Tyrosine hydroxylase: mechanisms of oxygen radical formation.
A new mechanism of oxygen radical formation in dopaminergic neurons is proposed, based on the oxidative mechanism of tyrosine hydroxylase. The cofactor (6R,6S)-5,6,7,8-tetrahydrobiopterin can rearrange in solution which allows an autoxidation reaction producing O2.-, H2O2 and HO.. The combination of tyrosine hydroxylase and the cofactor produces more oxygen radicals than does the autoxidation of the cofactor. This production of oxygen radicals could be damaging to dopaminergic neurons. In the presence of tyrosine, the enzyme produces less radicals than it does in the absence of tyrosine. Mechanisms are proposed for the generation of reactive oxygen species during the autoxidation of the cofactor and during enzymatic catalysis. The generation, by tyrosine hydroxylase, of very small amounts of oxygen radicals over the period of 65 years could contribute to the oxidative stress that causes Parkinson's disease.
Adams
J D
JD
Department of Molecular Pharmacology and Toxicology, School of Pharmacy, University of Southern California, Los Angeles 90033, USA. jadams@hsc.usc.edu
Klaidman
L K
LK
Ribeiro
P
P
D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000378:metabolism; D001708:Biopterins / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D004578:Electron Spin Resonance Spectroscopy; D005609:Free Radicals / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism; D017665:Hydroxyl Radical / Q000378:metabolism; D007980:Levodopa / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D010084:Oxidation-Reduction; D016716:PC12 Cells; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism*
D000975:Antioxidants; D005609:Free Radicals; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D013481:Superoxides; D001708:Biopterins; D017665:Hydroxyl Radical; D007980:Levodopa; D006861:Hydrogen Peroxide; D014446:Tyrosine 3-Monooxygenase; C003402:sapropterin