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

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。在这个由数学和物理科学理事会资助并设在化学部门的项目中，阿巴拉契亚州立大学的迈克尔·雷迪什教授和他的学生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、真菌、细菌和古细菌的广泛化学反应。细胞色素P450酶在药物、类固醇和其他化学物质的代谢中发挥着天然的作用。了解细胞色素P450酶的工作原理可以设计新药和更环保的工业过程。雷迪什教授还将利用这个项目的资源：(1)支付本科生的费用，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)开发一种新的化学入门教学方法，重点是建立群体，使所有学生都感到科学是受欢迎的；(3)在阿巴拉契亚州立大学（Appalachian State University）高级生物化学实验室共同领导一项基于课程的本科生研究经验（CURE）。这些活动将使更多的学生了解研究，并鼓励具有不同历史的学生成为研究人员。雷迪什教授建议将重点放在人类细胞色素P450 27A1与人类铁氧还蛋白肾上腺素还蛋白的相互作用上。众所周知，铁氧还蛋白为细胞色素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作用。该项目将包括一种结构方法，以确定肾上腺素是否通过迫使酶变成更“活跃”的形状来促进催化。该项目还将测试肾上腺素是否通过改变与酶结合的配体或改变酶利用的分子氧的反应性来改变酶的功能。研究人员提出，清楚地了解肾上腺素还毒素在细胞色素P450 27A1催化中的所有作用，将有助于更好地了解其他铁氧化还毒素如何从各种来源促进细胞色素P450催化，以及如何修改它们的反应性。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

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.