Abstract
The highly similar aldehyde dehydrogenase isozymes (ALDH1A1 and ALDH2) have been implicated in the metabolism of toxic biogenic aldehydes such as 3,4-dihydroxyphenylacetaldehyde (DOPAL) and 4-hydroxy-2E-nonenal. We report the down-regulation of ALDH1A1 mRNA found in substantia nigra tissue of human Parkinson's disease (PD) samples using the Genome-Wide SpliceArray(™) (GWSA(™)) technology. Since DOPAL can rapidly inactivate ALDH1A1 in vitro, we set up a DOPAL-induced ALDH1A1 inactivation assay and used this assay to demonstrate that Alda-1, a compound originally identified as an activator of ALDH2, can also activate ALDH1A1. We carried out a virtual screening of 19,943 compounds and the top 21 hits from this screen were tested in the DOPAL inactivation assay with ALDH1A1 which led to identification of an activator as well as two inhibitors among these hits. These findings represent an attractive starting point for developing higher potency activator compounds that may have utility in restoring the metabolism of DOPAL in PD.
MeSH terms
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3,4-Dihydroxyphenylacetic Acid / analogs & derivatives
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3,4-Dihydroxyphenylacetic Acid / metabolism
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3,4-Dihydroxyphenylacetic Acid / pharmacology
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Aldehyde Dehydrogenase / chemistry
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Aldehyde Dehydrogenase / genetics*
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Aldehyde Dehydrogenase / metabolism
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Aldehyde Dehydrogenase 1 Family
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Aldehyde Dehydrogenase, Mitochondrial
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Benzamides / metabolism
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Benzamides / pharmacology*
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Benzodioxoles / metabolism
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Benzodioxoles / pharmacology*
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Binding Sites
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Case-Control Studies
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Enzyme Activation / drug effects
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Gene Expression Regulation, Enzymologic
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Humans
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Ligands
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Molecular Docking Simulation
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Parkinson Disease / enzymology*
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Parkinson Disease / genetics
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Retinal Dehydrogenase
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Small Molecule Libraries / pharmacology
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Substantia Nigra / enzymology
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User-Computer Interface
Substances
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Benzamides
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Benzodioxoles
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Ligands
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N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide
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Small Molecule Libraries
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3,4-Dihydroxyphenylacetic Acid
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3,4-dihydroxyphenylacetaldehyde
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Aldehyde Dehydrogenase 1 Family
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ALDH2 protein, human
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Aldehyde Dehydrogenase
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Aldehyde Dehydrogenase, Mitochondrial
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ALDH1A1 protein, human
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Retinal Dehydrogenase