LAUSR

Imidazole-containing dipeptides (IDPs), such as carnosine and anserine, are found exclusively in various animal tissues, especially in skeletal muscles and nerves. They show antioxidant activity through metal chelating and free radical scavenging mechanisms. However, the underlying mechanisms that could explain the antioxidant effects of IDPs remain obscure. In the present study, we comprehensively analyze carnosine and its related small peptides in the soluble fraction of mouse muscle homogenates and detect IDPs and their oxidized derivatives. Based on the LC-ESI-MS/MS analysis of the synthetic compounds, these derivatives are identified as the 2-oxo-histidine-containing IDPs (2-oxo-IDPs). 2-Oxo-IDPs are ubiquitously detected in all mouse tissues examined. The enhanced production of 2-oxo-IDPs is seen in the brain of a mouse model of sepsis-associated encephalopathy. The exposure of the SH-SY5Y human neuroblastoma cells stably expressing carnosine synthase to H2O2 results in the intracellular production of 2-oxo-carnosine, which is associated with a significant inhibition of H2O2 cytotoxicity. Conversion of IDPs to 2-oxo-IDPs was reproduced by in vitro incubation of IDPs with ascrobate in the presence of Cu2+. The oxidation of histidine residues of IDPs to generate 2-oxo-IDPs may underlie the antioxidant function of the endogenous peptides and provide a novel regulatory mechanism for oxygen sensing.