Journal article
Inhibition and Covalent Modification of Tyrosine Hydroxylase by 3,4-Dihydroxyphenylacetaldehyde, a Toxic Dopamine Metabolite
Neurotoxicology (Park Forest South), Vol.32(4), pp.471-477
08/2011
DOI: 10.1016/j.neuro.2011.03.013
PMCID: PMC3109233
PMID: 21514317
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.
Details
- Title: Subtitle
- Inhibition and Covalent Modification of Tyrosine Hydroxylase by 3,4-Dihydroxyphenylacetaldehyde, a Toxic Dopamine Metabolite
- Creators
- Lydia M Mexas - Division of Medicinal and Natural Products Chemistry, College of Pharmacy, The University of Iowa, 323 Phar, 115 S. Grand Ave, Iowa City, Iowa 52242, USAVirginia R Florang - Division of Medicinal and Natural Products Chemistry, College of Pharmacy, The University of Iowa, 323 Phar, 115 S. Grand Ave, Iowa City, Iowa 52242, USAJonathan A Doorn - Division of Medicinal and Natural Products Chemistry, College of Pharmacy, The University of Iowa, 323 Phar, 115 S. Grand Ave, Iowa City, Iowa 52242, USA
- Resource Type
- Journal article
- Publication Details
- Neurotoxicology (Park Forest South), Vol.32(4), pp.471-477
- DOI
- 10.1016/j.neuro.2011.03.013
- PMID
- 21514317
- PMCID
- PMC3109233
- NLM abbreviation
- Neurotoxicology
- ISSN
- 0161-813X
- eISSN
- 1872-9711
- Grant note
- R01 ES015507-01A1 || ES / National Institute of Environmental Health Sciences : NIEHS K22 ES012982-03 || ES / National Institute of Environmental Health Sciences : NIEHS R01 ES015507-02 || ES / National Institute of Environmental Health Sciences : NIEHS R01 ES015507-03 || ES / National Institute of Environmental Health Sciences : NIEHS
- Language
- English
- Date published
- 08/2011
- Academic Unit
- Iowa Neuroscience Institute; Pharmaceutical Sciences and Experimental Therapeutics; Medicinal and Natural Products Chemistry
- Record Identifier
- 9984070732202771
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