Collaborative Research: Interfacing Students at Three Universities to Elucidate Enzymatic Transformations of Guanide Compounds that Impact Health and the Environment

合作研究：与三所大学的学生合作，阐明影响健康和环境的胍化合物的酶促转化

• 批准号: 2203750
• 负责人: Lawrence Wackett
• 金额: $ 39.84万
• 依托单位: University of Minnesota-Twin Cities
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2203750&HistoricalAwards=false
• 关键词: Collaborative; Research; Interfacing; Students; Three

With the support of the Chemistry of Life Processes (CLP) program in the Division of Chemistry, Drs. Martin St. Maurice from Marquette University, Lawrence Wackett from University of Minnesota-Twin Cities, and Betsy Martinez-Vaz from Hamline University are studying the enzymes and metabolic pathways that microbes use to degrade guanide and biguanide compounds that are commonly found in fertilizers, fuel propellants and pharmaceuticals. The most notable example is the biguanide drug metformin, which represents the fourth most prescribed pharmaceutical on the planet. Metformin is entering wastewater treatment plants at an alarming rate, with no clear sense of how it is being degraded by microorganisms. Using detailed studies of enzyme structure/function, chemical biology, comparative genomics and microbiology, this project aims to identify the metabolic pathway(s) and characterize the bacterial enzymes responsible for biodegrading metformin and related guanide and biguanide compounds. This project is expected to provide useful data to assist scientists and engineers in the development of better bioremediation practices in municipal water treatment plants where metformin is a major entering chemical. Further, this project integrates teaching, mentorship and training across three universities by incorporating the proposed research directly into graduate training, multi-institutional undergraduate courses, career mentorship and summer internships, significantly broadening the impact of the project.This project seeks to generate a comprehensive description of the metabolic pathways that are available naturally for the degradation of guanidinium compounds by microbial species and their relevant enzymes in wastewater and also in the human gut environment. The central metabolic artery includes the combined activities of guanylurea hydrolase, guanidine carboxylase, carboxyguanidine deiminase and allophanate hydrolase. The molecular contributions to the substrate selectivity of guanidine carboxylase will be characterized by x-ray crystallography and enzyme kinetic analysis. The structure and function of the carboxyguanidine deiminase enzyme will be examined by investigating the mechanism of catalysis, the functional role of the subunits and the potential for substrate channeling. The pathway and enzyme(s) responsible for bacterial metformin degradation will be identified by a combination of enzyme isolation, purification, and comparative genomics, across potentially relevant bacterial species, followed by detailed structural and functional characterization of the metformin-degrading enzyme(s). This project is expected to provide new information on how biguanide compounds are funneled into biodegradation pathways, providing a gateway to better understanding of how one important class of nitrogen-rich man-made compounds, produced across a variety of industrial sectors, is environmentally degraded.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

在化学过程的化学过程（CLP）计划的支持下，博士。马奎特大学的马丁·圣莫里斯（Martin St. Maurice），明尼苏达大学 - 两者大学城市的劳伦斯·瓦克特（Lawrence Wackett推进剂和药品。最值得注意的例子是Biguanide药物二甲双胍，它代表了地球上第四种规定的药物。二甲双胍以惊人的速度进入废水处理厂，没有明确的了解微生物如何降解。使用酶结构/功能，化学生物学，比较基因组学和微生物学的详细研究，该项目旨在鉴定代谢途径，并表征负责生物降解二甲苯蛋白和相关鸟巢和BIGUANIDE化合物的细菌酶。预计该项目将提供有用的数据，以帮助科学家和工程师在市政水处理厂开发更好的生物修复实践，而二甲双胍是主要进入化学物质的。此外，该项目通过将拟议的研究直接纳入研究生培训，多机构的本科课程，职业指导和暑期实习，将教学，指导和培训整合到三所大学中，从而大大拓宽了该项目的影响。描述自然可用于在废水中以及在人类肠道环境中的微生物物种及其相关酶降解的代谢途径。中央代谢动脉包括鸟苷水解酶，鸟苷羧化酶，羧基甘油丁胺脱氨酸酶和同种素水解酶的联合活性。对鸟嘌呤羧化酶底物选择性的分子贡献将以X射线晶体学和酶动力学分析为特征。羧基胰蛋白酶脱节酶的结构和功能将通过研究催化的机制，亚基的功能作用和底物通道的潜力来检查。负责细菌二甲双胍降解的途径和酶将通过跨潜在相关细菌物种的酶隔离，纯化和比较基因组学的结合来鉴定，然后是详细的结构和功能表征，详细的结构和功能特征。预计该项目将提供有关如何将Biguanide化合物插入生物降解途径的新信息，从而为更好地理解一类重要的氮富含氮的人造化合物提供了一个门户，这些化合物是如何在各个工业领域产生的。该奖项反映了NSF的法定使命，并通过使用基金会的知识分子和更广泛的影响审查标准进行评估而被认为值得支持。