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：

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微管蛋白结合生物碱秋水仙碱的全生物合成

秋水仙碱 ( 1 ) 是一种生物活性植物生物碱，来自秋水仙属和嘉兰属植物，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，这不仅促进抗炎作用，而且使秋水仙碱成为一种强效的有丝分裂毒药。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，潜在的酶促机制才变得清晰。在这里，我们报告了嘉兰菊中多途径酶的发现，这些酶可以重建完整的代谢途径1 . 这包括三种酶，它们通过调整氮原子将先前建立的含有托酚酮的中间体加工成1 。我们进一步证明了通过模型植物中的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提供了未来的努力。此外，我们的结果提供了对秋水仙碱生物合成所需的后期修饰的时间和组织特异性的深入了解，这可能与本地生产植物中此类药用生物碱的生物学功能有关。