigated for over 50 years, but only recently has the underlying enzymatic machinery become clear. Here, we report the discovery of multiple pathway enzymes from Gloriosa superba that allows for the reconstitution of a complete metabolic route to 1. This includes three enzymes that process a previously established tropolone-containing intermediate into 1 via tailoring of the nitrogen atom. We further demonstrate the total biosynthesis of enantiopure (−)-1 from primary metabolites via heterologous production in a model plant, thus enabling future efforts for the metabolic engineering of this medicinal alkaloid. Additionally, our results provide insight into the timing and tissue specificity for the late stage modifications required in colchicine biosynthesis, which are likely connected to the biological functions for this class of medicinal alkaloids in native producing plants.

中文翻译：

微管蛋白结合生物碱秋水仙碱的总生物合成

秋水仙碱（1）是一种来自秋水仙属和 Gloriosa 物种的生物活性植物生物碱，用作炎症性疾病的药物治疗，包括痛风性关节炎和家族性地中海热。这种生物碱的活性归因于其结合微管蛋白二聚体和抑制微管组装的能力，这不仅促进了抗炎作用，而且使秋水仙碱成为一种有效的有丝分裂毒物。秋水仙碱生物合成的生化起源已经研究了 50 多年，但直到最近才清楚潜在的酶机制。在这里，我们报告了从 Gloriosa superba 中发现的多种途径酶，该酶允许将完整的代谢途径重建为 1。这包括三种酶，它们通过定制氮原子将先前建立的含 tropolone 的中间体加工成 1。我们进一步证明了通过在模式植物中异源生产从初级代谢物中对映体纯（-）-1 的总生物合成，从而为这种药用生物碱的代谢工程的未来工作奠定了基础。此外，我们的结果提供了对秋水仙碱生物合成中所需的后期修饰的时间和组织特异性的见解，这可能与天然生产植物中此类药用生物碱的生物学功能有关。

更新日期：2021-11-24

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