J. Am. Chem. Soc. 134, 19240–19245 (2012)

In response to infection, activated white blood cells known as phagocytes undergo what is known as an 'oxidative burst', during which they generate large amounts of reactive oxygen species to combat the invading pathogen. The enzyme myeloperoxidase is also generated and this catalyses the reaction of hydrogen peroxide with Cl−, to produce HOCl — a highly potent cytotoxic oxidant. Overproduction of HOCl, however, can have harmful effects. Carnosine is a naturally produced dipeptide — made up of β-alanine and L-histidine — that is able to scavenge HOCl and protect against damage caused by its excessive production. Now Leo Radom, Amir Karton and colleagues from the University of Sydney, have studied the mechanism by which this occurs.

Carnosine contains four nitrogen atoms, two of which can be chlorinated on reaction with HOCl. To effectively trap the chlorine, the carnosine must react to form the stable thermodynamic product in which the nitrogen atom of the primary amine group in the alanine residue is chlorinated. However, the kinetics of the reaction favours the formation of the less stable product, in which chlorine reacts with one of the imidazole nitrogen atoms of the histidine ring. Using ab initio and density functional theory calculations, Radom, Karton and colleagues show that an intramolecular Cl shift may occur, which transforms the initially formed kinetic product into the more stable thermodynamic product.

They explore the potential energy surface for the shift reaction and see that the migration occurs through three intramolecular steps: a proton shift that positively charges the imidazole ring, followed by the Cl shift from the imidazole ring to the amino end of the molecule, followed by a subsequent amino proton shift. Radom, Karton and colleagues also calculated the free-energy barriers for this mechanism in molecules structurally similar to carnosine, inserting or removing CH2 groups to effectively lengthen or shorten the molecule. Shortening the molecule increases the free-energy barrier for Cl transfer, whereas lengthening it by one or two CH2 groups has the opposite effect. The changes are related to the ease with which the transition state for chlorine transfer can form and provides a design principle for making improved HOCl scavengers.