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Imidazole-containing dipeptides (IDPs), such as carnosine and anserine, are recognized for their diverse biological functions, particularly their antioxidant properties. However, the enzymatic degradation of carnosine by human serum carnosinase 1 (CN1) limits its bioavailability. Recently, an Osaka Metropolitan University-led research team identified the endogenous production of 2-oxo-IDPs, such as 2-oxo-carnosine, as functional oxidized derivatives of IDPs and demonstrated that these derivatives exhibit significantly greater antioxidant activity than their unmodified counterparts. Despite this, the relationship between 2-oxo-IDPs and CN1 remains unclear.

The researchers aimed to investigate the interaction between 2-oxo-IDPs and CN1 using mass spectrometric analysis and in vivo animal models. Recombinant human CN1 efficiently hydrolyzed carnosine and anserine, whereas 2-oxo-IDPs remained largely resistant to degradation. Kinetic and in silico analyses suggested that oxidation of carnosine disrupts its interaction with CN1, reducing its affinity and conferring resistance to degradation by CN1. Additionally, 2-oxo-IDPs also exhibited greater stability than carnosine in both human and Syrian hamster serum. Furthermore, administration studies revealed that 2-oxo-carnosine possesses higher stability than carnosine in Syrian hamster blood and that elevated levels of 2-oxo-carnosine in blood were associated with increased plasma antioxidant activity in mice.

Their findings suggest that oxidative modification of IDPs not only imparts their antioxidant properties but also enhances resistance to CN1-mediated degradation, indicating that in vivo conversion of IDPs to 2-oxo-IDPs may play a significant biological and physiological role. Collectively, the researchers’ results highlight 2-oxo-IDPs as functional oxidized metabolites with potential translational relevance for oxidative stress-related disorders.

Paper information

Journal: Free Radical Biology and Medicine
Title: 2-oxo-imidazole-containing dipeptides resist degradation by carnosinase 1
DOI: 10.1016/j.freeradbiomed.2025.11.014
Authors: Somei Komae, Shingo Kasamatsu, Kei Moritsugu, Koji Uchida and Hideshi Ihara
Published:  9 November 2025
URL: https://doi.org/10.1016/j.freeradbiomed.2025.11.014

Contact

Hideshi Ihara
Graduate School of Science
Email: iharah[at]omu.ac.jp

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