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.

该奖项全部或部分根据2021年美国救援计划法案（公法117-2）资助。 在这个项目中，由数学和物理科学理事会资助，并设在化学部，教授迈克尔Reddish和他的学生在阿巴拉契亚州立大学将研究如何一组蛋白质，称为铁氧还蛋白，使细胞色素P450酶催化广泛的化学反应在动物，植物，真菌，细菌和古细菌。细胞色素P450酶天然地在药物、类固醇和其他化学物质的代谢中发挥作用。了解细胞色素P450酶的工作原理有助于设计新药和更环保的工业工艺。Reddish教授还将利用该项目的资源：（1）支付本科生，使他们能够通过研究而不是外部工作来满足他们的经济需求;（2）开发一种新的方法来教授入门化学，重点是群体建设，使所有学生都感到科学的欢迎;以及（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经验（CURE）。Reddish教授建议集中研究人类细胞色素P450 27 A1与人类铁氧还蛋白肾上腺素的相互作用。已知铁氧还蛋白质向细胞色素P450酶提供电子。来自不同研究人员的证据表明肾上腺素还可能以其他方式进一步促进催化。该项目将包括一个结构的方法，以确定是否肾上腺素能促进催化，迫使酶更“活跃”的形状。该项目还将测试肾上腺素还蛋白是否通过改变配体与酶的结合或改变酶所利用的分子氧的反应性来改变酶的功能。明确了解肾上腺氧还蛋白在细胞色素P450 27 A1催化中的所有作用，将有助于更好地了解其他铁氧还蛋白如何从各种来源实现细胞色素P450催化，以及如何改变其反应性。该奖项反映了NSF的法定使命，并被认为值得通过使用基金会的智力价值和更广泛的影响进行评估来支持审查标准。