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Journal article
Nitration and Inactivation of Tyrosine Hydroxylase by Peroxynitrite
The Journal of biological chemistry, v 276(49), pp 46017-46023
07 Dec 2001
PMID: 11590168
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Abstract
Tyrosine hydroxylase (TH) is modified by nitration after exposure of mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydrophenylpyridine. The temporal association of tyrosine nitration with inactivation of TH activityin vitro suggests that this covalent post-translational modification is responsible for the in vivo loss of TH function (Ara, J., Przedborski, S., Naini, A. B., Jackson-Lewis, V., Trifiletti, R. R., Horwitz, J., and Ischiropoulos, H. (1998)Proc. Natl. Acad. Sci. U. S. A. 95, 7659–7663). Recent data showed that cysteine oxidation rather than tyrosine nitration is responsible for TH inactivation after peroxynitrite exposure in vitro (Kuhn, D. M., Aretha, C. W., and Geddes, T. J. (1999) J. Neurosci. 19, 10289–10294). However, re-examination of the reaction of peroxynitrite with purified TH failed to produce cysteine oxidation but resulted in a concentration-dependent increase in tyrosine nitration and inactivation. Cysteine oxidation is only observed after partial unfolding of the protein. Tyrosine residue 423 and to lesser extent tyrosine residues 428 and 432 are modified by nitration. Mutation of Tyr423 to Phe resulted in decreased nitration as compared with wild type protein without loss of activity. Stopped-flow experiments reveal a second order rate constant of (3.8 ± 0.9) × 103m−1s−1 at pH 7.4 and 25 °C for the reaction of peroxynitrite with TH. Collectively, the data indicate that peroxynitrite reacts with the metal center of the protein and results primarily in the nitration of tyrosine residue 423, which is responsible for the inactivation of TH.
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Details
- Title
- Nitration and Inactivation of Tyrosine Hydroxylase by Peroxynitrite
- Creators
- Béatrice Blanchard-Fillion - Children's Hospital of PhiladelphiaJosé M. Souza - University of the RepublicThomas Friel - Children's Hospital of PhiladelphiaGeorge C.T. Jiang - Wake Forest UniversityKent Vrana - Wake Forest UniversityVictor Sharov - University of KansasLorena Barrón - University of KansasChristian Schöneich - University of KansasCelia Quijano - University of the RepublicBeatriz Alvarez - University of the RepublicRafael Radi - University of the RepublicSerge Przedborski - Columbia UniversityGayani S. Fernando - iDepartment of Pharmacology and Physiology, M. C. P. Hahnemann School of Medicine, Philadelphia, Pennsylvania 10912Joel Horwitz - iDepartment of Pharmacology and Physiology, M. C. P. Hahnemann School of Medicine, Philadelphia, Pennsylvania 10912Harry Ischiropoulos - Children's Hospital of Philadelphia
- Publication Details
- The Journal of biological chemistry, v 276(49), pp 46017-46023
- Publisher
- Elsevier
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Web of Science ID
- WOS:000172573100072
- Scopus ID
- 2-s2.0-0035824528
- Other Identifier
- 991019168471204721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology