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.

中文翻译：

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禾草酸及其代谢物与醛脱氢酶 2 的相对抑制效力：对酶抑制机制的影响

Molinate 是一种硫代氨基甲酸酯类除草剂，用作稻田中的芽前除草剂。它有两种主要的亚砜氧化代谢物，禾草胺亚砜和禾草胺砜。先前的工作表明，在长期服用这种化合物的狗中，用禾草胺和运动功能缺陷治疗的大鼠体内肝醛脱氢酶 (ALDH) 活性降低。ALDH 是一种在许多神经递质（如多巴胺）的分解代谢中很重要的酶。这种酶的抑制可能导致内源性神经毒性代谢物的积累，例如 3,4-二羟基苯乙醛，一种多巴胺代谢物，这可能是观察到的神经毒性的原因。在这项研究中，研究了禾草胺及其两种磺化氧化代谢物对 ALDH 的相对反应性，以及抑制机制。在两种不同的模型系统中监测 ALDH 活性，即人类重组 ALDH (hALDH2) 和小鼠纹状体突触体。发现与禾草胺和禾草胺亚砜相比，禾草胺砜是最有效的 ALDH 抑制剂。还评估了这三种化合物的反应性，使用N-乙酰半胱氨酸、模型肽和 hALDH2。确定禾草酯砜能够共价修饰 Cys 残基，包括 ALDH 的催化性 Cys302，解释了观察到的酶抑制。