Deciphering complex machineries that produce ribosomally synthesised natural products

破译生产核糖体合成天然产物的复杂机器

• 批准号: BB/W003090/1
• 负责人: Jesko Koehnke
• 金额: $ 59.28万
• 依托单位: University of Glasgow
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FW003090%2F1
• 关键词: Deciphering; complex; machineries; produce; ribosomally

Human society is in constant need of new drugs, for example to win the arms race with emerging antibiotic resistant superbugs. Historically, natural products have been our best source of novel, bioactive compounds (for example, penicillin which was first isolated from a fungal mold). In fact, in the important fields of cancer and microbiology, almost 75% of all drugs on the market are natural products isolated from plants, marine organisms or microorganisms, such as bacteria. The ability of bacteria to make these sought-after natural products is encoded in their genomes. Over 300,000 bacterial genomes have been sequenced and made publicly available. They provide data for millions of unknown natural products, some of which will prove essential to curing diseases. The problem we face is that it is impossible to work on all of them, so we need to make smart choices.Ribosomally synthesized and post-translationally modified peptides (RiPPs) are natural products made by many different types of cells. RiPPs display a wide variety of promising bioactivities, including anti-viral, anti-tumor and antibiotic. They have also been linked to anti-fungal and painkilling activities. As a result of their manifold bioactivities, a variety of RiPP derivatives are currently undergoing therapeutic evaluation and RiPPs in general are the focus of many biotech start-up companies whose aim is to try to harness them as medicines of the future. RiPPs are made by the cell's ribosomes - the molecular machines that make proteins and shorter chains of amino acids. RiPPs start off as short chains of amino acids that are then modified by a cascade of enzymes within the cell to produce the final bioactive product. The chemical and structural diversity introduced by the modifying enzymes expands the available repertoire of products far beyond the 20 amino acids that would otherwise be available from the ribosome.A result of this remarkable chemical and structural diversity is that the prediction of RiPP structures from the bacterial genome sequence alone is largely impossible. We need a much better understanding of the enzymes involved in their biosynthesis to make robust predictions and thus prioritize pathways to work on. A detailed understanding of the enzymes involved in RiPP biosynthesis will address this issue, and will allow us and others to improve the bioengineering of enzymes in order to improve their function and to induce them to make an even wider variety of useful medically valuable products. It will also address problems with the supply of natural products, inspire new methods for their production and, crucially, inform the process of rational compound modifications for drug development.We have selected two protein complexes involved in the biosynthesis of RiPPs that share mechanistic but not chemical commonalities. These two complexes will be investigated using state-of-the art techniques that have never been combined to study RiPP complexes before. This approach and the results generated will provide a step-change in our understanding of the selected RiPP biosynthetic complexes and be instrumental in unlocking their full potential. We expect that the results of this work will enable research laboratories and biopharmaceutical companies to produce more of the drug compounds that the world needs and expects.

人类社会不断需要新的药物，例如赢得与新兴抗生素耐药性超级细菌的军备竞赛。从历史上看，天然产物一直是我们最好的新型生物活性化合物来源（例如，青霉素，它首先从真菌霉菌中分离出来）。事实上，在癌症和微生物学等重要领域，市场上几乎75%的药物都是从植物、海洋生物或微生物（如细菌）中分离出来的天然产物。细菌制造这些受欢迎的天然产物的能力在它们的基因组中编码。超过300，000个细菌基因组已被测序并公开。它们为数百万种未知的天然产物提供了数据，其中一些将被证明对治疗疾病至关重要。我们面临的问题是，不可能对所有这些肽进行研究，因此我们需要做出明智的选择。核糖体合成和后修饰肽（RIPPs）是由许多不同类型的细胞产生的天然产物。RIPPs具有广泛的生物活性，包括抗病毒、抗肿瘤和抗生素等。它们还与抗真菌和止痛活动有关。由于其多种生物活性，目前正在对各种RiPP衍生物进行治疗评估，并且RIPP通常是许多生物技术初创公司的焦点，这些公司的目标是试图将其作为未来的药物。RIPP是由细胞的核糖体制造的，核糖体是制造蛋白质和氨基酸短链的分子机器。RIPP起始于氨基酸的短链，然后通过细胞内的酶级联进行修饰，以产生最终的生物活性产物。修饰酶引入的化学和结构多样性使可利用的产物库远远超出了原本可从核糖体获得的20个氨基酸。这种显著的化学和结构多样性的结果是，仅从细菌基因组序列预测RiPP结构在很大程度上是不可能的。我们需要更好地了解参与其生物合成的酶，以做出可靠的预测，从而优先考虑工作的途径。详细了解参与RiPP生物合成的酶将解决这个问题，并将使我们和其他人能够改进酶的生物工程，以改善其功能，并诱导它们产生更广泛的有用的医学价值的产品。它还将解决天然产物的供应问题，激发新的生产方法，至关重要的是，为药物开发提供合理的化合物修饰过程的信息。我们选择了两种参与RIPPs生物合成的蛋白质复合物，它们具有共同的机制，但没有化学共性。这两种复合物将使用最先进的技术进行研究，这些技术以前从未结合起来研究RiPP复合物。这种方法和产生的结果将为我们对所选RiPP生物合成复合物的理解提供一个步骤，并有助于释放其全部潜力。我们希望这项工作的结果将使研究实验室和生物制药公司能够生产出更多世界需要和期望的药物化合物。