Mechanisms in RiPP Natural Product Biosynthesis

RiPP 天然产物生物合成机制

• 批准号: RGPIN-2017-04485
• 负责人: Thibodeaux, Christopher
• 金额: $ 1.97万
• 依托单位: McGill University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=666735
• 关键词: Mechanisms; RiPP; Natural; Product; Biosynthesis

Natural products are chemical compounds made by living organisms that serve numerous biological, ecological, and anthropological functions – most notably as medicines to treat a variety of human illnesses. Indeed, the majority of all drugs approved for human use by the US Food and Drug Administration are either natural products or are synthetic derivatives of natural products, clearly underscoring the importance of these molecules to the quality of human life in the 21st century. In recent years, however, many of the natural products that have been traditionally used to treat human bacterial infections have lost their effectiveness due to the widespread emergence of antimicrobial resistance. In light of this daunting threat, renewed efforts in discovering and developing novel antimicrobial natural products are urgently needed. The proposed research program seeks to address this growing crisis through several distinct, but cohesive research directions that aim to illuminate the mechanistic principles of the enzymes that construct natural products. Initial studies will be focused on developing several emerging biophysical methods to characterize biosynthetic enzymes from unique perspectives. These studies will provide a molecular mechanistic understanding of what enables biosynthetic enzymes to perform their functions, and will provide insights into how those functions may potentially be manipulated for synthetic purposes. In addition, the program will identify and characterize molecules with unusual structures and enzymes with unusual functions, as potential avenues for identifying new antimicrobial compounds and new tools for the structural modification of compounds, respectively. Altogether, understanding*natural product biosynthesis on a molecular mechanistic level provides a*critical foundation for guiding the characterization of new natural products, for the rational*engineering of structures that do not exist in nature, a-nd for the targeted production of molecules of interest. As such, the proposed research program is expected to greatly benefit the ongoing and mounting struggle to combat drug resistant human pathogens - an endeavor of immense importance to the people of Canada and across the world.

天然产物是由生物体产生的化合物，具有许多生物学，生态学和人类学功能-最显着的是作为治疗各种人类疾病的药物。 事实上，美国食品和药物管理局批准用于人类使用的大多数药物要么是天然产品，要么是天然产品的合成衍生物，这清楚地强调了这些分子对21世纪人类生活质量的重要性。 然而，近年来，许多传统上用于治疗人类细菌感染的天然产品由于抗菌素耐药性的广泛出现而失去了有效性。 鉴于这一令人生畏的威胁，迫切需要重新努力发现和开发新的抗微生物天然产品。拟议的研究计划旨在通过几个不同但有凝聚力的研究方向来解决这一日益严重的危机，这些研究方向旨在阐明构建天然产物的酶的机械原理。 最初的研究将集中在开发几种新兴的生物物理方法，从独特的角度来表征生物合成酶。 这些研究将提供一个分子机制的理解是什么使生物合成酶执行其功能，并将提供洞察这些功能可能如何被操纵用于合成目的。 此外，该计划将识别和表征具有不寻常结构的分子和具有不寻常功能的酶，分别作为识别新抗菌化合物和化合物结构修饰的新工具的潜在途径。 总之，在分子机理水平上理解天然产物的生物合成为指导新天然产物的表征、为合理设计自然界中不存在的结构以及为目标分子的生产提供了重要的基础。 因此，拟议的研究计划预计将大大有利于正在进行的和日益增加的斗争，以打击耐药的人类病原体-一个非常重要的努力，加拿大和世界各地的人民。