Combinatorial Biosynthesis of Fungal Meroterpenoid Assembly Lines

该研究项目的科学目标是利用真菌类萜生物合成机制，通过组合生物合成方法产生具有潜在新的或改进的生物学特性的新型分子结构。类萜属于具有药学相关特征的杂合次级代谢物的结构多样性组。该组的已知成员及其合成衍生物在临床上用作免疫抑制药物或已被开发为商业杀虫剂。其他已知的部分萜类化合物含有结构基序，其是有前途的药物先导，目前正在研究用于治疗动脉粥样硬化或神经退行性疾病如阿尔茨海默病。除了化学合成方法之外，组合生物合成方法是产生新的或改变的分子结构的独特工具，并且通过重组不同的生物合成基因来利用代谢途径的系统操纵。将这种方法应用于meroterpenoids的遗传基础最近才被发现，并且meroterpenoids途径的合理和受控重组以创建第二代分子是本研究项目的重点。具体而言，潜在的关键酶，最近发现的meroterpenoid环化酶家族，催化形成新的分子支架将被利用。为此，将详细研究它们的底物混杂性，并基于所获得的结果，设计人工生物合成途径并在异源宿主中重建。通过这种方法可以实现新的“非天然”天然产物的有效生产，并将研究所获得化合物的生物活性。该研究项目的结果可能有助于通过获得新的候选药物或药物先导结构来改善人类健康。与此同时，对类萜生物合成的酶基础的深入了解将有助于未来的进展，以工程和进化其催化活性，以满足人类或生态目的。

The scientific goal of the research project is the utilization of fungal meroterpenoid biosynthetic machineries to generate novel molecular structures with potentially new or improved biological properties by a combinatorial biosynthetic approach.Meroterpenoids belong to a structurally diverse group of hybrid secondary metabolites with pharmaceutically relevant features. Known members of this group and synthetic derivatives thereof are clinically used as immunosuppressant drugs or have been developed as commercial insecticides. Other known meroterpenoids contain structural motifs, which are promising drug leads and are currently investigated for the treatment of atherosclerosis or neurodegenerative diseases like Morbus Alzheimer. Besides chemical synthetic approaches, the combinatorial biosynthesis method is a unique tool to generate novel or altered molecular structures and makes use of the systematic manipulation of metabolic pathways by recombination of different biosynthetic genes. The genetic basis to apply this method to meroterpenoids has only recently been discovered and the rational and controlled recombination of meroterpenoid pathways to create second-generation molecules is the focus of this research project. Specifically, the potential of key enzymes, the recently discovered family of meroterpenoid cyclases, to catalyze formation of new molecular scaffolds will be exploited. For that purpose, their substrate promiscuity will be investigated in detail and based on the obtained results, artificial biosynthetic pathways will be designed and reconstituted in a heterologous host. By this method an efficient production of the new "unnatural" natural products can be achieved and the biological activity of the obtained compounds will be investigated.The results from this research project can potentially contribute to improve human health by obtaining new drug candidates or drug lead structures. At the same time, the in-depth knowledge about the enzymatic basis of meroterpenoid biosynthesis will contribute to future advances to engineer and evolve their catalytic activities to meet human or ecological purposes.