title: Inhibition and covalent modification of tyrosine hydroxylase by 3,4-dihydroxyphenylacetaldehyde, a toxic dopamine metabolite.
abstract: 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.
authors.affiliation: Division of Medicinal and Natural Products Chemistry, College of Pharmacy, The University of Iowa, 115 S. Grand Avenue, Iowa City, IA 52242, USA. lydia-mexas@uiowa.edu
authors.forename: Lydia M
authors.initials: LM
authors.lastname: Mexas
authors.forename: Virginia R
authors.initials: VR
authors.lastname: Florang
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Doorn
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D000311:Adrenal Glands / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000633:toxicity*; D007700:Kinetics; D007980:Levodopa / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D051381:Rats; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D015102:3,4-Dihydroxyphenylacetic Acid; D007980:Levodopa; C007430:3,4-dihydroxyphenylacetaldehyde; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine