Insights into myeloperoxidase biosynthesis from its inherited deficiency

Abstract

Myeloperoxidase (MPO) is a heme protein present in the granules of neutrophils and monocytes. The activated neutrophil releases MPO into the phagolysosome or into the extracellular space in response to a variety of agonists. During concomitant activation of the NADPH-dependent oxidase, the stimulated neutrophil also generates hydrogen peroxide, and in this way the MPO-hydrogen peroxide-halide system exerts its potent microbicidal activity. Recent interest in MPO has extended well beyond the domain of innate host defense against infection and includes generalized inflammatory diseases, atherosclerosis, and degenerative neurologic diseases. Search of the various data banks using the cDNA sequence for MPO has uncovered previously unsuspected relationships among peroxidatively active proteins in widely different species. In addition, application of the analytical tools of cell and molecular biology has allowed definition of specific genotypes underlying MPO deficiency and the impact of particular mutations on the fate of MPO precursors along the biosynthetic pathway. In parallel, such studies have allowed significant advances in understanding of the normal steps in MPO biosynthesis and intracellular targeting.

Neutrophils: Molecules, Functions and Pathophysiological Aspects

“…Given the important role of this system in the antimicrobial activity of circulating neutrophils, it seemed predictable that inherited deficiency of MPO would be severe and likely to be uncommon in the general population. Several inherited MPO deficiencies were described with severe infections with Candida (Nauseef, 1998). Likewise, knock-out MPO mice, which have recently been described (Koyama et al, 1999), show increased susceptibility to Candida infection.…”

NADPH oxidases in lung biology and pathology: Host defense enzymes, and more

“…Intraphagosomal production of these peroxidase-derived oxidants, which are more reactive and less diffusible than H 2 O 2 , may also act on locally secreted antimicrobial proteins, and alter their antimicrobial properties (25). However, compared to the dramatic consequences of NADPH oxidase deficiency (due to mutations in NOX2 or associated proteins), genetic deficiencies in either MPO or EPO are relatively non-consequential and do not result in significant antimicrobial or antifungal defects (26). This suggests that NOX2-mediated antimicrobial actions must also include mechanisms that are independent of heme peroxidases (23).…”

Extracellular Release of Bactericidal/Permeability-Increasing Protein in Newborn Infants

“…MPO, a heme protein that is a major component of azurophil granules of PMN and monocytes, is necessary for the effects of the oxygen-dependent microbicidal system (12,13).…”