# New mechanism of cellular protein oxidation

> **NIH NIH R21** · GEORGETOWN UNIVERSITY · 2020 · $194,375

## Abstract

Project Summary/Abstract
Reactive oxygen species (ROS) cause oxidative stress and play an important role in the pathogenesis of
various diseases. However, the exact mechanism of ROS action is unknown. ROS oxidize DNA, proteins,
lipids, and small molecules. Carbonylation is one mode of protein oxidation that occurs in response to iron-
catalyzed, hydrogen peroxide (H2O2)-dependent oxidation of amino acid side chains. Although
carbonylated proteins are generally thought to be eliminated by the proteasome-dependent degradation,
my laboratory discovered the protein de-carbonylation mechanism, in which formed carbonyl groups are
enzymatically eliminated without proteins being degraded. Major amino acid residues that are susceptible
to carbonylation include proline and arginine, both of which get oxidized to become glutamic semialdehyde
that contains a carbonyl group. Further, the oxidation of glutamic semialdehyde produces glutamic acid.
Thus, I hypothesize that, through the ROS-mediated formation of glutamic semialdehyde, proline, arginine
and glutamic acid residues within the protein structure may be interchangeable. Our recent mass
spectrometry results demonstrated that proline 45 (a conserved residue within the catalytic sequence) of
the peroxiredoxin 6 protein molecule can be converted into glutamic acid in human cells, establishing a
revolutionizing concept that iron-catalyzed oxidation elicits the amino acid conversion within the protein
structure in the biological system. The objective of this R21 project is to define the occurrence of oxidant-
mediated amino acid conversion as a novel mechanism of oxidative stress. The objective of this application
will be accomplished by pursuing two specific aims: 1) Identify the occurrence of oxidant-mediated amino
acid conversions in cultured human cells and in intact animals; 2) Define functions of oxidant-mediated
amino acid conversions. The proposed work is highly innovative because it will address a revolutionizing
concept that site-directed mutagenesis/protein engineering-like events occur naturally. Results will be
significant because they are expected to provide a new molecular mechanism through which ROS cause
biological damage and help develop strategies to prevent and/or treat various diseases.

## Key facts

- **NIH application ID:** 9822154
- **Project number:** 5R21AI142649-02
- **Recipient organization:** GEORGETOWN UNIVERSITY
- **Principal Investigator:** YUICHIRO Justin SUZUKI
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $194,375
- **Award type:** 5
- **Project period:** 2018-11-13 → 2021-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9822154

## Citation

> US National Institutes of Health, RePORTER application 9822154, New mechanism of cellular protein oxidation (5R21AI142649-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9822154. Licensed CC0.

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