Myeloperoxidase: Mechanisms, Reactions and Inhibition as a Therapeutic Strategy in Inflammatory Diseases

Abstract

Heme peroxidases are a major source of reactive oxidants at sites of inflammation in biological systems. The formation of some of these oxidants (e.g. hypochlorous acid, HOCl) is important in the innate immune response of activated neutrophils and leukocytes to invading pathogens (e.g. bacteria, yeasts, fungi parasites), and responsible for the anti-microbial activity present in excreted fluids (e.g. hypothiocyanous acid, HOSCN, generated by lactoperoxidase). Other oxidants formed by heme peroxidase family members are important in tissue development (e.g. hypobromous acid, HOBr, formation by peroxidasin) and in the synthesis of thyroid hormones (hypoiodous acid, HOI, synthesized by thyroid peroxidase). However, inadvertent, misplaced or poorly-controlled production of these species can result in host tissue damage, and this underlies the strong association between high levels of some of these enzymes and multiple inflammatory pathologies. As a consequence, there is widespread interest in understanding the kinetics and mechanisms of biomolecule modification by these species, which differ dramatically in their actions, the nature of the products formed (as some of these are specific biomarkers of enzyme activity), and the biological consequences of these reactions in a wide range of diseases associated with acute or chronic inflammation. Increased knowledge of these processes, has allowed the development of a number of alternative and complementary strategies that allow modulation of oxidant formation and subsequent damage. This review discusses developments in these fields and the prospects for tailored inhibition of specific members of this enzyme family.