Myeloperoxidase-mediated Protein Oxidation: Its Possible Biological Functions

Abstract

Oxidation of proteins occurs both as a side-effect of aerobic energy metabolism and as an effect of specific metabolism of phagocytic polymorphonuclear granulocytes producing O2- and H2O2. In contrast to other cells, which control their H2O2 level by degrading it to O2 and H2O, polymorphonuclear neutrophilic leukocytes (PMN) use H2O2 as a substrate for oxidizing chloride ions to HOCl which rapidly react with all neighboring thiol, disulfide and amino residues. Chloramines, which are the most abundant HOCl reaction products, react with proteins, modifying only certain exposed methionine and cysteine residues. This may account for selective inactivation of a number of enzymes, carrier proteins and peptide mediators, including the alpha1-proteinase inhibitor, alpha2-macroglobulin and plasminogen activator inhibitor. Inactivaton of plasma proteinase inhibitors protects PMN elastase, collagenase, cathepsin G and other serine proteases in the inflammatory foci. This promotes proteolytic degradation of damaged tissue, removal of bacterial debris and wound healing, as well as tissue remodeling related to the inflammatory processes. Oxidative control of protease-anti-protease balance affects the development of the inflammatory processes. Moreover, inactivation of plasma proteinase inhibitors facilitates primary antigen processing, upregulates lymphocyte proliferative response and activates the local immune response. Oxidation produces a specific protein tagging which attracts and stimulates immune active cells. Therefore, humoral response against oxidatively modified proteins occurs more effectively than that of the native proteins. The effect is dose-dependent with respect to the amount of oxidant employed. Glycol aldehyde, which is the serine chloramine spontaneous decay product, in mice immunized with glycol aldehyde-modified egg-white albumin, yields specific IgG production manifold higher than that in mice immunized with native albumin. Immunopotentiation is produced by proliferation expansion of the same immunocompetent clones. Oxidative tagging of proteins may also affect the autoimmune-type reaction. Thus, a growing body of data suggest that the specific role of protein oxidation by activated PMN is oxidative protein tagging facilitating further development of the immune reaction.

Regulation of Protein Function by Reversible Methionine Oxidation and the Role of Selenoprotein MsrB1

“…While Mical and FMO are believed to oxidize Met to MetO by a direct transfer of a single oxygen, myeloperoxidase (MPO) adopts a unique system that generates HOCl in a reaction with hydrogen peroxide in polymorphonuclear leukocytes, thereby working as an efficient oxidant for Met that may account for selective inactivation of enzymes such as high-density lipoprotein (HDL) proteins, a 1 -proteinase inhibitor, and a 2 -macroglobulin (8,45,51,57,66). In addition, taurine chloramine (Tau-NHCl)-mediated oxidation of Met residue on IkBa, the inhibitor of nuclear factor kB (NF-kB), was shown to prevent activation of the NF-kB pathway in Jurkat cells (42,48).…”

Does the oxidation of methionine in thrombomodulin contribute to the hypercoaguable state of smokers and diabetics?

“…This study was undertaken because an increased tendency toward coagulation is a common complication of inflammation, and thrombosis is an important contributor to death in inflammatory processes such as sepsis. The examination of methionine oxidation was a natural extension of various observations of regulation of activity by methionine oxidation wherein methionine is oxidized to the sulfoxide form by the reactive oxygen species generated by leukocytes and neutrophils during inflammation [41][42][43][44][45]. To cite just one example, it has been shown that the C5 component of the complement system, normally activated by proteolysis, can be activated by the oxidation of a specific methionine residue [46][47][48].…”

“…Oxidants found naturally in biological systems [33,44,[65][66][67], cigarette smoke [68][69][70][71][72], and ozone [73,74] or other environmental oxidants [75,76] have all been demonstrated to cause methionine sulfoxide formation in proteins and peptides. Methionine oxidation often reduces or eliminates biological activity [77,78].…”

“…Reactive oxygen species have lately become more widely recognized as biologically important messengers [44,[83][84][85][86][87] and methionine is one likely target for oxidation by such species [44,45,88,89]. Indeed, recent and somewhat surprising work has shown that the rate of reaction of methionine with hypochlorous acid is faster than the reaction with cysteine [90].…”

Nitrite‐mediated protection against hypochlorous acid–induced chondrocyte toxicity: A novel cytoprotective role of nitric oxide in the inflamed joint?

“…For example, it deactivates serine protease inhibitors such as ␣ 1 -antitrypsin, ␣ 2 -macroglobulin, plasminogen activator inhibitor (14), and tissue inhibitor of metalloproteinases 1 (15), and activates procollagenases including gelatinase and matrilysin (16)(17)(18)(19)(20). HOCl also enhances the collagenase activity of cathepsin G (21), and exposure of fibronectin to HOCl enhances neutrophil elastase-mediated fibronectin degradation (22).…”