Heme proteins myeloperoxidase

Hydrogen peroxide is a substrate for myeloperoxidase, a multisubunit heme protein of M.W. 150,C, present in primary neutrophilic granules. The active prosthetic groups are two hemes covalently attached to the apoen-zyme. This enzyme catalyzes many kinds of oxidation reactions, but oxidation of halide ions to hypohalite ions appears to be the most important. Hypochlorite ion is the principal compound formed, although Br , I, and SCN (a pseudohalide) can also serve as substrates. The reaction catalyzed is... 

Myeloperoxidase contains two Fe heme-like centers, which give it the green color seen in pus. Hypochlorous acid is a powerful toxin that destroys bacteria within seconds through halogenation and oxidation reactions. It oxidizes many Fe and S-containing groups (e.g., sulfhydryl groups, iron-sulfur centers, ferredoxin, heme-proteins, methionine), oxidatively decarboxylates and deaminates proteins, and cleaves peptide bonds. Aerobic bacteria under attack rapidly lose membrane... 

Another endogenous HNO source relies on the oxidation of hydroxylamine (HA), or other alcohol amine, such as hydroxyurea or A -hydroxy arginine. In vivo, such a process is postulated to depend on the activity of several heme proteins, which are able to stabilize oxo ferryl species (compound I and compound II), such as peroxidases. Recently, Donzelli et al. evaluated HNO production by this mechanism (22), with a newly developed selective assay in which the reaction products, GS(0)NH, in the presence of reduced glutathione (GSH) are quantified by HPLC. Their results showed that metmyoglobin, horse radish peroxidase, and myeloperoxidase were efficient HNO producers using hydroxylamine as substrate. However, there are several remaining unresolved questions concerning the proposed mechanism (which is outlined below, Eq. (2)). 

By oxidation with copper or hypochlorous acid, HDL loses its ability to remove cholesterol from cultured cells. This effect would be expected to be detrimental and promote cardiovascular disease. In contrast, however, HDL becomes more effective in protecting mice against atherosclerosis by exposing it to tyrosyl radicals generated by myeloperoxidase, a heme protein seereted by macrophages in human atherosclerotic lesions. The resulting tyrosylated HDL... 

Myeloperoxidase is the principal heme protein of the mammalian neutrophil functioning in the phagocytic process through its capacity at acid pH to peroxidize chloride ions to hypochlorous acid. Investigations of the structure of myeloperoxidase from various species have shown it to be a two-heme protein with a molecular weight in the region 135,000-150,000 (Agner, 1958, 1970 Harrison and Schultz, 1976 Harrison et al, 1977). 

Myeloperoxidase (MPO) is a heme containing protein that catalyzes the two electron oxidation of halides (Cl-, Br- and I-) and pseudohalide (SCN-) to the corresponding hypohalous acid (Eq. (51)) in a process that is dependent upon [X-], [H202] and [H+] (135). MPO is found in high concentrations in neutrophiles and plays important roles in immune response and inflammation (136). 

Figure 16-12 Linkage of heme to mammalian peroxidases. There are two ester linkages to carboxylate side chains from the protein.220 221 Myeloperoxidase contains a third linkage.222 2223...

Horseradish peroxidase, which is the most fully characterized of the heme(Fe )-centered enzymes for the activation of HOOH, has an axial histidine ligand this also is the case for myeloperoxidase (uses HOOH and CF to form HOCl). In contrast, the catalase protein (catalyzes the harmless destruction of HOOH into O2 and H2O) has an axial tyrosine ligand in place of the histidine... 

Figure 9 Structure of myeloperoxidase (MPO) along with the heme environment as observed in the high-resoiution crystal stmcture. (This figure was generated from coordinates of ICXP deposited in the Protein Data Banlr)...

The opportunities for MCD spectroscopy in the visible region are far more extensive. The MCD of the visible absorption bands of porphyrins have been probed by MCD since the beginning of the field. The sensitivity of the MCD spectra to the environment of porphyrin derivatives, in solution as well as embedded in proteins, provides information on both electronic structure and physical conformation. As an example, Dawson and colleagues have used MCD to probe the identity of the heme-type prosthetic group of myeloperoxidase. Such capabilities combined with the seemingly infinite number of metalloproteins available in nature provide ample opportunities for the productive use of MCD. 

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