Monoterpenoid indole alkaloid biosynthesis

植物具有显著的特性，能够执行复杂的和生物创新的生物化学，产生各种颜色、香味、芳香和生物活性有机分子。虽然产生的大多数分子对生存不是直接必要的，但许多分子可能在植物适应生物和非生物环境中发挥关键作用。这种化学多样性独特的生物活性提供了药物和预防疾病的分子，人类已经使用这些分子来预防/治疗许多毁灭性的疾病。单萜类吲哚生物碱(MIA)是最大、最多样的化合物，在夹竹桃科(4700种)、马钱科(600种)和茜草科(10,000种)植物家族的许多成员中都有发现。MIA化学的复杂性与它们对活体的显著不同作用相匹配，导致它们被用作预防疟疾(奎宁)和治疗神经疾病(利血平)、癌症(喜树碱、长春新碱和长春新碱)的药物，用作血管扩张剂(育亨宾)，作为痛风治疗的消炎药(秋水仙碱)，以及作为潜在的止痛药和人类的新型止痛药(刀豆素)。在过去的25年里，我的实验室在马达加斯加长春花(长春花)抗癌MIA的生物合成方面取得了许多关键发现，在过去的45年里，这些MIA已经被用于化疗。从这些发现中获得的遗传资源和生化知识目前正在被利用，以提高玫瑰花中有价值的药物化合物的生产，或通过在包括酵母在内的其他生物中进行合成生物学实验，或在微生物工厂中进行。在重组生物中生产MIA药物为以较低成本生产现有MIA药物和生产天然来源无法获得的新的独特药物创造了独特的机会。在这一模式植物中的初步发现也极大地改进了可用于发现在自然中发现的其他MIA途径的基因以及了解MIA在植物适应性和对其环境的适应中所起的生态作用的工具。

Plantshave remarkable attributes for being able to perform complex and biologicallyinnovative biochemistry that generates a diversity of colors, fragrances, aromasand biologically active organic molecules. While the majority of the molecules produced arenot directly essential for survival, many may play key roles in plantadaptation to the biotic and abiotic environment. The unique biologicalactivities of this chemical diversity have provided medicinal and diseasepreventing molecules that have been used by humanity to prevent/cure manydevastating diseases. The monoterpenoid indole alkaloids (MIAs) makeup the largest and most diverse class of compounds that are characteristicallyfound within many members of the Apocynaceae (4700 species), the Loganiaceae(600 species) and the Rubiaceae (> 10,000 species) plant families. Thecomplexity of MIA chemistry is matched by their remarkably diverse effects onliving organisms that has led to their use as drugs for preventing malaria(quinine) and for treating neurological disorders (reserpine), cancer(camptothecin, vinblastine and vincristine), as vasodilators (yohimbine), asanti-inflammatories for gout treatments (colchicine) and as potential analgesics and novel painkillers (conolidine) in human beings. Over the past >25 years my laboratoryhas made many key discoveries about the biosynthesis ofanti-cancer MIAs of the Madagascar periwinkle (Catharanthus roseus) that have been used in chemotherapy treatmentsover the past 45 years. The genetic resources and biochemical knowledge derived from these discoveries arepresently being exploited to enhance the production of valuable medicinalcompounds in C. roseus or through synthetic biology experiments in other organisms including yeast or in microbialfactories. The production of MIA pharmaceuticals in recombinant organismscreates unique opportunities for less expensive manufacturing of existing MIA drugsand for generating new and unique medicines not available from natural sources. The initial discoveries made in this model plant have also greatly improved the tools available for gene discovery of other MIA pathways found in Nature and for learning about the ecological roles that MIAs play in plant fitness and adaptations to their environment.