Biochemical Engineering Group, Plant Biochemistry Section, Department of Plant and Environment Sciences, Faculty of Science, University of Copenhagen, Frederiksberg C, Denmark.
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Nat Chem. 2023 Sep;15(9):1236-1246. doi: 10.1038/s41557-023-01245-7. Epub 2023 Jun 26.
Obesity is a major health risk still lacking effective pharmacological treatment. A potent anti-obesity agent, celastrol, has been identified in the roots of Tripterygium wilfordii. However, an efficient synthetic method is required to better explore its biological utility. Here we elucidate the 11 missing steps for the celastrol biosynthetic route to enable its de novo biosynthesis in yeast. First, we reveal the cytochrome P450 enzymes that catalyse the four oxidation steps that produce the key intermediate celastrogenic acid. Subsequently, we show that non-enzymatic decarboxylation-triggered activation of celastrogenic acid leads to a cascade of tandem catechol oxidation-driven double-bond extension events that generate the characteristic quinone methide moiety of celastrol. Using this acquired knowledge, we have developed a method for producing celastrol starting from table sugar. This work highlights the effectiveness of combining plant biochemistry with metabolic engineering and chemistry for the scalable synthesis of complex specialized metabolites.
肥胖是一个主要的健康风险，仍然缺乏有效的药物治疗。一种有效的抗肥胖药物，雷公藤红素，已经在雷公藤的根部被发现。然而，需要一种有效的合成方法来更好地探索其生物学用途。在这里，我们阐明了雷公藤红素生物合成途径中缺失的 11 个步骤，以使其在酵母中能够从头合成。首先，我们揭示了催化产生关键中间产物 celastrogenic acid 的四个氧化步骤的细胞色素 P450 酶。随后，我们表明，非酶促脱羧触发的 celastrogenic acid 激活导致一连串的邻苯二酚氧化驱动的双键延伸事件，产生雷公藤红素的特征醌甲醚部分。利用这些获得的知识，我们已经开发了一种从普通糖开始生产雷公藤红素的方法。这项工作突出了将植物生物化学与代谢工程和化学相结合用于复杂特殊代谢物的可扩展合成的有效性。
