Relative inhibitory potency of molinate and metabolites with aldehyde dehydrogenase 2: implications for the mechanism of enzyme inhibition

Erin M G Allen; David G R Anderson; Virginia R Florang; May Khanna; Thomas D Hurley; Jonathan A Doorn

doi:10.1021/tx100317q

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Relative inhibitory potency of molinate and metabolites with aldehyde dehydrogenase 2: implications for the mechanism of enzyme inhibition

Journal article

Open access

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Relative inhibitory potency of molinate and metabolites with aldehyde dehydrogenase 2: implications for the mechanism of enzyme inhibition

Erin M G Allen, David G R Anderson, Virginia R Florang, May Khanna, Thomas D Hurley and Jonathan A Doorn

Chemical research in toxicology, Vol.23(11), pp.1843-1850

11/15/2010

DOI: 10.1021/tx100317q

PMCID: PMC2989800

PMID: 20954713

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Abstract

Molinate is a thiocarbamate herbicide used as a pre-emergent in rice patty fields. It has two predominant sulfoxidation metabolites, molinate sulfoxide and molinate sulfone. Previous work demonstrated an in vivo decrease in liver aldehyde dehydrogenase (ALDH) activity in rats treated with molinate and motor function deficits in dogs dosed chronically with this compound. ALDH is an enzyme important in the catabolism of many neurotransmitters, such as dopamine. Inhibition of this enzyme may lead to the accumulation of endogenous neurotoxic metabolites such as 3,4-dihydroxyphenylacetaldehyde, a dopamine metabolite, which may account for the observed neurotoxicity. In this study, the relative reactivity of molinate and both of its sulfoxidation metabolites toward ALDH was investigated, as well as the mechanism of inhibition. The ALDH activity was monitored in two different model systems, human recombinant ALDH (hALDH2) and mouse striatal synaptosomes. Molinate sulfone was found to be the most potent ALDH inhibitor, as compared to molinate and molinate sulfoxide. The reactivity of these three compounds was also assessed, using N-acetyl Cys, model peptides, and hALDH2. It was determined that molinate sulfone is capable of covalently modifying Cys residues, including catalytic Cys302 of ALDH, accounting for the observed enzyme inhibition.

Recombinant Proteins - metabolism

Amino Acid Sequence

Recombinant Proteins - antagonists & inhibitors

Thiocarbamates - metabolism

Aldehyde Dehydrogenase - antagonists & inhibitors

Humans

Aldehyde Dehydrogenase - genetics

Herbicides - toxicity

Recombinant Proteins - genetics

Thiocarbamates - toxicity

Synaptosomes - metabolism

Tandem Mass Spectrometry

Animals

Azepines - metabolism

Mice

Kinetics

Aldehyde Dehydrogenase - metabolism

Herbicides - metabolism

Azepines - toxicity

Details

Title: Subtitle: Relative inhibitory potency of molinate and metabolites with aldehyde dehydrogenase 2: implications for the mechanism of enzyme inhibition
Creators: Erin M G Allen - Division of Medicinal and Natural Products Chemistry, College of Pharmacy, The University of Iowa, Iowa City, Iowa 52242, USA
David G R Anderson
Virginia R Florang
May Khanna
Thomas D Hurley
Jonathan A Doorn
Resource Type: Journal article
Publication Details: Chemical research in toxicology, Vol.23(11), pp.1843-1850
DOI: 10.1021/tx100317q
PMID: 20954713
PMCID: PMC2989800
NLM abbreviation: Chem Res Toxicol
ISSN: 0893-228X
eISSN: 1520-5010
Publisher: United States
Grant note: S10 RR023384-01 / NCRR NIH HHS T32 GM067795 / NIGMS NIH HHS R01 ES015507 / NIEHS NIH HHS K22 ES012982 / NIEHS NIH HHS K22 ES012982-03 / NIEHS NIH HHS R01 ES015507-03 / NIEHS NIH HHS R01 ES15507 / NIEHS NIH HHS R01 AA018123 / NIAAA NIH HHS K22 ES12982 / NIEHS NIH HHS S10 RR023384 / NCRR NIH HHS T32 GM067795-04 / NIGMS NIH HHS R01 ES015507-02 / NIEHS NIH HHS
Language: English
Date published: 11/15/2010
Academic Unit: Iowa Neuroscience Institute; Pharmaceutical Sciences and Experimental Therapeutics; Medicinal and Natural Products Chemistry
Record Identifier: 9984070590402771

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