Expression of NAD(P)H:quinone oxidoreductase in the normal and Parkinsonian substantia nigra

Muiswinkel, F. L. Van; Vos, Rob A. I. de; Bol, John G.J.M.; Andringa, Gerda; Steur, Ernst N.H. Jansen; Ross, David; Siegel, David; Drukarch, Benjamin

doi:10.1016/j.neurobiolaging.2003.12.010

Cited by 146 publications

(90 citation statements)

References 45 publications

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“…The detoxification of catecholamine quinones by two-electron reduction was proposed to be QR1 (46). However, various genetic studies on QR1 association with PD are inconclusive (25,31,47,48).…”

Section: Discussionmentioning

confidence: 99%

Quinone Reductase 2 Is a Catechol Quinone Reductase

Buryanovskyy

Zhang

2008

Journal of Biological Chemistry

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The functions of quinone reductase 2 have eluded researchers for decades even though a genetic polymorphism is associated with various neurological disorders. Employing enzymatic studies using adrenochrome as a substrate, we show that quinone reductase 2 is specific for the reduction of adrenochrome, whereas quinone reductase 1 shows no activity. We also solved the crystal structure of quinone reductase 2 in complexes with dopamine and adrenochrome, two compounds that are structurally related to catecholamine quinones. Detailed structural analyses delineate the mechanism of quinone reductase 2 specificity toward catechol quinones in comparison with quinone reductase 1; a side-chain rotational difference between quinone reductase 1 and quinone reductase 2 of a single residue, phenylalanine 106, determines the specificity of enzymatic activities. These results infer functional differences between two homologous enzymes and indicate that quinone reductase 2 could play important roles in the regulation of catecholamine oxidation processes that may be involved in the etiology of Parkinson disease.Cytosolic quinone reductases consist of two enzymes termed quinone reductase 1 (also referred to as QR1, 2 NQO1, DTdiaphorase) and quinone reductase 2 (also referred to as QR2, NQO2) which catalyze the two-electron reduction of quinones without the formation of reactive intermediates (1). They play important roles against oxidative stress imposed by quinones. Quinone reductase 2 was first described in 1961 (2), although its biological function has eluded scientists for decades until recently (3-5). However, quinone reductase 1 has been very well studied (6). In particular, conclusive evidence points to QR1 having a protective function for cells against the toxicity of electrophiles and reactive forms of oxygen. In addition, its induction protects cells against carcinogenesis. Therefore, QR1 is acknowledged as belonging to the group of enzymes classified as phase 2 detoxification enzymes.There are two major classes of quinones: 1,4-quinones (paraquinones or p-quinones, see Fig. 1) and 1,2-quinones (orthoquinones, catechol quinones or o-quinones). Both classes of quinones can be derived from oxidation of xenobiotics as well as endogenous molecules. 1,4-Quinones include vitamin K analogues, such as VK3 (menadione), whereas catechol quinones include the oxidation products of catecholamines, amino acid tyrosine as well as estradiols (7,8).Although QR2 and QR1 have high sequence and structural similarities, they possess significantly different catalytic actions (9). Both QR1 and QR2 can catalyze the two-electron reduction of p-quinones such as menadione (vitamin K3), only QR1 uses NADH and NADPH as electron donors. Instead, QR2 can use N-ribosyldihydronicotinamide (NRH) or a variety of NRH analogues as electron donors in the reduction of quinones in vitro (see Fig. 1) (10). While NADH and NADPH are electron donors for a variety of enzymes in various reactions and their biological metabolism and concentrations are very well charact...

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Section: Discussionmentioning

confidence: 99%

Quinone Reductase 2 Is a Catechol Quinone Reductase

Buryanovskyy

Zhang

2008

Journal of Biological Chemistry

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“…dopamine neurons) but a much more pervasive disorder that involves glial cells and neurons both within and beyond the nigra. This view is based on evidence from human studies [22][23][24][25][26][27] as well as from experimental PD models [28][29][30][31]. Therefore, it is obvious that, if one limits their experimental design to studying just one cell type, many important aspects of the disease will be missed.…”

Section: Transcriptome Analysis Reveals Link Between Proteasomal and mentioning

confidence: 99%

Transcriptome analysis reveals link between proteasomal and mitochondrial pathways in Parkinson’s disease

et al. 2006

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There is growing evidence that dysfunction of the mitochondrial respiratory chain and failure of the cellular protein degradation machinery, specifically the ubiquitin-proteasome system, play an important role in the pathogenesis of Parkinson's disease. We now show that the corresponding pathways of these two systems are linked at the transcriptomic level in Parkinsonian substantia nigra. We examined gene expression in medial and lateral substantia nigra (SN) as well as in frontal cortex using whole genome DNA oligonucleotide microarrays. In this study, we use a hypothesis-driven approach in analysing microarray data to describe the expression of mitochondrial and ubiquitin-proteasomal system (UPS) genes in Parkinson's disease (PD). Although a number of genes showed up-regulation, we found an overall decrease in expression affecting the majority of mitochondrial and UPS sequences. The down-regulated genes include genes that encode subunits of complex I and the Parkinson's-disease-linked UCHL1. The observed changes in expression were very similar for both medial and lateral SN and also affected the PD cerebral cortex. As revealed by "gene shaving" clustering analysis, there was a very significant correlation between the transcriptomic profiles of both systems including in control brains. Therefore, the mitochondria and the proteasome form a higher-order gene regulatory network that is severely perturbed in Parkinson's disease. Our quantitative results also suggest that Parkinson's disease is a disease of more than one cell class, i.e. that it goes beyond the catecholaminergic neuron and involves glia as well.

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“…So, NRF2 activity declines with ageing, which is the main risk factor for PD. In the dopaminergic neurons from the SNpc, NRF2 is located in the cytosol, whereas in age-matched PD patients, it is found in the nucleus [72] and the NRF2 signature, represented by expression of NQO1 [73] and HO-1 [39,[74][75][76] is up-regulated, suggesting an attempt of brain protection through this pathway [77]. In postmortem samples of PD patients, the cytoprotective proteins associated with NRF2 expression, NQO1 and p62, were partly sequestered in Lewy bodies, suggesting impaired neuroprotective capacity of the NRF2 signature [23].…”

Section: Parkinson's Disease and Its Connection With Nrf2mentioning

confidence: 99%

Role of the Transcription Factor Nrf2 in Parkinson’s Disease: New Insights

Lastres‐Becker¹

2017

J Alzheimers Dis Parkinsonism

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Expression of NAD(P)H:quinone oxidoreductase in the normal and Parkinsonian substantia nigra

Cited by 146 publications

References 45 publications

Quinone Reductase 2 Is a Catechol Quinone Reductase

Quinone Reductase 2 Is a Catechol Quinone Reductase

Transcriptome analysis reveals link between proteasomal and mitochondrial pathways in Parkinson’s disease

Role of the Transcription Factor Nrf2 in Parkinson’s Disease: New Insights

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