Can Histidines Stabilize a Carnosine-Derived Pyrazinium Radical?
Annals of the New York Academy of Sciences
Aims/Hypothesis. Foreign antigens include glycated proteins formed from oxidized carbohydrates reacting with endogenous proteins. They become ligands for RAGEs (receptors for advanced glycation end products) on macrophages, astrocytes, and injured neurons, leading to chronic inflammation, hypersensitization, and irreversible tissue damage. Carnosine, an antiinflammatory agent, sequesters oxidized carbohydrates by a currently unknown mechanism. We propose that carnosine forms a stable pyrazinium cation radical.
Methods. Molecular modeling techniques proposing a structure to be further characterized were used with a chemical structure drawing program (CS ChemDraw, CambridgeSoft Corp.), applying previously published data.
Results. The proposed product from the reaction of carnosine with a glycating agent includes two molecules of carnosine with a 1,4 di-substituted pyrazinium radical cation. The pyrazine ring contains a carbon-centered radical. Amine nitrogens from the beta-alanyl moieties exist at the 1 and 4 positions and the imidazoles of the histidines are turned back towards the pyrazinium radical: a scorpion-like conformation. Support for this proposal comes from the published finding of a 14-membered ring when carnosine is modified by acrolein, which puts the beta-alanyl amine in close proximity to the N-3 of the histidinyl imidazole. Due to the structural position of the histidines, they can delocalize the radical preventing further reaction.
Conclusions. We provide a putative model for further investigation, suggesting that this structure may be the vehicle for the excretion of oxidized carbohydrates, which are potentially toxic.
Seidler NW, Yeargans G. Can Histidines Stabilize a Carnosine-Derived Pyrazinium Radical?. Annals of the New York Academy of Sciences. 2006; 1043(1). doi: 10.1196/annals.1333.102.