Inhibition of the Fe(III)-Catalyzed Dopamine Oxidation by ATP and Its Relevance to Oxidative Stress in Parkinson’s Disease

Abstract

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 O 2 from accessing the Fe(III) center and its further reaction with DA. The biological relevance of this complex is strongly implicated by the identification of the ternary complex in the substantia nigra of rat brain and 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 resultant impairment toward the inhibition of the Fe(III)-catalyzed DA oxidation may contribute to the pathogenesis of PD. Our finding provides new insight into the pathways of DA oxidation and its relationship with synaptic activity.

Detection of dopamine on a mercapto-terminated hexanuclear Fe(III) cluster modified gold electrode

“…[28,36]. Such a complex is capable of binding the oxidant to form a ternary complex, thus making the easy arrival of DA molecules to the surface of the modified electrode [37]. In this study, we suggest the following general mechanism for the oxidation of DA on the Au/Fe6 electrode:…”

Elucidation of the interplay between Fe(II), Fe(III), and dopamine with relevance to iron solubilization and reactive oxygen species generation by catecholamines

“…It has previously been shown that the oxidation of DA can be catalyzed in the presence of iron (Chinta and Andersen ; Jiang et al . ) resulting in an abnormal accumulation of the intermediate oxidation product 6‐hydroxydopamine (Pezzella et al . ) and enhanced formation of neuromelanin, the end‐product of the oxidation of dopamine (Sulzer et al .…”

“…In addition, a number of the previous studies have used extremely high iron concentrations (Jiang et al . ), low pH (García et al . ) or complexing buffer solutions (Napolitano et al .…”

“…It has previously been shown that the oxidation of DA can be catalyzed in the presence of iron (Chinta and Andersen 2008;Jiang et al 2013) resulting in an abnormal accumulation of the intermediate oxidation product 6-hydroxydopamine (Pezzella et al 1997) and enhanced formation of neuromelanin, the end-product of the oxidation of dopamine (Sulzer et al 2000). The presence of this polymeric material in the brain has been proposed to both induce and alleviate PD (Double et al 2002;Segura-Aguilar et al 2014) with the ability of iron to catalyze its formation suggesting a role of iron in the pathogenicity of PD (Martin et al 2008;Berg et al 2011).…”

“…Moreover, even though the formation of Fe(III)-DA complexes through the direct reaction of DA and iron and the subsequent reduction in the Fe(III) metal-center and release of Fe(II) have long been recognized to occur (Avdeef et al 1978;El-Avaan et al 1997;Hermida-Ameijeiras et al 2004), very little quantification of the rate constants associated with these dynamic processes has been undertaken at physiological pH with the result that our ability to predict the impact of increase or decrease in iron levels in the brain on ironinduced oxidative stress is very limited. In addition, a number of the previous studies have used extremely high iron concentrations (Jiang et al 2013), low pH (Garc ıa et al 2012) or complexing buffer solutions (Napolitano et al 1999) which may well have resulted in complications in interpretation of the results obtained. Given the widespread distribution of iron, DA, and its analogous compounds in the human brain, it is imperative to understand the mechanisms that govern their cytotoxicity at physiological pH.…”