The effects of biologically important divalent and trivalent metal cations on the cyclization step of dopamine autoxidation reaction : a quantum chemical study

Umek, Nejc (author)

Dopamine is the most essential monoaminergic neurotransmitter involved in the pathophysiology of neurodegenerative disorders, and its autoxidation has been recognized as one of the potential trigger factors for dopaminergic neuron loss. The cyclization of dopamine o-quinone was shown to be the irreversible and rate-limiting step of the autoxidation reaction at physiologic pH values. Furthermore, various metal ions such as Al$^{3+}$, Fe$^{3+}$, Fe$^{2+}$, Co$^{2+}$, Ni$^{2+}$, Cu$^{2+}$, Zn$^{2+}$, Cd$^{2+}$, Pb$^{2+}$, and Mn$^{2+}$ have been clinically associated with neurodegeneration, especially Parkinsonism and dementia. It has been proposed that these metal ions could increase the rate of the dopamine autoxidation reaction; however, the exact mechanism has not yet been fully understood. Using advanced quantum chemical calculations with the inclusion of solvent effects we showed that except for Mn$^{2+}$, the studied metal cations could form complexes with dopamine o-quinone and significantly increase the dopamine o-quinone cyclization rate in aqueous solution; first, by enabling the cyclization to proceed spontaneously without the attack of the unprotonated amino group by hydroxide ion; second, by decreasing the intrinsic activation energy; and third, by decreasing the free energy of protonated amino group deprotonation. The latter also decreases the protective effect of acidic pH on dopamine autoxidation found in synaptic vesicles. The results are fully consistent with experimental data and provide deeper understanding of the effects of metal cations on the dopamine autoxidation reaction at physiologic pH values.

• Language: English
• Keywords: dopamine, autoxidation, neurodegeneration, metal cations, Parkinsonism
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: MF - Faculty of Medicine
• Publication status: Published
• Publication version: Version of Record
• Year: 2022
• Number of pages: 10 str.
• Numbering: Vol. 15, iss. 10, art. 104153
• PID: 20.500.12556/RUL-139745
• UDC: 54
• ISSN on article: 1878-5379
• DOI: 10.1016/j.arabjc.2022.104153
• COBISS.SI-ID: 117026819
• Publication date in RUL: 07.09.2022

Record is a part of a journal

• Title: Arabian journal of chemistry
• Publisher: Elsevier, King Saud University
• ISSN: 1878-5379
• COBISS.SI-ID: 117017347

Licences

• License: CC BY-NC-ND 4.0, Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
• Link: http://creativecommons.org/licenses/by-nc-nd/4.0/
• Description: The most restrictive Creative Commons license. This only allows people to download and share the work for no commercial gain and for no other purposes.

Secondary language

• Language: Slovenian
• Keywords: dopamin, avtooksidacija, nevrodegeneracija

Projects

• Funder: ARRS - Slovenian Research Agency
• Project number: P3-0043
• Name: Molekularni mehanizmi razvoja in delovanja skeletne mišice