Functional Dynamics and Interactions of CYP19

Cytochromes P450 (CYPs) metabolize a wide range of drugs, carcinogens, hormones, and other xenobiotics. Their role in detoxification makes them crucial for optimizing drug safety. Steroid biosynthetic CYPs are targets for cancer, endocrine, and infectious diseases. Their ability to activate stable C−H bonds has led to ongoing interest in engineering them as novel biocatalysts. Our long-term objectives are to unravel the fundamental structure-function- dynamics relationships that govern CYP function. We have chosen the aromatase (CYP19) family as a model system. Aromatase holds significant importance as the most primitive human CYP, catalyzing a mechanistically intricate multistep synthesis of estrogens from androgens. This process is crucial for human health and plays a vital role in disease treatment. In this proposal, we aim to investigate several key questions that hold general relevance to the entire CYP superfamily. These questions include: 1. What are the critical functional dynamics of CYP19? 2. How are CYP19 and cytochrome P450 reductase (CPR) oriented in membranes? 3. How are CYP-CPR complexes organized in and scaffolded by membranes? The proposed studies will integrate classical biophysical techniques with cutting-edge tools, such as synchrotron X-ray foot printing mass spectrometry (XFMS), small X-ray scattering (SAXS), small-angle neutron scattering (SANS), and novel structural refinement methods. These advanced techniques will provide valuable insights into the critical, conserved functional dynamics underlying CYP19 function, the details of CYP19- and CPR membrane interactions, and the architecture of the CYP19-CPR complex. Project Number: 1R35GM161790-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: John Hackett | Institution: FLORIDA INTERNATIONAL UNIVERSITY, MIAMI, FL | Award Amount: $405,625 | Activity Code: R35 | Study Section: Special Emphasis Panel[ZRG1 MBBC-A (57)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11260688