Inhibition of the Fe(III)-Catalyzed Dopamine Oxidationby ATP and Its Relevance to Oxidative Stress in Parkinson’sDisease

摘要

Parkinson’s disease (PD) is characterized by the progressive degeneration of dopaminergic cells, which implicates a role of dopamine (DA) in the etiology of PD. A possible DA degradation pathway is the Fe(III)-catalyzed oxidation of DA by oxygen, which produces neuronal toxins as side products. We investigated how ATP, an abundant and ubiquitous molecule in cellular milieu, affects the catalytic oxidation reaction of dopamine. For the first time, a unique, highly stable DA–Fe(III)–ATP ternary complex was formed and characterized in vitro. ATP as a ligand shifts the catecholate–Fe(III) ligand metal charge transfer (LMCT) band to a longer wavelength and the redox potentials of both DA and the Fe(III) center in the ternary complex. Remarkably, the additional ligation by ATP was found to significantly reverse the catalytic effect of the Fe(III) center on the DA oxidation. The reversal is attributed to the full occupation of the Fe(III) coordination sites by ATP and DA, which blocks O2 from accessing the Fe(III) center and its further reaction with DA. The biological relevanceof this complex is strongly implicated by the identification of theternary complex in the substantia nigra of rat brainand its attenuation of cytotoxicity of the Fe(III)–DA complex.Since ATP deficiency accompanies PD and neurotoxin 1-methyl-4-phenylpyridinium(MPP⁺) induced PD, deficiency of ATP and the resultantimpairment toward the inhibition of the Fe(III)-catalyzed DA oxidationmay contribute to the pathogenesis of PD. Our finding provides newinsight into the pathways of DA oxidation and its relationship withsynaptic activity.