Relative inhibitory potency of molinate and metabolites with aldehyde dehydrogenase 2: implications for the mechanism of enzyme inhibition.
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.
Allen
Erin M G
EM
Division of Medicinal and Natural Products Chemistry, College of Pharmacy, The University of Iowa, Iowa City, Iowa 52242, USA.
Anderson
David G R
DG
Florang
Virginia R
VR
Khanna
May
M
Hurley
Thomas D
TD
Doorn
Jonathan A
JA
D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001381:Azepines / Q000378:metabolism* / Q000633:toxicity; D006540:Herbicides / Q000378:metabolism* / Q000633:toxicity; D006801:Humans; D007700:Kinetics; D051379:Mice; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013574:Synaptosomes / Q000378:metabolism; D053719:Tandem Mass Spectrometry; D013859:Thiocarbamates / Q000378:metabolism* / Q000633:toxicity
D001381:Azepines; D006540:Herbicides; D011994:Recombinant Proteins; D013859:Thiocarbamates; C009821:molinate; D000444:Aldehyde Dehydrogenase