Dopamine Autoxidation Is Controlled by Acidic pH

Abstract

We studied the reaction mechanism of dopamine autoxidation using quantum chemical methods. Unlike other biogenic amines important in the central nervous system, dopamine and noradrenaline are capable of undergoing a non-enzymatic autoxidative reaction giving rise to a superoxide anion that further decomposes to reactive oxygen species. The reaction in question, which takes place in an aqueous solution, is as such not limited to the mitochondrial membrane where scavenging enzymes such as catalase and superoxide dismutase are located. With the experimental rate constant of 0.147 s−1, the dopamine autoxidation reaction is comparably as fast as the monoamine oxidase B catalyzed dopamine decomposition with a rate constant of 1 s−1. By using quantum chemical calculations, we demonstrated that the rate-limiting step is the formation of a hydroxide ion from a water molecule, which attacks the amino group that enters intramolecular Michael addition, giving rise to a pharmacologically inert aminochrome. We have shown that for dopamine stability on a time scale of days, it is essential that the pH value of the synaptic vesicle interior is acidic. The pathophysiologic correlates of the results are discussed in the context of Parkinson's disease as well as the pathology caused by long-term amphetamine and cocaine administration.

Coassemble dopamine and GHK tripeptide into fluorescent nanoparticles for pH sensing

“…Commonly, DA is very easy to be oxidized in air or alkaline conditions. [ 28 ] In the evolution procedure of oxidation, DA will be firstly deprotonated and then dehydrated to a two‐ring structure (Figure 1). If without any protecting measures, this indole‐like two‐ring structure can be further cross‐linked to polymeric molecules, such as melanin.…”

ZnT2 is an electroneutral proton-coupled vesicular antiporter displaying an apparent stoichiometry of two protons per zinc ion

“…However, it should be noted that in contrast to the chemically inert zinc ion, it is essential that dopamine and noradrenaline are stored within acidic vesicles where they cannot be autoxidized. Specifically, unlike other biogenic amines important in the central nervous system, dopamine and noradrenaline are capable of undergoing a non-enzymatic autoxidative reaction giving rise to a superoxide anion that further decomposes to reactive oxygen species [49]. This autoxidative reaction was suggested to affect the incidence of Parkinson disease [49,50].…”

“…Specifically, unlike other biogenic amines important in the central nervous system, dopamine and noradrenaline are capable of undergoing a non-enzymatic autoxidative reaction giving rise to a superoxide anion that further decomposes to reactive oxygen species [49]. This autoxidative reaction was suggested to affect the incidence of Parkinson disease [49,50]. The vesicular acetylcholine transporter (VAchT/SLC18A3) is also a proton-coupled antiporter which mediates the concentration of acetylcholine within acidic vesicles in cholinergic presynaptic neurons, while consistently moving two protons to the cytoplasm per acetylcholine molecule transported [48].…”

Hydride Abstraction as the Rate-Limiting Step of the Irreversible Inhibition of Monoamine Oxidase B by Rasagiline and Selegiline: A Computational Empirical Valence Bond Study

“…However, SEL is linked with a variety of side effects, mainly caused by its major L-amphetamine-like metabolite, which can cause appetite suppression, insomnia, and increased irritability [ 36 , 37 ]. In addition to that, amphetamines inhibit dopamine’s transport to vesicles [ 38 , 39 ], which potentiate autooxidation in the cytoplasm [ 40 ]. This process provides an additional source of the reactive oxygen species.…”