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Kinetics of oxidation of aliphatic and aromatic thiols by myeloperoxidase compounds I and II
Author(s) -
Burner Ursula,
Jantschko Walter,
Obinger Christian
Publication year - 1999
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/s0014-5793(98)01727-x
Subject(s) - chemistry , thiol , myeloperoxidase , cysteamine , cysteine , glutathione , deprotonation , stereochemistry , medicinal chemistry , reaction rate constant , redox , tautomer , kinetics , organic chemistry , enzyme , medicine , ion , physics , quantum mechanics , inflammation
Myeloperoxidase (MPO) is the most abundant protein in neutrophils and plays a central role in microbial killing and inflammatory tissue damage. Because most of the non‐steroidal anti‐inflammatory drugs and other drugs contain a thiol group, it is necessary to understand how these substrates are oxidized by MPO. We have performed transient kinetic measurements to study the oxidation of 14 aliphatic and aromatic mono‐ and dithiols by the MPO intermediates, Compound I ( k 3 ) and Compound II ( k 4 ), using sequential mixing stopped‐flow techniques. The one‐electron reduction of Compound I by aromatic thiols (e.g. methimidazole, 2‐mercaptopurine and 6‐mercaptopurine) varied by less than a factor of seven (between 1.39±0.12×10 5 M −1 s −1 and 9.16±1.63×10 5 M −1 s −1 ), whereas reduction by aliphatic thiols was demonstrated to depend on their overall net charge and hydrophobic character and not on the percentage of thiol deprotonation or redox potential. Cysteamine, cysteine methyl ester, cysteine ethyl ester and α‐lipoic acid showed k 3 values comparable to aromatic thiols, whereas a free carboxy group (e.g. cysteine, N ‐acetylcysteine, glutathione) diminished k 3 dramatically. The one‐electron reduction of Compound II was far more constrained by the nature of the substrate. Reduction by methimidazole, 2‐mercaptopurine and 6‐mercaptopurine showed second‐order rate constants ( k 4 ) of 1.33±0.08×10 5 M −1 s −1 , 5.25±0.07×10 5 M −1 s −1 and 3.03±0.07×10 3 M −1 s −1 . Even at high concentrations cysteine, penicillamine and glutathione could not reduce Compound II, whereas cysteamine (4.27±0.05×10 3 M −1 s −1 ), cysteine methyl ester (8.14±0.08×10 3 M −1 s −1 ), cysteine ethyl ester (3.76±0.17×10 3 M −1 s −1 ) and α‐lipoic acid (4.78±0.07×10 4 M −1 s −1 ) were demonstrated to reduce Compound II and thus could be expected to be oxidized by MPO without co‐substrates.