Harnessing enzymes from plants for selective functionalisation of triterpenoid scaffolds

利用植物酶选择性功能化三萜类支架

• 批准号: BB/S016023/1
• 负责人: Anne Osbourn
• 金额: $ 69.13万
• 依托单位: John Innes Centre
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FS016023%2F1
• 关键词: Harnessing; enzymes; plants; selective; functionalisation

Plants are chemical engineers par excellence. The natural products that they produce have tremendous value in the pharmaceutical, agrochemical and industrial biotechnology industries. However, the availability of such compounds is limited by difficulties in accessing source species, low yield, purification problems, and concerns about environmental sustainability. This problem is further confounded by the fact that the vast majority of plant natural products have highly complex structures and are beyond the reach of chemical synthesis. This means that a vast reservoir of potential new drugs and other valuable chemicals remain locked up inside the plants that produce them. The availability of a growing number of plant genome sequences is now making it possible to 'mine' these sequences for genes encoding the enzymes that make these diverse chemicals. If these enzymes can be harnessed and assembled into a toolkit that would enable biosynthesis and systematic diversification of common core scaffolds this would enable humans to mimic and expand on the chemical diversity found in the plant kingdom and, for example, to make new drugs with improved efficacy and reduced side effects. We are especially interested in a very large and structurally complex class of plant natural products known as triterpenoids. This class of >20,000 natural products, all derived from the same chemically simple common precursor display enormous structural diversity and are a rich source of bioactive molecules. Well known examples include ginsenosides, associated with the 'feel good factor' of ginseng, and glycyrrhizin, a sweetener and anti-inflammatory produced by liquorice. There is considerable interest in the pharmaceutical properties of triterpenoids and several have recently entered clinical trials as anti-inflammatory/anti-cancer drugs (glycyrrhetinic acid and the semi-synthetic triterpenoid bardoxolone methyl). In this proposal, we describe how we will discover how plants synthesise and diversify complex triterpenoid scaffolds. We will garner the enzymes that catalyse these processes and deploy them into a strain of engineered baker's yeast optimised to support triterpene scaffold diversification. We will then investigate the features of these molecules that determine their biological activities.

植物是卓越的化学工程师。它们生产的天然产品在制药、农业化学和工业生物技术行业具有巨大价值。然而，这些化合物的可用性受到难以获得源物种、低产量、纯化问题和对环境可持续性的担忧的限制。这个问题进一步被以下事实所混淆，即绝大多数植物天然产物具有高度复杂的结构，并且超出了化学合成的范围。这意味着大量潜在的新药和其他有价值的化学物质仍然被锁在生产它们的植物中。越来越多的植物基因组序列的可用性现在使得“挖掘”这些序列中编码这些不同化学物质的酶的基因成为可能。如果这些酶可以被利用并组装成一个工具包，使生物合成和系统多样化的共同核心支架，这将使人类能够模仿和扩大在植物王国中发现的化学多样性，例如，制造具有提高疗效和减少副作用的新药。我们特别感兴趣的是一个非常大的和结构复杂的一类植物天然产物称为三萜类化合物。这类> 20，000种天然产物，都来自相同的化学简单的共同前体，显示出巨大的结构多样性，是生物活性分子的丰富来源。众所周知的例子包括人参皂苷，与人参的“感觉良好的因素”有关，以及人参皂苷，一种由人参产生的甜味剂和抗炎剂。三萜类化合物的药物特性引起了相当大的兴趣，并且最近有几种已经作为抗炎/抗癌药物（大黄酸和半合成三萜类化合物甲基巴多索酮）进入临床试验。在这个提议中，我们描述了我们将如何发现植物如何合成和多样化复杂的三萜类支架。我们将收集催化这些过程的酶，并将其部署到一种经过优化的工程面包酵母菌株中，以支持三萜支架多样化。然后，我们将研究这些分子的特征，这些特征决定了它们的生物活性。

项目成果

Subtelomeric assembly of a multi-gene pathway for antimicrobial defense compounds in cereals.

• DOI: 10.1038/s41467-021-22920-8
• 发表时间: 2021-05-07
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Li Y;Leveau A;Zhao Q;Feng Q;Lu H;Miao J;Xue Z;Martin AC;Wegel E;Wang J;Orme A;Rey MD;Karafiátová M;Vrána J;Steuernagel B;Joynson R;Owen C;Reed J;Louveau T;Stephenson MJ;Zhang L;Huang X;Huang T;Fan D;Zhou C;Tian Q;Li W;Lu Y;Chen J;Zhao Y;Lu Y;Zhu C;Liu Z;Polturak G;Casson R;Hill L;Moore G;Melton R;Hall N;Wulff BBH;Doležel J;Langdon T;Han B;Osbourn A
• 通讯作者: Osbourn A

Pathogen-induced biosynthetic pathways encode defense-related molecules in bread wheat.

• DOI: 10.1073/pnas.2123299119
• 发表时间: 2022-04-19
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1

Making drugs out of sunlight and 'thin air': an emerging synergy of synthetic biology and natural product chemistry

利用阳光和“稀薄空气”制造药物：合成生物学和天然产物化学的新兴协同作用

• DOI: 10.1042/bio20200044
• 发表时间: 2020
• 期刊: The Biochemist
• 作者: Stephenson M

Complex scaffold remodeling in plant triterpene biosynthesis.

植物三萜生物合成中的复杂支架重塑。

• DOI: 10.1126/science.adf1017
• 发表时间: 2023-01-27
• 期刊: Science (New York, N.Y.)