Fungal Natural Products: Engineering Biosynthetic Pathways to Deliver Novel Bioactive Compounds

天然产物研究在为作物科学和制药工业提供新型生物活性化合物的科学努力中起着至关重要的作用。真菌培养的探索在发现关键药物(如抗生素（青霉素）和降胆固醇药物（洛伐他汀）以及农业方面的领先地位（如strobilurin，商业上重要的抗真菌化合物azoxystrobin的灵感来源）方面取得了特别丰硕的成果。此外，真菌天然产物的生物合成研究为遗传学和酶学提供了令人着迷的见解，并有望操纵途径以清洁高效地提供新的生物活性产物。该项目将重点研究马来烯基化合物，这是一个重要的聚酮衍生的天然产物家族，其特征是一个中等大小的脂环，其中包含一个或两个融合的马来酸酐基团，例如：byssochlamic acid（一个非二烯基化合物组装在一个9元环核上）和zopfiellin，一个八烯基化合物（具有一个8元中心环）。它们表现出重要的生物活性，例如rubbratoxin A具有增强抗癌免疫从而导致肿瘤消退的潜力，而cornexistin是一种选择性除草剂，可以抑制杂草的生长，但对玉米作物无害。马来烯是通过迷人的途径生物合成的，其中包括区域化学二聚化反应，由相同的一组独特的马来烯酶控制。化学。Int。编辑，2016,55,6784)。最初的变化是由不同的单体链长度和饱和水平引入的，由高度还原的聚酮合酶控制。多种二聚化模式导致核心原生马来烷环结构的多样性，然后进行进一步的裁剪，增加成熟化合物的复杂性。裁剪反应包括羟基化、γ -羟基丁烯内酯生成和环收缩。我们将筛选产生雄性激素的真菌，以表征它们的生物合成基因。将阐明其生物合成途径的关键步骤（例如，环收缩的迷人机制，化学科学，2020,11,11570）。新化合物库将使用一系列技术生成，包括基因敲除、异种表达、生物转化和后期化学功能化，并将评估它们的生物活性。

Natural products research plays a vital role in scientific endeavour leading to novel bioactive compounds for use in crop science and the pharmaceutical industry. Exploration of fungal cultures has been particularly fruitful in the discovery of key pharmaceuticals such as antibiotics (penicillin) and cholesterol lowering drugs (lovastatin) as well as leads in agriculture (e.g. strobilurin, an inspiration for the commercially important antifungal compound azoxystrobin). In addition, biosynthetic studies on fungal natural products are providing fascinating insights into genetics and enzymology with the prospect of manipulating pathways to provide new bioactive products cleanly and efficiently.This project will focus on the maleidrides, an important family of polyketide-derived natural products characterised by a medium-sized alicyclic ring with one or two fused maleic anhydride moieties e.g. byssochlamic acid (a nonadride assembled on a 9-membered ring core) and zopfiellin, an octadride (with an 8-membered central ring). They exhibit important bioactivities e.g. rubratoxin A has the potential to enhance anticancer immunity leading to tumour regression and cornexistin, a selective herbicide, inhibits the growth of weeds, but is not harmful to maize crops.The maleidrides are biosynthesised via fascinating pathways which include regiochemical dimerisation reactions, controlled by the same unique set of maleidride enzymes (Angew. Chem. Int. Ed, 2016, 55, 6784). Initial variation is introduced by differing monomer chain lengths and saturation level, controlled by highly reducing polyketide synthases. Multiple dimerisation modes lead to diversity in the core primary maleidride cyclic structure, which then undergoes further tailoring, increasing the complexity of the mature compound. Tailoring reactions can include hydroxylation, gamma-hydroxybutenolide generation, and ring contraction. We will screen maleidride producing fungi to characterise their biosynthetic genes. Key steps in their biosynthetic pathways will be elucidated (e.g. the fascinating mechanism of ring contraction, Chem Sci, 2020, 11, 11570). A library of novel compounds will be generated using a range of techniques including gene knock-out, heterologous expression, biotransformations and late-stage chemical functionalisation and their bioactivities will be assessed.