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

Sun, Yingying; Pham, A. Ninh; Waite, T. David

doi:10.1111/jnc.13615

Cited by 50 publications

(99 citation statements)

References 92 publications

(190 reference statements)

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“…[45] Thepresence of redox-active metals,such as Cu 2+ [46] and Fe 3+ , [47] further promote DA oxidation, particularly when coordinated by suitable donor ligands,a s discussed in Section 3.2. [45] Thepresence of redox-active metals,such as Cu 2+ [46] and Fe 3+ , [47] further promote DA oxidation, particularly when coordinated by suitable donor ligands,a s discussed in Section 3.2.…”

Section: Dopamine Reactionsmentioning

confidence: 99%

“…[51,[85][86][87][88] Iron(III) forms complexes with the catechol moiety of DA which are more stable than those formed by copper(II), but are still sensitive to O 2 ,y ielding DASQ,D AQ and other decomposition products. [47] However,w hile several studies have addressed the binding of Fe 3+ and Fe 2+ ions to Ab [90] and aSyn, [91,92] as well as the possible generation of ROSs pecies, data on DA oxidation promoted by Fe-peptide complexes are absent. [47] However,w hile several studies have addressed the binding of Fe 3+ and Fe 2+ ions to Ab [90] and aSyn, [91,92] as well as the possible generation of ROSs pecies, data on DA oxidation promoted by Fe-peptide complexes are absent.…”

Section: Metal-catalyzed Dopamine Oxidationmentioning

confidence: 99%

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Dopamine, Oxidative Stress and Protein–Quinone Modifications in Parkinson's and Other Neurodegenerative Diseases

et al. 2019

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Dopamine (DA) is the most important catecholamine in the brain, as it is the most abundant and the precursor of other neurotransmitters. Degeneration of nigrostriatal neurons of substantia nigra pars compacta in Parkinson's disease represents the best‐studied link between DA neurotransmission and neuropathology. Catecholamines are reactive molecules that are handled through complex control and transport systems. Under normal conditions, small amounts of cytosolic DA are converted to neuromelanin in a stepwise process involving melanization of peptides and proteins. However, excessive cytosolic or extraneuronal DA can give rise to nonselective protein modifications. These reactions involve DA oxidation to quinone species and depend on the presence of redox‐active transition metal ions such as iron and copper. Other oxidized DA metabolites likely participate in post‐translational protein modification. Thus, protein–quinone modification is a heterogeneous process involving multiple DA‐derived residues that produce structural and conformational changes of proteins and can lead to aggregation and inactivation of the modified proteins.

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Section: Dopamine Reactionsmentioning

confidence: 99%

Section: Metal-catalyzed Dopamine Oxidationmentioning

confidence: 99%

Dopamine, Oxidative Stress and Protein–Quinone Modifications in Parkinson's and Other Neurodegenerative Diseases

et al. 2019

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“…), particularly in the presence of excess reactive Fe (Sun et al . ). Iron has a high affinity to neuromelanin (NM) (Bohic et al .…”

mentioning

confidence: 97%

l‐3,4‐dihydroxyphenylalanine (l‐DOPA) modulates brain iron, dopaminergic neurodegeneration and motor dysfunction in iron overload and mutant alpha‐synuclein mouse models of Parkinson's disease

Billings

Gordon

Rawling

et al. 2019

Journal of Neurochemistry

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Treatment with the dopamine (DA) precursor l‐3,4‐dihydroxyphenylalanine (l‐DOPA) provides symptomatic relief arising from DA denervation in Parkinson's disease. Mounting evidence that DA autooxidation to neurotoxic quinones is involved in Parkinson's disease pathogenesis has raised concern about potentiation of oxidative stress by l‐DOPA. The rate of DA quinone formation increases in the presence of excess redox‐active iron (Fe), which is a pathological hallmark of Parkinson's disease. Conversely, l‐DOPA has pH‐dependent Fe‐chelating properties, and may act to ‘redox silence’ Fe and partially allay DA autoxidation. We examined the effects of l‐DOPA in three murine models of parkinsonian neurodegeneration: early‐life Fe overexposure in wild‐type mice, transgenic human (h)A53T mutant α‐synuclein (α‐syn) over‐expression, and a combined ‘multi‐hit’ model of Fe‐overload in hA53T mice. We found that l‐DOPA was neuroprotective and prevented age‐related Fe accumulation in the substantia nigra pars compacta (SNc), similar to the mild‐affinity Fe chelator clioquinol. Chronic l‐DOPA treatment showed no evidence of increased oxidative stress in wild‐type midbrain and normalized motor performance, when excess Fe was present. Similarly, l‐DOPA also did not exacerbate protein oxidation levels in hA53T mice, with or without excess nigral Fe, and showed evidence of neuroprotection. The effects of l‐DOPA in Fe‐fed hA53T mice were somewhat muted, suggesting that Fe‐chelation alone is insufficient to attenuate neuron loss in an animal model also recapitulating altered DA metabolism. In summary, we found no evidence in any of our model systems that l‐DOPA treatment accentuated neurodegeneration, suggesting DA replacement therapy does not contribute to oxidative stress in the Parkinson's disease brain.

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“…[51,84] Das wichtigste eisenhaltige Protein im Gehirn ist Ferritin (ein aus vielen Untereinheiten bestehendes Eisenspeicherprotein mit H-und L-Ketten), das in besonders großen Mengen in Gliazellen und in geringeren Mengen in dopaminergen Neuronen vorkommt. [47] Während sich jedoch verschiedene Studien mit der Bindung von Fe 3+ -u nd Fe 2+ -Ionen an Ab [90] und aSyn [91,92] und der mçglichen Erzeugung von ROS-Verbindungen befassen, gibt es keine Daten über die DA-Oxidation durch Fe-Peptidkomplexe.I nj edem Fall spielt Eisen eine wichtige Rolle bei der Bildung von Neuromelanin durch DA-Oxidation (siehe Abschnitt 6). [89] In einer detaillierten Untersuchung wird gezeigt, wie das Verhältnis zwischen DA und Fe 3+ -oder Fe 2+ -Salzen die Redoxaktivitätbeeinflusst und dass unter geeigneten Bedingungen bedeutsame Mengen an H 2 O 2 (wahrscheinlich bei der Dismutation von Superoxid) gebildet werden kçnnen.…”

Section: Methodsunclassified

“…[45] Die Gegenwart redoxaktiver Metalle wie Cu 2+ [46] und Fe 3+ [47] beschleunigt die DA-Oxidation weiter,besonders wenn diese mit geeigneten Donorliganden koordiniert sind (siehe Abschnitt 3.2). [45] Die Gegenwart redoxaktiver Metalle wie Cu 2+ [46] und Fe 3+ [47] beschleunigt die DA-Oxidation weiter,besonders wenn diese mit geeigneten Donorliganden koordiniert sind (siehe Abschnitt 3.2).…”

Section: Dopaminreaktionenunclassified

Dopamin, oxidativer Stress und Protein‐Chinonmodifikationen bei Parkinson und anderen neurodegenerativen Erkrankungen

Monzani¹,

Nicolis²,

Dell’Acqua³

et al. 2019

Angewandte Chemie

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Dopamin (DA) ist das wichtigste und häufigste Catecholamin im Gehirn und zugleich Vorläufer anderer Neurotransmitter. Die Degeneration von Neuronen des Nigrostriatums (Substantia nigra, Pars compacta) bei Parkinson‐Kranken ist die am besten untersuchte Verknüpfung zwischen Neurotransmission und Neuropathologie durch DA. Catecholamine sind reaktive Moleküle, für die es komplexe Kontroll‐ und Transportsysteme gibt. Unter normalen Bedingungen werden kleine Mengen cytosolischen Dopamins unter Melanisierung von Peptiden und Proteinen schrittweise zu Neuromelanin umgewandelt. Überschießendes cytosolisches oder extraneuronales DA kann allerdings unselektive Proteinmodifikationen auslösen. Die dabei ablaufende Oxidation von DA zu Chinonverbindungen hängt von der Gegenwart redoxaktiver Übergangsmetallionen wie Eisen und Kupfer ab. Auch andere oxidierte DA‐Metaboliten sind wahrscheinlich an posttranslationalen Proteinmodifikationen beteiligt. Die Protein‐Chinonmodifikation ist also ein heterogener Vorgang mit verschiedenen DA‐Abkömmlingen, die Struktur‐ und Konformationsänderungen von Proteinen hervorrufen; dies kann zur Aggregation und Inaktivierung der modifizierten Proteine führen.

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

Abstract: The non-enzymatically catalyzed oxidation of dopamine (DA) and the resultant formation of powerful oxidants such as the hydroxyl radical (

Cited by 50 publications

References 92 publications

Dopamine, Oxidative Stress and Protein–Quinone Modifications in Parkinson's and Other Neurodegenerative Diseases

Dopamine, Oxidative Stress and Protein–Quinone Modifications in Parkinson's and Other Neurodegenerative Diseases

l‐3,4‐dihydroxyphenylalanine (l‐DOPA) modulates brain iron, dopaminergic neurodegeneration and motor dysfunction in iron overload and mutant alpha‐synuclein mouse models of Parkinson's disease

Dopamin, oxidativer Stress und Protein‐Chinonmodifikationen bei Parkinson und anderen neurodegenerativen Erkrankungen

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