# Dynamics and Interactions of Cytochrome P450 19A1

> **NIH NIH R01** · FLORIDA INTERNATIONAL UNIVERSITY · 2022 · $335,914

## Abstract

The cytochromes P450 (CYPs) are responsible for a dazzling array of transformations in the disposition of
xenobiotics and biosyntheses of hormones. Over 70% of drugs are metabolized by CYPs; hence tremendous
resources are devoted to identification of substrates and inhibitors in drug development to avoid later attrition,
or adverse drug interactions following introduction into the clinic. Among these, CYPs involved in steroid
hormone biosyntheses are among the key targets for the pharmacotherapy of endocrine disorders and
cancers. The range of catalytic selectivity and the breadth of substrates transformed by CYPs are immense;
however the interplay of protein dynamics, ligand binding, and catalysis used to achieve this flexibility remains
poorly understood. Within this void, nothing is known about how these are impacted by their physiological
context. We have adopted human aromatase (CYP19A1), responsible for estrogen biosynthesis from
androgens, as a model to address these longstanding and important questions. Phylogenetic analysis supports
that CYP19A1 is among the most primordial human CYPs and it is functionally representative of those
steroidogenic enzymes catalyzing sequential transformations. The translational relevance of CYP19A1 cannot
be underestimated since it has vital role in maintaining numerous tissues and has demonstrated immense
value as a pharmacotherapy target for gynecological disorders, cancers and infertility. There are three Specific
Aims to test our hypotheses, we will: 1) Map pathways for 19A1 ligand entry, product egress, and delineate the
structural underpinnings of selectivity. The working hypotheses are that i) substrates, intermediate products,
and inhibitors give rise to unique equilibrium dynamics and ii) that selectivity is conferred by transient bound
states as ligands enter and exit the enzyme through distinct channels. 2) Delineate the impact of membrane
complexity on catalysis, ligand binding kinetics and global dynamics in 19A1. The working hypotheses are i)
Selectivity is dominated by kinetics involving multiple protein states and conformational transitions, ii) catalytic
and inhibitory 19A1 complexes display distinct dynamics, and iii) both protein dynamics and binding kinetics
are impacted by membrane properties. 3) Determine the architecture of 19A1-NDs in variable environments by
small-angle x-ray and neutron scattering. The working hypothesis is that the insertion depth and orientation of
19A1 are determined by the surface and bulk properties of the bilayer. These Aims are technically-
independent, but convergent approaches that are highly synergistic in combination, and will not only allow
novel insight into CYP19A1, but also unveil paradigms that will transform our understanding of CYP function.

## Key facts

- **NIH application ID:** 10401431
- **Project number:** 5R01GM135414-04
- **Recipient organization:** FLORIDA INTERNATIONAL UNIVERSITY
- **Principal Investigator:** John C Hackett
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $335,914
- **Award type:** 5
- **Project period:** 2020-07-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10401431

## Citation

> US National Institutes of Health, RePORTER application 10401431, Dynamics and Interactions of Cytochrome P450 19A1 (5R01GM135414-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10401431. Licensed CC0.

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