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

真菌天然产物：工程生物合成途径以提供新型生物活性化合物

• 批准号: 2752289
• 金额: --
• 依托单位: University of Bristol
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2752289
• 关键词: Fungal; Natural; Products; Engineering; Biosynthetic

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.

天然产物研究在科学努力中发挥着至关重要的作用，导致用于作物科学和制药工业的新型生物活性化合物。对真菌培养物的探索在发现关键药物方面特别富有成效，如抗生素（青霉素）和降胆固醇药物（洛伐他汀）以及农业中的铅（例如嗜球果伞素，商业上重要的抗真菌化合物嘧菌酯的灵感）。此外，对真菌天然产物的生物合成研究为遗传学和酶学提供了迷人的见解，并具有操纵途径以清洁有效地提供新的生物活性产物的前景。本项目将侧重于马来酸酐，聚酮衍生天然产物的一个重要家族，特征为具有一个或两个稠合马来酸酐部分的中等大小脂环，例如，bysochlamic acid（组装在9元环核上的九元环）和zopfiellin，八元环（具有8元中心环）。它们表现出重要的生物活性，例如，红曲霉毒素A具有增强抗癌免疫力的潜力，从而导致肿瘤消退，并且选择性除草剂玉米黄素抑制杂草的生长，但对玉米作物无害。国际化学艾德，2016，55，6784）。初始变化是通过不同的单体链长和饱和度引入的，由高度还原的聚酮化合物脱氢酶控制。多种二聚化模式导致核心初级马来酸酐环状结构的多样性，然后经历进一步的剪裁，增加成熟化合物的复杂性。定制反应可以包括羟基化、γ-羟基丁烯二酸生成和环收缩。我们将筛选产生马来酸酐的真菌，以鉴定其生物合成基因。将阐明其生物合成途径中的关键步骤（例如，环收缩的迷人机制，Chem Sci，2020，11，11570）。将使用一系列技术（包括基因敲除、异源表达、生物转化和后期化学功能化）生成新型化合物库，并将评估其生物活性。