Myeloperoxidase (MPO) is a peroxidase enzyme that in humans is encoded by the MPO gene on chromosome 17.MPO is most abundantly expressed in neutrophil granulocytes (a subtype of white blood cells), and produces hypohalous acids to carry out their antimicrobial activity. It is a lysosomal protein stored in azurophilic granules of the neutrophil and released into the extracellular space during degranulation. MPO has a heme pigment, which causes its green color in secretions rich in neutrophils, such as pus and some forms of mucus.
Myeloperoxidase (MPO) is a lysosomal haemoprotein located in the azurophilic granules of polymorphonuclear (PMN) leukocytes and monocytes. It is part of the host defense system of human polymorphonuclear leukocytes, responsible for microbicidal activity against a wide range of organisms. In the stimulated PMN, MPO catalyzes the production of hypohalous acids, primarily hypochlorous acid in physiologic situations, and other toxic intermediates that greatly enhance PMN microbicidal activity. MPO is located in the nucleus as well as in the cytoplasm.
Phagocytes also secrete the heme protein myeloperoxidase, which interacts with hydrogen peroxide to generate antimicrobial toxins. In the presence of halide ions, specifically Cl-, MPO produces hypochlorous acid (HOCl). HOCl in turn is an extrememly potent oxidant which can cause oxidative stress. MPO has also been found to inactivate nitric oxide (NO). Because NO is a potent vasodilator, inactivation of it can lead to vasoconstriction.
Myeloperoxidase is one of the most abundant proteins in phagocytes, representing 5% of neutrophil protein and ~1% of monocyte protein. Recent studies suggest that it is also present in human macrophages in vivo. It is stored in the azurophilic granules of mammalian neutrophils, the immune system's first response to local infection or injury. Myeloperoxidase plays a key role in host defense against foreign pathogens, but recent observations suggest that the enzyme inflicts tissue injury at sites of inflammation.
The role of myeloperoxidase in phagocyte function has been investigated using enzyme inhibitors and myeloperoxidase-deficient neutrophils. In vitro experiments using myeloperoxidase-deficient human neutrophils demonstrate increased oxidative metabolism, normal or increased phagocytosis. The bactericidal activity observed with myeloperoxidasedeficient neutrophils is generally retarded, but not completely absent. The most significant finding is the complete absence of candidacidal activity by myeloperoxidasedeficient phagocytes, which may be clinically significant since some humans with myeloperoxidase-deficiency are more susceptible to fungal infections.
Myeloperoxidase and atherosclerotic vascular disease
Oxidative modification of low density lipoprotein (LDL) plays a critical role in atherogenesis, but the mechanisms for damage in the human artery wall have not been established. The most widely studied pathway for LDL oxidation involves free metal ions. In vitro studies using cultured smooth muscle cells demonstrate oxidation of LDL if micromolar concentrations of iron or copper are present in the medium. These results indicate that one pathway for LDL oxidation in vitro is dependent on free metal ions. The mechanism of this pathway has not been clearly defined despite numerous studies, but has been suggested to involve initial reduction of the metal ion by cell-generated reductants such as superoxide or thiols, and may involve generation of metal-oxygen complexes.
One strategy to explore the role of metal ions in LDL oxidation in vivo is to look for stable, specific markers of metal-dependent lipid peroxidation. Several unnatural isomers of tyrosine form when LDL is exposed to metal ions in vitro, specifically orthoand meta-tyrosine. These products are formed by hydroxyl radical, a reactive intermediate in many metal ion-dependent reactions. Both of these products are stable to acid hydrolysis and are readily quantified by isotope dilution gas chromatography mass spectrometry. Levels of ortho- and meta-tyrosine have recently been quantified in human atherosclerotic tissue and LDL isolated from atherosclerotic lesions. Lesion LDL did not contain higher concentrations of either marker than did peripheral blood LDL. The levels were also not elevated in fatty streak or intermediate lesions compared with normal aortic tissue. The only region with higher levels of ortho- and meta-tyrosine than normal tissue was advanced atherosclerotic tissue, suggesting that metal ions released by necrotic cells may contribute to LDL oxidation late in atherogenesis.
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