INTRODUCTION 
Myeloperoxidase (MPO), a member of the haem peroxidase-cyclooxygenase superfamily, is abundantly expressed in
- neutrophils
- and to a lesser extent in monocytes and certain type of macrophages.
MPO participates in innate immune defence mechanism through formation of microbicidal reactive oxidants and diffusible radical species. A unique activity of MPO is its ability to use chloride as a cosubstrate with hydrogen peroxide to generate chlorinating oxidants such as hypochlorous acid, a potent antimicrobial agent. However, evidence has emerged that MPO-derived oxidants contribute to tissue damage and the initiation and propagation of acute and chronic vascular inflammatory disease. The fact that circulating levels of MPO have been shown to predict risks for major adverse cardiac events and that levels of MPO-derived chlorinated compounds are specific biomarkers for disease progression, has attracted considerable interest in the development of therapeutically useful MPO inhibitors. Today, detailed information on the structure of ferric MPO and its complexes with low- and high-spin ligands is available. This, together with a thorough understanding of reaction mechanisms including redox properties of intermediates, enables a rationale attempt in developing specific MPO inhibitors that still maintain MPO activity during host defence and bacterial killing but interfere with pathophysiologically persistent activation of MPO.
STRUCTURE
Myeloperoxidase is a 150-165 kDa protein synthesized during myeloid differenziation. It is a dimer composed of two 15 kDa light chains and two variable-weight glycosylated heavy chains bound to a prosthetic heme group.
The x-ray crystal structure of human myeloperoxidase has been extended to 1.8 Å resolution, using x-ray data recorded at 180 °C (r = 0.197, free r = 0.239). Results confirm that the heme is covalently attached to the protein via two ester linkages between the carboxyl groups of Glu242 and Asp94 and modified methyl groups on pyrrole rings A and C of the heme as well as a sulfonium ion linkage between the sulfur atom of Met243 and the -carbon of the vinyl group on pyrrole ring A. In the native enzyme a bound chloride ion has been identified at the amino terminus of the helix containing the proximal His336. Determination of the x-ray crystal structure of a myeloperoxidase-bromide complex (r = 0.243, free r = 0.296) has shown that this chloride ion can be replaced by bromide. Bromide is also seen to bind, at partial occupancy, in the distal heme cavity, in close proximity to the distal His95, where it replaces the water molecule hydrogen bonded to Gln91. The bromide-binding site in the distal cavity appears to be the halide-binding site responsible for shifts in the Soret band of the absorption spectrum of myeloperoxidase.
GENETICS
The gene is located on chromosome 17 (17q23.1) and is composed of 12 exons and 11 introns. S1 mapping analysis of human myeloperoxidase mRNA identified the single transcription initiation site at 180 base pairs upstream of the ATG initiation codon. In the 5'- flanking region of the human myeloperoxidase gene, there are several blocks of sequences which are homologous to the sequences found on the 5'-promoter region of the human c-myc proto-oncogene.
OMIM MPO deficiency
FUNCTION
Observations that destruction of microorganisms occurs in the phagosome of neutrophils and that MPO is among the enzymes discharged into these phagocytic vacuoles from cytoplasmic granules suggest an important role of MPO in bacterial killing (Klebanoff, 2005). Among the antimicrobial systems present in the phagosome, a major proportion consists of MPO, hydrogen peroxide (H2O2, formed during the respiratory burst), and a halide (X-), particularly chloride (Cl-) (Hampton et al., 1998).
The initial product of the MPO–H2O2–Cl- system is the potent antimicrobial oxidant hypochlorous acid/hypochlorite (HOCl/OCl-, pKa 7.53).
However, under pathological conditions, persistent activation of the
MPO–H2O2 system of activated phagocytes may adversely affect tissues.
HOCl is able to initiate modification reactions targeting lipids,
DNA and (lipo)proteins, including halogenation, nitration and oxidative crosslinking. There is no well-defined pH optimum for
MPO-catalysed chlorination because it depends on the relative concentrations of Cl- and
H2O2. However, at constant concentrations of these reaction partners, the rate of
HOCl release increases with decreasing pH (Andrews and Krinsky, 1982). It is important to realize that at high concentrations,
H2O2 inactivates
MPO.
PHYSIOLOGICAL AND PATHOPHYSIOLOGICAL ROLE
