Inhibition of binding of aldehydes of biogenic amines in tissues

Ungar, Frieda; Tabakoff, Boris; Alivisatos, Spyridon G.A.

doi:10.1016/0006-2952(73)90050-6

Cited by 34 publications

(37 citation statements)

References 17 publications

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“…19 who demonstrated that AscH − , Cys, GSH and pargyline all inhibited binding of radiolabeled DA to proteins in tissue homogenate. The effectiveness of pargyline as an MAO inhibitor indicated that a DA metabolite was the modifying agent as opposed to DA or DA-quinone.…”

Section: Discussionmentioning

confidence: 99%

Antioxidant-Mediated Modulation of Protein Reactivity for 3,4-Dihydroxyphenylacetaldehyde, a Toxic Dopamine Metabolite

Anderson

Florang

Schamp

et al. 2016

Chem. Res. Toxicol.

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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 Lys; 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 N-acetyl Lys 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 detoxifying metabolism of DOPAL, may present a survival challenge to dopaminergic cells targeted in Parkinson’s disease.

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Section: Discussionmentioning

confidence: 99%

Antioxidant-Mediated Modulation of Protein Reactivity for 3,4-Dihydroxyphenylacetaldehyde, a Toxic Dopamine Metabolite

Anderson

Florang

Schamp

et al. 2016

Chem. Res. Toxicol.

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“…Stock concentrations were determined using an ALDH assay with nicotinamide adenine dinucleotide (NAD + ) and HPLC [16]. MOPAL was biosynthesized as previously outlined [14].…”

Section: Methodsmentioning

confidence: 99%

Inactivation of glyceraldehyde-3-phosphate dehydrogenase by the dopamine metabolite, 3,4-dihydroxyphenylacetaldehyde

Vanle

Florang

Murry

et al. 2017

Biochemical and Biophysical Research Communications

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Background The aldehyde metabolite of dopamine, 3,4-dihydroxyphenylacetaldehyde (DOPAL) is an endogenous neurotoxin implicated in Parkinson’s Disease. Elucidating protein targets of DOPAL is essential in understanding it’s pathology. The enzyme, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a target of DOPAL. Methods GAPDH activity was measured via reduction of NAD+ cofactor (340 nm). Protein aggregation was assessed with SDS-PAGE methods and specific modification via chemical probes. Results Low micromolar levels of DOPAL caused extensive GAPDH aggregation and irreversibly inhibited enzyme activity. The inactivation of GAPDH was dependent on both the catechol and aldehyde moieties of DOPAL. It is suggested that Cys are modified and oxidized by DOPAL. Conclusions The mechanism by which DOPAL modifies GAPDH can serve as a mechanistic explanation to the pathological events in Parkinson’s Disease.

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“…DOPAL was biosynthesized as previously described using enzyme-catalyzed conversion of DA to DOPAL by rat liver MAO (Nilsson & Tottmar 1987), and the concentration was determined using an ALDH assay with NAD (Ungar et al 1973) and HPLC analysis as described below. 3,4-dihydroxyphenylethanol (DOPET) was obtained via reduction of DOPAL using a 10-fold excess of sodium borohydride.…”

Section: Methodsmentioning

confidence: 99%

“…Physiological concentrations of DOPAL were measured to be ~2–3 μM, and it was shown that when levels of DOPAL are slightly elevated (6.6 μM), there is a decrease in TH-positive cells, indicating dopaminergic cell death (Kristal et al 2001, Mattammal et al 1995, Burke et al 2003, Burke 2003). Furthermore, DOPAL has been implicated in protein modification (Rees et al 2007, Helander & Tottmar 1989, Ungar et al 1973, Nilsson & Tottmar 1987, LaVoie et al 2005). Studies have demonstrated the ability of DOPAL to covalently modify Lys residues via the aldehyde (Rees et al 2009), forming a Schiff-base structure predicted to interfere with normal protein function.…”

Section: Introductionmentioning

confidence: 99%

Inhibition and covalent modification of tyrosine hydroxylase by 3,4-dihydroxyphenylacetaldehyde, a toxic dopamine metabolite

2011

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Parkinson's disease (PD) is a neurodegenerative disorder marked by the selective loss of dopaminergic neurons, leading to a decrease of the neurotransmitter dopamine (DA). DA is metabolized by monoamine oxidase to 3,4-dihydroxyphenyacetaldehyde (DOPAL). While the mechanism of pathogenesis of PD is unknown, DOPAL has demonstrated the ability to covalently modify proteins and cause cell death at concentrations elevated from physiologic levels. Currently, the identities of protein targets of the aldehyde are unknown, but previous studies have demonstrated the ability of catechols and other DA-catabolism products to interact with and inhibit tyrosine hydroxylase (TH). Given that DOPAL is structurally related to DA and is a highly reactive electrophile, it was hypothesized to modify and inhibit TH. The data presented in this study positively identified TH as a protein target of DOPAL modification and inhibition. Furthermore, western blot analysis demonstrated a concentration-dependent decrease in antibody recognition of TH. DOPAL in cell lysate significantly inhibited TH activity as measured by decreased L-DOPA production. Inhibition of TH was semi-reversible, with the recovery of activity being time and concentration-dependent upon removal of DOPAL. These data indicate DOPAL to be a reactive DA-metabolite with the capability of modifying and inhibiting an enzyme important to DA synthesis.

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Inhibition of binding of aldehydes of biogenic amines in tissues

Cited by 34 publications

References 17 publications

Antioxidant-Mediated Modulation of Protein Reactivity for 3,4-Dihydroxyphenylacetaldehyde, a Toxic Dopamine Metabolite

Antioxidant-Mediated Modulation of Protein Reactivity for 3,4-Dihydroxyphenylacetaldehyde, a Toxic Dopamine Metabolite

Inactivation of glyceraldehyde-3-phosphate dehydrogenase by the dopamine metabolite, 3,4-dihydroxyphenylacetaldehyde

Inhibition and covalent modification of tyrosine hydroxylase by 3,4-dihydroxyphenylacetaldehyde, a toxic dopamine metabolite

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