Functional dynamics and interactions of CYP19

The National Institute of General Medical Sciences awarded Florida International University $405,625 on April 1, 2026, under the Biomedical Research and Research Training program (CFDA 93.859) to investigate the functional dynamics, membrane orientation, and complex organization of cytochrome P450 aromatase (CYP19) and its interactions with cytochrome P450 reductase (CPR).

The research integrates classical biophysical techniques with advanced tools including synchrotron X-ray footprinting mass spectrometry, small-angle X-ray scattering, small-angle neutron scattering, and novel structural refinement methods to address three core questions: the critical functional dynamics of CYP19; the membrane orientation of CYP19 and CPR; and how CYP-CPR complexes are organized and scaffolded within membranes. The work aims to uncover structure-function-dynamics relationships governing CYP function broadly, using the aromatase family as a model system for understanding how this enzyme catalyzes the multistep synthesis of estrogens from androgens, with applications to cancer, endocrine, and infectious disease treatment.

Performance occurs in Miami, Florida. The award period runs from April 1, 2026, through January 31, 2031. This is a project grant, the assistance type used by NIGMS for investigator-initiated biomedical research of demonstrated scientific merit.

Abstract

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.