LEAPS-MPS: Determining All the Contributions of Adrenodoxin to Cytochrome P450 Catalysis

LEAPS-MPS：确定肾上腺氧还蛋白对细胞色素 P450 催化的所有贡献

• 批准号: 2213207
• 负责人: Michael Reddish
• 金额: $ 24.98万
• 依托单位: Appalachian State University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2213207&HistoricalAwards=false
• 关键词: LEAPS; MPS; Determining; Contributions; Adrenodoxin

This award is funded in whole or in part under the American Rescue Plan Act of 2021 (Public Law 117-2). In this project, funded by the Mathematical and Physical Sciences Directorate and housed in the Chemistry Division, Professor Michael Reddish and his students at Appalachian State University will investigate how a group of proteins, called ferredoxin proteins, enable cytochrome P450 enzymes to catalyze a wide range of chemical reactions in animals, plants, fungi, bacteria, and archaea. Cytochrome P450 enzymes naturally play a role in the metabolism of drugs, steroids, and other chemicals. Understanding how cytochrome P450 enzymes work enables the design of new medicines and more environmentally friendly industrial processes. Professor Reddish will also utilize resources from this project to: (1) Pay undergraduate students so they can meet their financial needs through research instead of external jobs; (2) Develop a new way to teach introductory chemistry that focuses on cohort-building so that all students feel welcome in science; and (3) Co-lead a course-based undergraduate research experience (CURE) in the upper-level biochemistry lab at Appalachian State University. These activities will enable more students to learn about research and encourage students with diverse histories to become researchers.Professor Reddish proposes to focus on the interactions of human cytochrome P450 27A1 and the human ferredoxin protein adrenodoxin. It is known that ferredoxin proteins supply electrons to cytochrome P450 enzymes. Evidence from various researchers suggests adrenodoxin may further promote catalysis in other ways. The project will include a structural approach to determine if adrenodoxin promotes catalysis by forcing the enzyme to a more “active” shape. The project will also test to see if adrenodoxin changes the functionality of the enzyme by altering ligand binding to the enzyme or altering reactivity of molecular oxygen utilized by the enzyme. It is proposed that a clear understanding of all roles of adrenodoxin in cytochrome P450 27A1 catalysis will allow for a better understanding of how other ferredoxins enable cytochrome P450 catalysis from a wide variety of sources and how their reactivity can be modified.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.

该奖项全部或部分由《2021 年美国救援计划法案》（公法 117-2）资助。在该项目中，由数学和物理科学理事会资助，设在化学系，Michael Reddish 教授和他的学生。阿巴拉契亚州立大学的研究人员将研究一组称为铁氧还蛋白的蛋白质如何使细胞色素 P450 酶催化动物、植物、细胞色素 P450 酶在药物、类固醇和其他化学物质的代谢中自然发挥作用。了解细胞色素 P450 酶的工作原理有助于设计新药物和更环保的工业流程。该项目的资源用于：（1）向本科生支付费用，以便他们能够通过研究而不是外部工作来满足他们的财务需求（2）开发一种新的化学入门教学方法，重点是群体建设，以便他们能够所有学生都感到科学受到欢迎；(3) 在阿巴拉契亚州立大学的高级生物化学实验室共同领导基于课程的本科生研究体验 (CURE) 这些活动将使更多的学生了解研究并鼓励学生进行研究。 Reddish 教授建议重点研究人类细胞色素 P450 27A1 和人类铁氧还蛋白蛋白肾上腺素的相互作用。众所周知，铁氧还蛋白为蛋白质提供电子。来自不同研究人员的证据表明，肾上腺素还可以通过其他方式进一步促进催化作用，该项目还将测试肾上腺素是否通过迫使酶形成更“活跃”的形状来促进催化作用。如果肾上腺素还通过改变配体与酶的结合或改变酶利用的分子氧的反应性来改变酶的功能，则建议清楚地了解肾上腺素还素在细胞色素中的所有作用。 P450 27A1 催化作用将有助于更好地了解其他铁氧还蛋白如何实现多种来源的细胞色素 P450 催化作用，以及如何修改它们的反应性。该奖项反映了 NSF 的法定使命，并通过使用基金会的知识产权进行评估，被认为值得支持。优点和更广泛的影响审查标准。