Reactions of myeloperoxidase-derived oxidants with biological substrates: Gaining chemical insight into human inflammatory diseases
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Reactions of myeloperoxidase-derived oxidants with biological substrates : Gaining chemical insight into human inflammatory diseases. / Pattison, D. I.; Davies, M. J.
In: Current Medicinal Chemistry, Vol. 13, No. 27, 2006, p. 3271-3290.Research output: Contribution to journal › Review › peer-review
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TY - JOUR
T1 - Reactions of myeloperoxidase-derived oxidants with biological substrates
T2 - Gaining chemical insight into human inflammatory diseases
AU - Pattison, D. I.
AU - Davies, M. J.
PY - 2006
Y1 - 2006
N2 - 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.
AB - 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.
KW - myeloperoxidase
KW - hypochlorous acid
KW - hypobromous acid
KW - chloramines
KW - bromamines
KW - kinetics
KW - protein oxidation
KW - lipid oxidation
KW - LOW-DENSITY-LIPOPROTEIN
KW - HYDROGEN-PEROXIDE-CHLORIDE
KW - NITROGEN-CENTERED RADICALS
KW - APOLIPOPROTEIN-A-I
KW - HUMAN ATHEROSCLEROTIC LESIONS
KW - HYPOCHLORITE-INDUCED DAMAGE
KW - ALPHA-AMINO-ACIDS
KW - ABCA1-DEPENDENT CHOLESTEROL EFFLUX
KW - ABSOLUTE RATE CONSTANTS
KW - GLYCATION END-PRODUCTS
U2 - 10.2174/092986706778773095
DO - 10.2174/092986706778773095
M3 - Review
VL - 13
SP - 3271
EP - 3290
JO - Current Medicinal Chemistry
JF - Current Medicinal Chemistry
SN - 0929-8673
IS - 27
ER -
ID: 314392702