# STUDIES ON FATTY ACID METABOLIZING CYTOCHROME P450 ENZYMES

> **NIH NIH R35** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $376,787

## Abstract

PROJECT SUMMARY AND ABSTRACT
 Cytochrome P450 enzymes (P450, CYP) are essential for the metabolism of xenobiotics and endobiotics. The
CYP4F family of fatty acid -hydroxylases consists of the isoforms CYP4F2, CYP4F3A, CYP4F3B, CYP4F11,
and CYP4F22 which share amino acid sequence identities up to 93%. All of these isoforms assume different
functions in the human body spanning vitamin K and drug metabolism, ceramide production, and the production
of the important lipid mediator 20-hydroxteicosatetraenoic acid (20-HETE) from arachidonic acid. 20-HETE
regulates the blood pressure but is also associated with human disease, such as hypertension, traumatic brain
injury, and cancer. An inhibition of 20-HETE producing CYP4 isoforms ameliorates these diseases in animal
models which demonstrated their tremendous potential as drug targets. Yet, the involvement of individual CYP4F
isoforms in distinct diseases has not been examined yet and too little is known about their differential structure
and function to target them individually. My research vision is to perform an in-depth functional and structural
characterization of CYP4F -hydroxylases to unravel their impact on cellular processes and promote their use
as drug targets. My lab will close three significant gaps in current CYP4F research.
 First, we will elucidate the function of CYP4F isoforms in physiology and disease. My lab has previously shown
that the isoform CYP4F11 is significantly overexpressed in lung cancer. A transient knockdown of CYP4F11 in
lung cancer cell lines leads to a significantly reduced cell proliferation and migration which is associated with
reduced 20-HETE production. Using lung cancer as a model disease, we will perform transcriptomics and
lipidomics studies to unravel metabolic pathways and differences in lipid composition which impact CYP4F11-
dependent cell proliferation. We will extend our studies to additional CYP4F isoforms and their involvement in
noncancerous diseases. Second, we will demonstrate that the function of CYP4F enzymes is regulated by the
redox partner proteins cytochrome P450 reductase (CPR) and cytochrome b5 (CYB5). Both proteins show a
significant allosteric effect on catalytic efficiency and ligand binding affinity for drug metabolizing and
steroidogenic P450 enzymes. However, their impact on CYP4F -hydroxylases has never been investigated.
Using recombinant human CPR and CYB5, my team will conduct a thorough evaluation of their impact on CYP4F
catalysis and the binding of substrates and drugs. Third, there is currently no structural information available for
any of the human CYP4 -hydroxylase which significantly hampers our understanding of enzyme function and
isoform specific substrate specificities. We will solve the very first structure of a human CYP4F -hydroxylase
using X-ray protein crystallography. My lab has successfully generated crystals of the isoform CYP4F11 in
complex with the inhibitor HET0016 which will soon be screened for diffracti...

## Key facts

- **NIH application ID:** 10938193
- **Project number:** 1R35GM155319-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Simone Brixius-Anderko
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $376,787
- **Award type:** 1
- **Project period:** 2024-07-01 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10938193

## Citation

> US National Institutes of Health, RePORTER application 10938193, STUDIES ON FATTY ACID METABOLIZING CYTOCHROME P450 ENZYMES (1R35GM155319-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10938193. Licensed CC0.

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