Monoterpene indole alkaloid gene discovery and evolution in the Apocynaceae

夹竹桃科单萜吲哚生物碱基因的发现和进化

基本信息

  • 批准号:
    RGPIN-2015-05151
  • 负责人:
  • 金额:
    $ 2.11万
  • 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:
    2016
  • 资助国家:
    加拿大
  • 起止时间:
    2016-01-01 至 2017-12-31
  • 项目状态:
    已结题

项目摘要

Collectively, plants produce over 400k natural products that they use for development and defence. Many of these compounds interact with human biological functions, and thus may serve as pharmaceutical agents. Given the high number of plant-derived natural products, a large number of plant natural products have not been tested for efficacy as potential drugs.       The natural products used as drugs are particularly abundant in certain plant families. For example, the Dogbane (Apocynaceae) and related plant families produce over 3000 monoterpene indole alkaloids (MIAs). Catharanthus roseus accumulates vinblastine and vincristine, which are used as chemotherapeutic drugs to combat a number of cancers. Recent genomics studies identified many of the genes and enzymes that produce these drugs. In this study, I will utilize these resources to develop a gene capture array that will be used to isolate DNA fragments that encode MIA biosynthetic genes. This array will then be used to capture new genes from other species that produce medicinal MIAs, and I will sequence these genes using next-generation sequencing techniques.      I will focus on the plant Tabernanthe iboga (iboga), which accumulates MIAs in its roots in quantities up to 6% by weight. Two of these alkaloids, coronaridine and ibogaine, have potential to treat opiate addictions. My laboratory will perform experiments to identify, clone and characterize the MIA biosynthetic genes and encoded enzymes that produce these compounds. We will concurrently develop an iboga ‘hairy root’ cell culture system. Using this system, we can introduce DNA fragments that we wish to be transferred and incorporated into the iboga genome. We will add DNA sequences to reduce the expression of the genes that produce the iboga alkaloids. A long term plan is to introduce the new MIA-biosynthetic genes that were identified from the gene capture experiments to screen for new biosynthetic capabilities.       These experiments will expand our knowledge of the diversity in MIA biosynthetic genes and enzymes. The development of the engineered iboga hairy root cultures has the potential to produce a myriad of novel MIAs which will be made available to pharmacologists for activity screening. Optimization of MIA biosynthesis in the hairy root culture system may allow for scaled-up production of these compounds. A future goal is to produce vinblastine and vincristine in this system, which will result in a sustainable supply of these drugs at a potentially lower cost compared to their extraction from C. roseus plants.
这些植物总共生产超过40万种天然产品,用于发展和防御。这些化合物中的许多与人类生物功能相互作用,因此可以用作药剂。鉴于大量的植物源性天然产物,大量的植物天然产物尚未被测试作为潜在药物的功效。       用作药物的天然产物在某些植物科中特别丰富。例如,夹竹桃科(夹竹桃科)和相关植物科产生超过3000种单萜吲哚生物碱(MIA)。长春花积累长春碱和长春新碱,它们被用作治疗多种癌症的化疗药物。最近的基因组学研究确定了许多产生这些药物的基因和酶。在这项研究中,我将利用这些资源开发一种基因捕获阵列,用于分离编码MIA生物合成基因的DNA片段。然后,这个阵列将被用来捕获其他物种的新基因,这些基因产生药用MIA,我将使用下一代测序技术对这些基因进行测序。 我将集中在植物Tabernanthe iboga(iboga),它在其根部积累的MIA的数量高达6%的重量。这些生物碱中的两种,coronaridine和iboclavin,具有治疗阿片类药物成瘾的潜力。我的实验室将进行实验来识别、克隆和表征MIA生物合成基因和编码产生这些化合物的酶。我们将同时开发iboga '毛状根'细胞培养系统。使用这个系统,我们可以引入我们希望转移并整合到iboga基因组中的DNA片段。我们将添加DNA序列以减少产生伊博加生物碱的基因的表达。一个长期计划是引入从基因捕获实验中鉴定的新的MIA生物合成基因,以筛选新的生物合成能力。       这些实验将扩大我们对MIA生物合成基因和酶的多样性的了解。工程伊博加毛状根培养物的开发有可能产生无数新的MIA,这些MIA将可供药理学家用于活性筛选。毛状根培养系统中MIA生物合成的优化可以允许这些化合物的规模化生产。未来的目标是在该系统中生产长春碱和长春新碱,这将导致这些药物的可持续供应,与从C.蔷薇属植物

项目成果

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Stout, Jake其他文献

Arabidopsis RAD16 Homologues Are Involved in UV Tolerance and Growth.
  • DOI:
    10.3390/genes14081552
  • 发表时间:
    2023-07-28
  • 期刊:
  • 影响因子:
    3.5
  • 作者:
    Alrayes, Linda;Stout, Jake;Schroeder, Dana
  • 通讯作者:
    Schroeder, Dana
Mutations in the cinnamate 4-hydroxylase gene impact metabolism, growth and development in Arabidopsis
  • DOI:
    10.1111/j.1365-313x.2009.03996.x
  • 发表时间:
    2009-12-01
  • 期刊:
  • 影响因子:
    7.2
  • 作者:
    Schilmiller, Anthony L.;Stout, Jake;Chapple, Clint
  • 通讯作者:
    Chapple, Clint

Stout, Jake的其他文献

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{{ truncateString('Stout, Jake', 18)}}的其他基金

Monoterpene indole alkaloid gene discovery and evolution in the Apocynaceae
夹竹桃科单萜吲哚生物碱基因的发现和进化
  • 批准号:
    RGPIN-2015-05151
  • 财政年份:
    2021
  • 资助金额:
    $ 2.11万
  • 项目类别:
    Discovery Grants Program - Individual
Monoterpene indole alkaloid gene discovery and evolution in the Apocynaceae
夹竹桃科单萜吲哚生物碱基因的发现和进化
  • 批准号:
    RGPIN-2015-05151
  • 财政年份:
    2019
  • 资助金额:
    $ 2.11万
  • 项目类别:
    Discovery Grants Program - Individual
Monoterpene indole alkaloid gene discovery and evolution in the Apocynaceae
夹竹桃科单萜吲哚生物碱基因的发现和进化
  • 批准号:
    RGPIN-2015-05151
  • 财政年份:
    2018
  • 资助金额:
    $ 2.11万
  • 项目类别:
    Discovery Grants Program - Individual
Monoterpene indole alkaloid gene discovery and evolution in the Apocynaceae
夹竹桃科单萜吲哚生物碱基因的发现和进化
  • 批准号:
    RGPIN-2015-05151
  • 财政年份:
    2017
  • 资助金额:
    $ 2.11万
  • 项目类别:
    Discovery Grants Program - Individual
Monoterpene indole alkaloid gene discovery and evolution in the Apocynaceae
夹竹桃科单萜吲哚生物碱基因的发现和进化
  • 批准号:
    RGPIN-2015-05151
  • 财政年份:
    2015
  • 资助金额:
    $ 2.11万
  • 项目类别:
    Discovery Grants Program - Individual

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康复是可以实现的:生物催化方法使帽柱木碱类似物多样化用于阿片类药物替代疗法
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康复是可以实现的:生物催化方法使帽柱木碱类似物多样化用于阿片类药物替代疗法
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Methods and Strategies for the Concise Synthesis of Complex Alkaloid Natural Products - Equipment Supplement
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  • 财政年份:
    2021
  • 资助金额:
    $ 2.11万
  • 项目类别:
Monoterpene indole alkaloid gene discovery and evolution in the Apocynaceae
夹竹桃科单萜吲哚生物碱基因的发现和进化
  • 批准号:
    RGPIN-2015-05151
  • 财政年份:
    2021
  • 资助金额:
    $ 2.11万
  • 项目类别:
    Discovery Grants Program - Individual
Monoterpenoid indole alkaloid biosynthesis
单萜吲哚生物碱生物合成
  • 批准号:
    RGPIN-2017-04145
  • 财政年份:
    2021
  • 资助金额:
    $ 2.11万
  • 项目类别:
    Discovery Grants Program - Individual
Monoterpenoid indole alkaloid biosynthesis
单萜吲哚生物碱生物合成
  • 批准号:
    RGPIN-2017-04145
  • 财政年份:
    2020
  • 资助金额:
    $ 2.11万
  • 项目类别:
    Discovery Grants Program - Individual
Monoterpene indole alkaloid gene discovery and evolution in the Apocynaceae
夹竹桃科单萜吲哚生物碱基因的发现和进化
  • 批准号:
    RGPIN-2015-05151
  • 财政年份:
    2019
  • 资助金额:
    $ 2.11万
  • 项目类别:
    Discovery Grants Program - Individual
Monoterpenoid indole alkaloid biosynthesis
单萜吲哚生物碱生物合成
  • 批准号:
    RGPIN-2017-04145
  • 财政年份:
    2019
  • 资助金额:
    $ 2.11万
  • 项目类别:
    Discovery Grants Program - Individual
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