Catechol and Aldehyde Moieties of 3,4-Dihydroxyphenylacetaldehyde Contribute to Tyrosine Hydroxylase Inhibition and Neurotoxicity

Lydia M. M Vermeer; Virginia R Florang; Jonathan A Doorn

doi:10.1016/j.brainres.2012.07.048

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Catechol and Aldehyde Moieties of 3,4-Dihydroxyphenylacetaldehyde Contribute to Tyrosine Hydroxylase Inhibition and Neurotoxicity

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Catechol and Aldehyde Moieties of 3,4-Dihydroxyphenylacetaldehyde Contribute to Tyrosine Hydroxylase Inhibition and Neurotoxicity

Lydia M. M Vermeer, Virginia R Florang and Jonathan A Doorn

Brain research, Vol.1474, pp.100-109

09/20/2012

DOI: 10.1016/j.brainres.2012.07.048

PMCID: PMC3428502

PMID: 22877852

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https://www.ncbi.nlm.nih.gov/pmc/articles/3428502View

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Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disorder which leads to the selective loss of dopaminergic neurons. This causes a decrease in the important neurotransmitter dopamine (DA), which is essential for coordinated movement. Previous studies have implicated the monoamine oxidase metabolite of DA, 3,4-dihydroxphenylacetaldehyde (DOPAL), in the pathogenesis of PD and have shown it to be a reactive intermediate capable of protein modification. DOPAL also has demonstrated the ability to cause mitochondrial dysfunction and lead to significant inhibition of the rate-limiting enzyme in DA synthesis, tyrosine hydroxylase (TH). The current study was undertaken to investigate four analogs of DOPAL, including a novel nitrile analog, to determine how the structure of DOPAL is related to its toxicity and inhibition of TH. Both mitochondrial function and inhibition of TH in cell lysate were investigated. Furthermore, a novel whole cell assay was designed to determine the consequence to enzyme action when DOPAL levels were elevated. The results presented here demonstrate that changes to DOPAL structure lead to a decrease in toxicity and inhibition of enzyme activity as compared to the parent compound. Furthermore, the production of superoxide anion but not hydrogen peroxide increased in the presence of elevated DOPAL. These results reveal the toxicity of DOPAL and demonstrate that both the catechol and aldehyde are required to potently inhibit TH activity.

mitochondrial dysfunction

Parkinson's disease

enzyme inhibition

Structure-activity relationship

tyrosine hydroxylase

Details

Title: Subtitle: Catechol and Aldehyde Moieties of 3,4-Dihydroxyphenylacetaldehyde Contribute to Tyrosine Hydroxylase Inhibition and Neurotoxicity
Creators: Lydia M. M Vermeer - Division of Medicinal and Natural Products Chemistry, College of Pharmacy, The University of Iowa, 115 S. Grand Ave, Iowa City, Iowa 52242, USA
Virginia R Florang - Division of Medicinal and Natural Products Chemistry, College of Pharmacy, The University of Iowa, 115 S. Grand Ave, Iowa City, Iowa 52242, USA
Jonathan A Doorn - Division of Medicinal and Natural Products Chemistry, College of Pharmacy, The University of Iowa, 115 S. Grand Ave, Iowa City, Iowa 52242, USA
Resource Type: Journal article
Publication Details: Brain research, Vol.1474, pp.100-109
DOI: 10.1016/j.brainres.2012.07.048
PMID: 22877852
PMCID: PMC3428502
NLM abbreviation: Brain Res
ISSN: 0006-8993
eISSN: 1872-6240
Grant note: name: J.A.D., award: NIH R01 ES15507
Language: English
Date published: 09/20/2012
Academic Unit: Iowa Neuroscience Institute; Pharmaceutical Sciences and Experimental Therapeutics; Medicinal and Natural Products Chemistry
Record Identifier: 9984070881802771

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