Novel Chemoenzymatic Approaches to 'Unnatural' Terpenes

“非天然”萜烯的新化学酶方法

• 批准号: 2264677
• 金额: --
• 依托单位: University of Warwick
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2264677
• 关键词: Novel; Chemoenzymatic; Approaches; Unnatural; Terpenes

Natural products constitute a rich source of molecules and materials, from which groundbreaking therapeutic agents for the treatment of human, animal and plant diseases derive, as well as valuable compounds of commercial and industrial use. In particular, terpenes constitute the most abundant class of natural products, with more than 75,000 characterised so far - including compounds of industrial and pharmaceutical significance, such as the antimalarial artemisinin, the anti-cancer agent taxol and natural rubber.Terpene carbon backbones are assembled in a 'modular' fashion through consecutive condensation of isoprenyl-based building blocks. Moreover, terpene synthase intermediates undergo extensive diversification, generating highly complex structures that are very challenging to prepare by synthetic chemistry methods. The difficulty of producing terpenes via total synthesis, as well as the fact that terpene synthase-derived drugs and biomaterials are still mostly produced biosynthetically or harvested, means that new approaches to novel valuable terpenoid generation should to be explored.The aim of this PhD project is to investigate and establish novel chemoenzymatic approaches to 'unnatural' terpenes, which may be as valuable, if not superior, to existing natural terpene products. This will be accomplished via the preparation of chemical probes capable of 'capturing' terpene intermediates throughout product assembly to gather in-depth pathway and mechanistic understanding; the preparation of chemical 'synthons' that can be uptaken and processed by engineered microorganisms and terpene pathways to generate the 'unnatural' molecules; the isolation and characterisation of these novel chemical entities, including the evaluation of their biological activity. The outcomes of this work will constitute the basis for the development of novel biocatalytic routes to diversified natural products.

天然产品含有丰富的分子和材料，从中衍生出用于治疗人类、动物和植物疾病的突破性治疗剂，以及商业和工业用途的有价值的化合物。特别是，萜类是最丰富的天然产物类别，到目前为止已有超过75,000种具有特征的化合物-包括具有工业和制药意义的化合物，如抗疟疾青蒿素、抗癌剂紫杉醇和天然橡胶。萜类碳主链通过基于异戊二烯的构建块的连续缩合以“模块化”的方式组装。此外，萜烯合成酶中间体经历了广泛的多样化，产生了高度复杂的结构，用合成化学方法制备是非常具有挑战性的。通过全合成来生产萜类化合物的难度，以及萜类合成酶衍生的药物和生物材料仍然主要是通过生物合成或收获的事实，意味着需要探索新的方法来产生有价值的萜类化合物。本博士项目的目的是研究和建立新的化学酶法方法来处理非天然的萜类化合物，这些方法可能与现有的天然萜类产品一样有价值，如果不是更好的话。这将通过以下方式实现：制备能够在整个产品组装过程中“捕获”萜类中间体的化学探针，以收集深入的途径和机理了解；制备可被工程微生物摄取和处理的化学“合成子”，以及生成“非天然”分子的萜类途径；分离和表征这些新的化学实体，包括评估它们的生物活性。这项工作的结果将为开发新的生物催化路线以获得多样化的天然产品奠定基础。