Monoterpenoid indole alkaloid biosynthesis

单萜吲哚生物碱生物合成

• 批准号: RGPIN-2017-04145
• 负责人: DeLuca, Vincenzo
• 金额: $ 5.03万
• 依托单位: Brock University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=744721
• 关键词: Monoterpenoid; indole; alkaloid; biosynthesis

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.

植物具有非凡的属性，能够进行复杂的和生物创新的生物化学，产生多种颜色，香味，芳香和生物活性有机分子。虽然产生的大多数分子不是生存的直接必需品，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。这种化学多样性的独特生物活性提供了药物和疾病预防分子，已被人类用于预防/治疗许多毁灭性疾病。单萜类吲哚生物碱（MIA）是夹竹桃科（4700种）、马钱科（600种）和茜草科（> 10，000种）植物中最大和最多样化的一类化合物。MIA化学的复杂性与它们对生物体的显著不同的作用相匹配，这导致它们被用作预防疟疾（奎宁）和治疗神经系统疾病（利血平）、癌症（喜树碱、长春碱和长春新碱）的药物，用作血管扩张剂（育亨宾），用作治疗痛风的抗炎剂（秋水仙碱）和用作人类的潜在镇痛剂和新型止痛药（康诺利定）。在过去的>25年里，我的实验室在马达加斯加长春花（Catharanthus roseus）抗癌MIA的生物合成方面取得了许多关键发现，这些MIA在过去的45年里一直用于化疗治疗。从这些发现中获得的遗传资源和生物化学知识目前正被用于提高C. roseus或通过在其他生物体中的合成生物学实验，包括酵母或微生物工厂。在重组生物体中生产MIA药物为现有MIA药物的低成本制造和产生无法从自然来源获得的新的和独特的药物创造了独特的机会。在这种模式植物中的初步发现也极大地改善了可用于自然界中发现的其他MIA途径的基因发现的工具，以及了解MIA在植物适应性和适应环境中发挥的生态作用。