Comparative reactivity of hypohalous acids with proteins: Chemistry, biological effects and consequences

Hypohalous acids (HOX) are chemical oxidants that are produced by different mammalian heme peroxidases, which can be released by activated immune cells. These oxidants play an important role in innate immunity, owing to their ability to rapidly kill and detoxify pathogens. However, HOX are also implicated in driving host tissue damage, due to the abundance and over-activation of immune cells in many inflammatory pathologies. Proteins are highly abundant in biological systems and constitute key targets for HOX. These reactions lead to the modification of amino acid side chains, together with protein unfolding, fragmentation and aggregation, which have significant structural and functional effects. This has led to a significant research effort focused on gaining a detailed understanding of the molecular mechanisms involved in HOX-induced protein damage, and how it contributes to the progression of disease and mortality. This review describes the reactivity of HOX with proteins, including the mechanisms involved in the modification of specific amino acid residues, and how this contributes to structural and functional changes. We describe potential pathways by which modification of proteins by HOX contribute to disease and outline some strategies to modulate this type of damage therapeutically.