Protein Reactivity of 3,4-Dihydroxyphenylacetaldehyde, a Toxic Dopamine Metabolite, is Dependent on both the Aldehyde and Catechol

Jennifer N Rees; Virginia R Florang; Laurie L Eckert; Jonathan A Doorn

doi:10.1021/tx9000557

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Protein Reactivity of 3,4-Dihydroxyphenylacetaldehyde, a Toxic Dopamine Metabolite, is Dependent on both the Aldehyde and Catechol

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Protein Reactivity of 3,4-Dihydroxyphenylacetaldehyde, a Toxic Dopamine Metabolite, is Dependent on both the Aldehyde and Catechol

Jennifer N Rees, Virginia R Florang, Laurie L Eckert and Jonathan A Doorn

Chemical research in toxicology, Vol.22(7), pp.1256-1263

07/2009

DOI: 10.1021/tx9000557

PMCID: PMC2717024

PMID: 19537779

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Abstract

Dopamine (DA) has been implicated as an endogenous neurotoxin to explain the selective neurodegeneration as observed for Parkinson's disease (PD). However, previous work demonstrated 3,4-dihydroxyphenylacetaldehyde (DOPAL) to be more toxic than DA. DOPAL is generated as a part of DA catabolism via the activity of monoamine oxidase and the mechanism of DOPAL toxicity is proposed to involve protein modification. Previous studies have demonstrated protein reactivity via the aldehyde moiety; however, DOPAL contains two reactive functional groups (catechol and aldehyde) both with the potential for protein adduction. The goal of this work was to determine whether protein modification by DOPAL occurs via a thiol-reactive quinone generated from oxidation of the catechol, which is known to occur for DA, or if the aldehyde forms adducts with amine nucleophiles. To accomplish this objective, the reactivity of DOPAL towards N-acetyl-lysine (NAL), N-acetyl-cysteine (NAC) and two model proteins was determined. In addition, several DOPAL analogues were obtained and used for comparison of reactivity. Results demonstrate that at pH 7.4 and 37°C, the order of DOPAL reactivity is NAL ≫ NAC and the product of NAL and DOPAL is stable in the absence of reducing agent. Moreover, DOPAL will react with model proteins, but in the presence of amine-selective modifiers citraconic anhydride and 2-iminothiolane hydrochloride, the reactivity of DOPAL towards the proteins is diminished. In addition, DOPAL-mediated protein cross-linking is observed when a model protein or a protein mixture (i.e. mitochondria lysate) are treated with DOPAL at concentrations of 5-100 μM. Protein cross-linking was diminished in the presence of ascorbate, suggesting the involvement of a quinone in DOPAL-mediated protein modification. These data indicate DOPAL to be highly reactive towards protein nucleophiles with the potential for protein cross-linking.

Details

Title: Subtitle: Protein Reactivity of 3,4-Dihydroxyphenylacetaldehyde, a Toxic Dopamine Metabolite, is Dependent on both the Aldehyde and Catechol
Creators: Jennifer N Rees - Division of Medicinal and Natural Products Chemistry, College of Pharmacy, The University of Iowa, Iowa City, IA 52242, USA
Virginia R Florang - Division of Medicinal and Natural Products Chemistry, College of Pharmacy, The University of Iowa, Iowa City, IA 52242, USA
Laurie L Eckert - Division of Medicinal and Natural Products Chemistry, College of Pharmacy, The University of Iowa, Iowa City, IA 52242, USA
Jonathan A Doorn - Division of Medicinal and Natural Products Chemistry, College of Pharmacy, The University of Iowa, Iowa City, IA 52242, USA
Resource Type: Journal article
Publication Details: Chemical research in toxicology, Vol.22(7), pp.1256-1263
DOI: 10.1021/tx9000557
PMID: 19537779
PMCID: PMC2717024
NLM abbreviation: Chem Res Toxicol
ISSN: 0893-228X
eISSN: 1520-5010
Language: English
Date published: 07/2009
Academic Unit: Iowa Neuroscience Institute; Pharmaceutical Sciences and Experimental Therapeutics; Medicinal and Natural Products Chemistry
Record Identifier: 9984070525702771

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