Antioxidant-Mediated Modulation of Protein Reactivity for 3,4-Dihydroxyphenylacetaldehyde, a Toxic Dopamine Metabolite.
3,4-Dihydroxyphenylacetaldehyde (DOPAL) is an endogenously produced toxic aldehyde. It is a bifunctional electrophile implicated in the loss of dopaminergic cells concomitant with Parkinson's disease and neurodegeneration. DOPAL is known to react with proteins and amino acids such as N-acetyl lysine (NAL); oxidation of the catechol moiety to the quinone of DOPAL increases this reactivity. Here, we demonstrate the ability of the antioxidants N-acetylcysteine, glutathione, and ascorbic acid to mitigate the reactivity of DOPAL with proteins and amino acids in a dose-dependent fashion. Conversely, Trolox did not lessen the observed reactivity with proteins. Interestingly, use of tricine, a buffer and reducing agent, in these systems also decreased the reactivity of DOPAL with amines, yielding tricine-derived free radical species. Modification of amines with aldehydes typically involves Schiff base chemistry; however, the observance of free radicals suggests that an oxidative step is involved in the reaction of DOPAL with lysine. Furthermore, while Schiff base formation is usually optimal at pH 5, the reaction rate of DOPAL with NAL is negligible at pH 5 and is enhanced under basic conditions (e.g., pH 9). Conditions of high pH are also favorable for catechol auto-oxidation, known to occur for DOPAL. The antioxidant-mediated protection demonstrated here suggests that oxidative stress may impart cellular vulnerability to protein modification by DOPAL. Therefore, depleted antioxidants and increased levels of lipid peroxidation products, known to prevent the detoxifying metabolism of DOPAL, may present a survival challenge to dopaminergic cells targeted in Parkinson's disease.
Department of Pharmaceutical Sciences and Experimental Therapeutics, Division of Medicinal and Natural Products Chemistry, College of Pharmacy, The University of Iowa , 115 South Grand Avenue, Iowa City, Iowa 52242-1112, United States.
David G
DG
Anderson
Department of Pharmaceutical Sciences and Experimental Therapeutics, Division of Medicinal and Natural Products Chemistry, College of Pharmacy, The University of Iowa , 115 South Grand Avenue, Iowa City, Iowa 52242-1112, United States.
Virginia R
VR
Florang
Department of Pharmaceutical Sciences and Experimental Therapeutics, Division of Medicinal and Natural Products Chemistry, College of Pharmacy, The University of Iowa , 115 South Grand Avenue, Iowa City, Iowa 52242-1112, United States.
Josephine H
JH
Schamp
Free Radical and Radiation Biology Program, ESR Facility, Department of Radiation Oncology, College of Medicine, University of Iowa , Iowa City, Iowa 52242-1101, United States.
Garry R
GR
Buettner
Department of Pharmaceutical Sciences and Experimental Therapeutics, Division of Medicinal and Natural Products Chemistry, College of Pharmacy, The University of Iowa , 115 South Grand Avenue, Iowa City, Iowa 52242-1112, United States.
Jonathan A
JA
Doorn
D015102:3,4-Dihydroxyphenylacetic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D000588:Amines / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration
D000588:Amines; D000975:Antioxidants; D015102:3,4-Dihydroxyphenylacetic Acid; C007430:3,4-dihydroxyphenylacetaldehyde; D004298:Dopamine