Characterization and engineering of the biosynthesis of alternative painkilling natural products

替代止痛天然产物的生物合成表征和工程

基本信息

  • 批准号:
    RGPIN-2020-04133
  • 负责人:
  • 金额:
    $ 2.7万
  • 依托单位:
  • 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

项目摘要

The plant kingdom remains a great source for complex and bioactive specialized metabolites for medicine. Flowering plants provide 11% of the essential medicines listed by the World Health Organization. For millions of years, these specialized metabolites have been evolving while they participate in plant-plant/microbe/animal communications and plant defense against various attacks. This evolution has resulted in their great structural diversity responsible for their diverse bioactivities. It is of great interest to study their biochemical assembly to understand the origin of such chemo-diversity and to provide solutions to access the rare bioactive compounds by emerging synthetic biology. As the NBHRF/Tetra Bio-Pharma Cannabis Health Research Chair at University of New Brunswick, I study the biochemistry and molecular regulations of the production of specialized metabolites, cannabinoids, in the cannabis plant. My cannabis research program is integral to my long-term objectives: i) to understand how the evolution of enzyme catalysts from different plant species contributes to Nature's chemo-diversity by elucidating the biochemical pathways involved, and ii) to identify and harness these enzymes for manufacturing important natural products. Support from NSERC will contribute to achieving this ambition. During the grant period, I will focus on the characterization and engineering of the biosynthesis of alternative painkilling natural products that may replace effective but problematic opioids. Short-term objectives include elucidating the complete biosynthesis of 1) conolidine, and 2) perrottetinene, and 3) engineering their microbial production for industrial manufacturing. Operating in a mode different from opioids, conolidine is a potent but non-addictive analgesic. Its extremely low content in source plants and the challenges remaining in chemical synthesis, however, impede its development as a medicine. Studying the biosynthesis of conolidine also contributes to understanding the chemical evolution of an important metabolite class: monoterpenoid indole alkaloids, which have impressive structural complexity and diversity that gives them fascinating bioactivities. Isolated from Radula spp. in the phylum of liverwort, perrottetinene shows astonishing structural similarity to tetrahydrocannabinol (THC) from the vascular plant Cannabis sativa, which was known as the only species for cannabinoids and diverged from liverworts 480 million years ago. As a human cannabinoid receptor ligand, perrottetinene may be developed into a promising analgesic, since the endocannabinoid system has become a target in pain management. By comparing this substance to the biosynthesis of THC, we aim to answer how these structurally similar compounds have evolved in two distantly related species, and also develop new enzyme catalysts for producing cannabinoid analgesics.
植物界仍然是一个巨大的来源,复杂的和生物活性的专门代谢物的药物。开花植物提供了世界卫生组织列出的11%的基本药物。数百万年来,这些特殊的代谢物一直在进化,同时它们参与植物-植物/微生物/动物之间的交流和植物对各种攻击的防御。这种进化导致了它们巨大的结构多样性,导致了它们多样化的生物活动。研究它们的生物化学组装对了解这种化学多样性的起源,并通过新兴的合成生物学为获取稀有生物活性化合物提供解决方案具有重要的意义。作为新不伦瑞克大学nhrf /Tetra Bio-Pharma大麻健康研究主席,我研究大麻植物中特殊代谢物大麻素生产的生物化学和分子调控。我的大麻研究项目是我长期目标的一部分:1)通过阐明所涉及的生化途径,了解来自不同植物物种的酶催化剂的进化如何对大自然的化学多样性做出贡献;2)识别和利用这些酶来制造重要的天然产物。NSERC的支持将有助于实现这一目标。在资助期间,我将专注于替代止痛药天然产物的生物合成的表征和工程,这些天然产物可能取代有效但有问题的阿片类药物。短期目标包括阐明1)共聚物和2)橄榄氨酸的完全生物合成,以及3)为工业生产设计它们的微生物生产。与阿片类药物不同,conolidine是一种有效但不成瘾性的镇痛药。然而,其在来源植物中的含量极低,化学合成仍存在挑战,阻碍了其作为药物的发展。研究conolidine的生物合成也有助于理解一类重要代谢物的化学进化:单萜类吲哚生物碱,它们具有令人印象深刻的结构复杂性和多样性,赋予它们迷人的生物活性。从肝草门的Radula spp.中分离出来的perrotetinene显示出与维管植物大麻中的四氢大麻酚(THC)惊人的结构相似性,大麻被认为是唯一的大麻素物种,并在4.8亿年前从肝草中分离出来。作为一种人类大麻素受体配体,由于内源性大麻素系统已成为疼痛治疗的靶点,因此可能会发展成为一种有前景的镇痛药。通过比较这种物质与四氢大麻酚的生物合成,我们旨在回答这些结构相似的化合物如何在两个远亲物种中进化,并开发新的酶催化剂来生产大麻素镇痛药。

项目成果

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Qu, Yang其他文献

Research on Mechanical and Carbonization Properties of Hybrid Fiber Iron Tailings Concrete Based on Deep Learning.
The longitudinal role of family conflict and neural reward sensitivity in youth's internalizing symptoms.
  • DOI:
    10.1093/scan/nsad037
  • 发表时间:
    2023-08-02
  • 期刊:
  • 影响因子:
    4.2
  • 作者:
    Yang, Beiming;Anderson, Zachary;Zhou, Zexi;Liu, Sihong;Haase, Claudia M.;Qu, Yang
  • 通讯作者:
    Qu, Yang
The association between preconception loss of control over eating and depressive symptom trajectories from childhood through first pregnancy.
  • DOI:
    10.1002/eat.24004
  • 发表时间:
    2023-09
  • 期刊:
  • 影响因子:
    5.5
  • 作者:
    Magee, Kelsey E.;Qu, Yang;Cheng, Yu;Hipwell, Alison E.;Levine, Michele D.
  • 通讯作者:
    Levine, Michele D.
Improved protein glycosylation enabled heterologous biosynthesis of monoterpenoid indole alkaloids and their unnatural derivatives in yeast.
  • DOI:
    10.1016/j.mec.2022.e00215
  • 发表时间:
    2023-06
  • 期刊:
  • 影响因子:
    5.2
  • 作者:
    Shahsavarani, Mohammadamin;Utomo, Joseph Christian;Kumar, Rahul;Paz-Galeano, Melina;Garza-Garcia, Jorge Jonathan Oswaldo;Mai, Zhan;Ro, Dae-Kyun;Qu, Yang
  • 通讯作者:
    Qu, Yang
Gut microbiota-derived metabolite trimethylamine-N-oxide and stroke outcome: a systematic review.
  • DOI:
    10.3389/fnmol.2023.1165398
  • 发表时间:
    2023
  • 期刊:
  • 影响因子:
    4.8
  • 作者:
    Zhang, Peng;Wang, Rui;Qu, Yang;Guo, Zhen-Ni;Yang, Yi
  • 通讯作者:
    Yang, Yi

Qu, Yang的其他文献

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{{ truncateString('Qu, Yang', 18)}}的其他基金

Characterization and engineering of the biosynthesis of alternative painkilling natural products
替代止痛天然产物的生物合成表征和工程
  • 批准号:
    RGPIN-2020-04133
  • 财政年份:
    2021
  • 资助金额:
    $ 2.7万
  • 项目类别:
    Discovery Grants Program - Individual
Discovery and engineering the biosynthesis of novel cannabinoid pharmaceuticals
新型大麻素药物的发现和生物合成工程
  • 批准号:
    565706-2021
  • 财政年份:
    2021
  • 资助金额:
    $ 2.7万
  • 项目类别:
    Alliance Grants
Characterization and engineering of the biosynthesis of alternative painkilling natural products
替代止痛天然产物的生物合成表征和工程
  • 批准号:
    DGECR-2020-00009
  • 财政年份:
    2020
  • 资助金额:
    $ 2.7万
  • 项目类别:
    Discovery Launch Supplement
Characterization and engineering of the biosynthesis of alternative painkilling natural products
替代止痛天然产物的生物合成表征和工程
  • 批准号:
    RGPIN-2020-04133
  • 财政年份:
    2020
  • 资助金额:
    $ 2.7万
  • 项目类别:
    Discovery Grants Program - Individual

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Characterization and engineering of the biosynthesis of alternative painkilling natural products
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