One-electron oxidation and reduction of glycosaminoglycan chloramides: A kinetic study |
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| Affiliation: | 1. Faculty of Health and Social Sciences, Leeds Metropolitan University, Leeds LS1 3HE, UK;2. Laboratoire de Chimie Physique, UMR 8000, Université d''Orsay, Paris-Sud, 91405 Orsay, France;3. Centre de Cinétique Rapide ELYSE, Laboratoire de Chimie Physique, UMR 8000, Université d''Orsay, Paris-Sud, 91405 Orsay, France;4. CNRS, 91405 Orsay, France;5. Manchester Institute of Biotechnology, Faculty of Life Science, University of Manchester, Manchester M1 7DN, UK;1. Pharmacology Program, ICBM, Faculty of Medicine, University of Chile, Santiago, Chile;2. Physiophathology Program, ICBM, Faculty of Medicine, University of Chile, Santiago, Chile;3. Cardiovascular Department, Clinical Hospital, University of Chile, Santiago, Chile;1. Departamento de Química Inorgánica-Instituto Universitario de Materiales de Alicante, Laboratorio de Materiales Avanzados, Universidad de Alicante, Apartado 99, 03080 Alicante, Spain;2. Departamento de Química, División de Ciencias Naturales y Exactas, Universidad de Guanajuato, Noria Alta s/n, Col. Noria Alta, C.P. 36050, Guanajuato, Guanajuato, México;1. Department of Physical Medicine & Rehabilitation, Qilu Hospital, Medical School of Shandong University, Jinan 250012, China;2. The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Shandong University, Qilu Hospital, Jinan, Shandong 250012, China;1. Department of Chemistry, M.V. Lomonosov Moscow State University, 1 Leninskie Gory, Moscow 119991, Russian Federation;2. Institute of Physiologically Active Compounds, Russian Academy of Sciences, 1 Severny proezd, Chernogolovka, Moscow Region 142432, Russian Federation;3. Skolkovo Institute of Science and Technology, 3 Nobel street, Moscow, 143026, Russian Federation;1. Departamento de Bioquimica y Biologia Molecular, Facultad de Medicina y Enfermeria, Universidad de Cordoba Cordoba, Spain;2. Instituto Maimonides de Investigacion Biomedica de Cordoba (IMIBIC), Cordoba, Spain;3. Departamento de Biologia Celular, Fisiología e Inmunología, Universidad de Cordoba, Cordoba, Spain;4. Departmento de Ciencias Morfologicas, Seccion de Histologia, Facultad de Medicina y Enfermeria, Universidad de Cordoba, Spain;5. Unidad de Gestion Clinica de Analisis Clinicos, Hospital Universitario Reina Sofia de Cordoba, Cordoba, Spain;6. Canvax Biotech S.L., Cordoba, Spain;7. Berenson-Allen Center for Noninvasive Brain Stimulation, Division of Cognitive Neurology, Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, USA;8. Departmento de Neuropatología Molecular, Instituto de Fisiologia Celular, Universidad Nacional Autonoma de Mexico (UNAM), Ciudad de Mexico, D.F., Mexico |
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| Abstract: | Hypochlorous acid and its acid–base counterpart, hypochlorite ions, produced under inflammatory conditions, may produce chloramides of glycosaminoglycans, these being significant components of the extracellular matrix (ECM). This may occur through the binding of myeloperoxidase directly to the glycosaminoglycans. The N–Cl group in the chloramides is a potential selective target for both reducing and oxidizing radicals, leading possibly to more efficient and damaging fragmentation of these biopolymers relative to the parent glycosaminoglycans. In this study, the fast reaction techniques of pulse radiolysis and nanosecond laser flash photolysis have been used to generate both oxidizing and reducing radicals to react with the chloramides of hyaluronan (HACl) and heparin (HepCl). The strong reducing formate radicals and hydrated electrons were found to react rapidly with both HACl and HepCl with rate constants of 1–1.7×108 and 0.7–1.2×108 M−1 s−1 for formate radicals and 2.2×109 and 7.2×108 M−1 s−1 for hydrated electrons, respectively. The spectral characteristics of the products of these reactions were identical and were consistent with initial attack at the N–Cl groups, followed by elimination of chloride ions to produce nitrogen-centered radicals, which rearrange subsequently and rapidly to produce C-2 radicals on the glucosamine moiety, supporting an earlier EPR study by M.D. Rees et al. (J. Am. Chem. Soc. 125: 13719–13733; 2003). The oxidizing hydroxyl radicals also reacted rapidly with HACl and HepCl with rate constants of 2.2×108 and 1.6×108 M−1 s−1, with no evidence from these data for any degree of selective attack on the N–Cl group relative to the N–H groups and other sites of attack. The carbonate anion radicals were much slower with HACl and HepCl than hydroxyl radicals (1.0×105 and 8.0×104 M−1 s−1, respectively) but significantly faster than with the parent molecules (3.5×104 and 5.0×104 M−1 s−1, respectively). These findings suggest that these potential in vivo radicals may react in a site-specific manner with the N–Cl group in the glycosaminoglycan chloramides of the ECM, possibly to produce more efficient fragmentation. This is the first study therefore to conclusively demonstrate that reducing radicals react rapidly with glycosaminoglycan chloramides in a site-specific attack at the N–Cl group, probably to produce a 100% efficient biopolymer fragmentation process. Although less reactive, carbonate radicals, which may be produced in vivo via reactions of peroxynitrite with serum levels of carbon dioxide, also appear to react in a highly site-specific manner at the N–Cl group. It is not yet known if such site-specific attacks by this important in vivo species lead to a more efficient fragmentation of the biopolymers than would be expected for attack by the stronger oxidizing species, the hydroxyl radical. It is clear, however, that the N–Cl group formed under inflammatory conditions in the extracellular matrix does present a more likely target for both reactive oxygen species and reducing species than the N–H groups in the parent glycosaminoglycans. |
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| Keywords: | Glycosaminoglycans Hyaluronan Heparin Pulse radiolysis Free radical |
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