Inhibition and covalent modification of tyrosine hydroxylase by 3,4-dihydroxyphenylacetaldehyde, a toxic dopamine metabolite
| Autor: | Virginia R. Florang, Lydia M. Mexas, Jonathan A. Doorn |
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| Rok vydání: | 2010 |
| Předmět: |
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4-Dihydroxyphenylacetic acid Time Factors Tyrosine 3-Monooxygenase Monoamine oxidase Cell Survival Dopamine Blotting Western 3 4-Dihydroxyphenylacetaldehyde Biology Toxicology Article Levodopa chemistry.chemical_compound Cell Line Tumor Adrenal Glands medicine Animals Enzyme Inhibitors Neurotransmitter Tyrosine hydroxylase Dose-Response Relationship Drug General Neuroscience Dopaminergic Rats Kinetics Biochemistry chemistry Catecholamine 3 4-Dihydroxyphenylacetic Acid Protein Processing Post-Translational medicine.drug |
| Zdroj: | Neurotoxicology. 32(4) |
| ISSN: | 1872-9711 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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