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

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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.