Reaction mechanism of the enzymatic chlorination of amino compounds catalyzed by the myeloperoxidase-hydrogen peroxide-chloride ion systema kinetic and computational approach

Abstract

Myeloperoxidase is a key enzyme of the immune system, quite abundant in neutrophils. It is actively involved in the protection against exogenous microorganisms and represents a significant factor in the development of numerous diseases. Unlike other peroxidases, unable to oxidize chloride anion, the main reaction catalyzed by this enzyme is the chlorination of nitrogen compounds. There are numerous studies on myeloperoxidase, particularly from a clinical or biochemical point of view, but the precise reaction mechanism of the chlorination process catalyzed by the enzyme was still unknown. A detailed knowledge of the structure and reactivity of myeloperoxidase, the substrates, and obtained chlorinated products, as well as the interaction between them, is essential for a comprehensive understanding of its enzymatic activity and the development of treatments and drugs. The main aim of this dissertation is to unravel the mechanism of the myeloperoxidase-mediated chlorination, and to explain the source of its high oxidation potential, and other unique features, relative to other peroxidases. Furthermore, subsequent decomposition of some chlorinated nitrogen compounds and the particular behaviour of the amino acid cysteine and the antioxidant glutathione when reacting with these chloramines are analyzed.