Reactions of myeloperoxidase-derived oxidants with biological substrates: gaining chemical insight into human inflammatory diseases.
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.
Pattison
D I
DI
The Heart Research Institute, 114 Pyrmont Bridge Rd, Camperdown, Sydney, NSW 2050, Australia. pattisond@hri.org.au
Davies
M J
MJ
D050197:Atherosclerosis / Q000201:enzymology / Q000209:etiology / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000201:enzymology / Q000209:etiology* / Q000378:metabolism; D007700:Kinetics; D009369:Neoplasms / Q000201:enzymology / Q000209:etiology / Q000378:metabolism; D016877:Oxidants / Q000378:metabolism*; D009195:Peroxidase / Q000378:metabolism*
D016877:Oxidants; D009195:Peroxidase