Reactions of Myeloperoxidase-Derived Oxidants with Biological Substrates:Gaining Chemical Insight into Human Inflammatory Diseases

Abstract

The heme enzyme myeloperoxidase (MPO) is released at sites of inflammation by activated leukocytes. A key function of MPO is the production of hypohalous acids (HOX, X = Cl, Br) which are strong oxidants with potent antibacterial properties. However, HOX can also damage host tissue when produced at the wrong place, time or concentration; this has been implicated in several human diseases. Thus, elevated blood and leukocyte levels of MPO are significant independent risk factors for atherosclerosis, and specific markers of HOX-mediated protein oxidation are often present at elevated levels in patients with inflammatory diseases (e.g. asthma). HOX react readily with amino acids, proteins, carbohydrates, lipids, nucleobases and antioxidants. Sulfur-containing amino acids (Cys, Met, cystine) and amines on amino acids, nucleobases, sugars and lipids are the major targets for HOX. Reaction with amines generates chloramines (RNHCl) and bromamines (RNHBr), which are more selective oxidants than HOX and are key intermediates in HOX biochemistry. As these and other products of MPO-derived oxidants are unstable, understanding the role of HOX-induced damage in disease cannot be obtained solely by stable product analysis, and knowledge of the reaction kinetics is essential. This review collates kinetic and product data for HOX, chloramine and bromamine reactions with biological substrates. It highlights how kinetic data may be used to predict the effect of HOX-mediated oxidation on complex biological targets, such as lipoproteins and extracellular matrix in atherosclerosis, or protein-DNA complexes in cancer, thereby providing a basis for unraveling the mechanisms by which these oxidants generate biological damage.

The High Reactivity of Peroxiredoxin 2 with H2O2 Is Not Reflected in Its Reaction with Other Oxidants and Thiol Reagents

“…Although chloramines were used in this study primarily as reagents to probe the reactivity of Prx2, they are physiologically important oxidants that are produced in inflammatory situations by the reaction of amino compounds with the myeloperoxidase product, hypochlorous acid (26,27). Chloramines are able to damage biomolecules and influence cell signaling events such as activation of mitogen-activated protein kinase and NFB pathways, cytokine production, and apoptosis (28,29).…”

Myeloperoxidase-induced Genomic DNA-centered Radicals

“…It also reacts rapidly with amino and sulfhydryl groups in proteins and with amino groups in nucleic acids (34,35). In addition, it reacts rapidly with lipids, carbohydrates, GSH, taurine, methionine, and L-ascorbate (19,36). Consequently, because of HOCl reactivity and the presence of cellular antioxidants, oxidation of genomic DNA by HOCl might occur only when HOCl is produced close to or within the cell nuclei.…”

Correlation, by multivariate statistical analysis, between the scavenging capacity against reactive oxygen species and the bioactive compounds from frozen fruit pulps

“…Therefore, the bioactive compounds considered in this study do not contribute greatly to the scavenging capacity of this specific ROS. On the other hand, carbohydrates, proteins, and amino acids are also components of the extracts and therefore can play a great hole in its scavenging capacity against H 2 O 2 since these compounds have been previously reported as efficient scavengers of ROS (PATTISON; DAVIES, 2006). For example, annatto seed extracts, which have both phenolic compounds (minor compounds) and carotenoids (major compounds) exhibited higher scavenging capacity against H 2 O 2 (IC 50 from 11 to 47 µg/mL) (CHISTÉ et al, 2011) than those of the 18 frozen fruit pulps analyzed in this study.…”