Elucidating and Engineering Legonmycin Biosynthesis: a framework for heterobicyclic biotransformation

阐明和设计乐冈霉素生物合成：杂双环生物转化的框架

• 批准号: BB/P00380X/1
• 负责人: Hai Deng
• 金额: $ 50.88万
• 依托单位: University of Aberdeen
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FP00380X%2F1
• 关键词: Elucidating; Engineering; Legonmycin; Biosynthesis; framework

Many currently used drugs that we rely on for the treatment of cancer, bacterial infection, immune disorders and viral infections are either natural products or are derived from natural products. As such natural products still remain the major source of lead compounds for the development of new drugs and diagnostic molecules. However, natural products are often complex in terms of structure and composition making them difficult for synthetic chemists to access and thus develop further. In contrast bacteria can possess an amazing inventory of complex chemistry that organic chemists only dream of. In making new molecules, a key challenge is often to identify plausible new scaffolds or motifs (also known as chemical diversity) which is at the heart of drug discovery. We are going to study two bacterial enzymes that have the capability to convert linear peptide into heterobicyclic molecules under mild reactive conditions. These heterobicyclic ring systems are a common motif in biologically important compounds but there does not have any good way of making them by synthetic chemistry. The use of the bacterial enzymes to accomplish chemical tasks is well established in food industry and the benefits in terms of sustainable manufacturing are well document. However, the application of enzymatic process/ industrial biotechnology processes are still under developed the fine chemical, pharmaceutical and agricultural industries. By working out the catalytic capabilities of the two enzymes we will gain the ability to develop their industrial biotechnological potential. In doing this, we will be able to make novel building blocks (also known as scaffolds) and, access new biologically active compounds.

目前我们依赖于治疗癌症、细菌感染、免疫疾病和病毒感染的许多药物都是天然产物或衍生自天然产物。因此，天然产物仍然是开发新药和诊断分子的先导化合物的主要来源。然而，天然产物在结构和组成方面往往很复杂，使得合成化学家难以获得它们，从而难以进一步开发。相比之下，细菌可以拥有有机化学家梦寐以求的复杂化学物质。在制造新分子的过程中，一个关键的挑战通常是识别合理的新支架或基序（也称为化学多样性），这是药物发现的核心。我们将研究两种细菌酶，它们具有在温和的反应条件下将线性肽转化为杂双环分子的能力。这些杂双环系统是生物重要化合物中的常见基序，但没有任何好的方法通过合成化学来制备它们。使用细菌酶来完成化学任务在食品工业中得到了很好的确立，并且在可持续制造方面的好处得到了很好的证明。然而，酶法/工业生物技术方法在精细化工、制药和农业工业中的应用仍处于开发阶段。通过研究这两种酶的催化能力，我们将获得开发其工业生物技术潜力的能力。在这样做的过程中，我们将能够制造新的积木（也称为支架），并获得新的生物活性化合物。

项目成果

Characterization of a class II ketol-acid reductoisomerase from Mycobacterium tuberculosis.

• DOI: 10.1039/d1ra08876a
• 发表时间: 2022-03-31
• 期刊: RSC advances
• 影响因子: 3.9
• 作者: Valera A;Wang S;Carr R;Trembleau L;Deng H
• 通讯作者: Deng H

Discovery and biosynthetic investigation of a new antibacterial dehydrated non-ribosomal tripeptide.

• DOI: 10.1002/anie.202012902
• 发表时间: 2020-10
• 期刊: Angewandte Chemie
• 作者: Shan Wang;Qing Fang;Zhou Lu;Yingli Gao;L. Trembleau;R. Ebel;J. H. Andersen;Carol Philips;Samantha Law;Hai Deng

Aminoacyl chain translocation catalysed by a type II thioesterase domain in an unusual non-ribosomal peptide synthetase.

一种不寻常的非核糖体肽合成酶中 II 型硫酯酶结构域催化的氨酰基链易位

• DOI: 10.1038/s41467-021-27512-0
• 发表时间: 2022-01-10
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Wang S;Brittain WDG;Zhang Q;Lu Z;Tong MH;Wu K;Kyeremeh K;Jenner M;Yu Y;Cobb SL;Deng H
• 通讯作者: Deng H