Novel Chemoenzymatic Approaches to 'Unnatural' Terpenes

天然产物是分子和材料的丰富来源，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都是从这些物质中衍生出来的。特别是，萜烯构成了最丰富的一类天然产物，迄今已鉴定出超过7.5万种——包括具有工业和制药意义的化合物，如抗疟疾的青蒿素、抗癌剂紫杉醇和天然橡胶。萜烯碳骨架通过异戊二烯基构建块的连续缩合以“模块化”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，通过合成化学方法制备非常具有挑战性。通过全合成生产萜烯的困难，以及萜烯合成酶衍生的药物和生物材料仍然主要是生物合成或收获的事实，意味着应该探索新的有价值的萜类化合物的新方法。这个博士项目的目的是研究和建立新的化学酶法来处理“非天然”萜烯，这种方法可能与现有的天然萜烯产品一样有价值，如果不是更好的话。这将通过制备能够在产品组装过程中“捕获”萜烯中间体的化学探针来完成，以收集深入的途径和机制理解；化学“合成子”的制备，可以被工程微生物和萜烯途径吸收和处理，以产生“非自然”分子；这些新型化学实体的分离和表征，包括其生物活性的评价。这项工作的结果将构成开发新的生物催化途径，以多样化的天然产物的基础。

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.