Department of Chemistry, Texas A&M University, College Station, Texas 77843, United States.
J Am Chem Soc. 2023 Jun 7;145(22):11933-11938. doi: 10.1021/jacs.3c03545. Epub 2023 May 25.
Flavoenzymes are highly versatile and participate in the catalysis of a wide range of reactions, including key reactions in the metabolism of sulfur-containing compounds. S-Alkyl cysteine is formed primarily by the degradation of S-alkyl glutathione generated during electrophile detoxification. A recently discovered S-alkyl cysteine salvage pathway uses two flavoenzymes (CmoO and CmoJ) to dealkylate this metabolite in soil bacteria. CmoO catalyzes a stereospecific sulfoxidation, and CmoJ catalyzes the cleavage of one of the sulfoxide C-S bonds in a new reaction of unknown mechanism. In this paper, we investigate the mechanism of CmoJ. We provide experimental evidence that eliminates carbanion and radical intermediates and conclude that the reaction proceeds via an unprecedented enzyme-mediated modified Pummerer rearrangement. The elucidation of the mechanism of CmoJ adds a new motif to the flavoenzymology of sulfur-containing natural products and demonstrates a new strategy for the enzyme-catalyzed cleavage of C-S bonds.
黄素酶具有高度的多功能性，参与了广泛的反应的催化，包括含硫化合物代谢中的关键反应。S-烷基半胱氨酸主要由在亲电解毒过程中产生的 S-烷基谷胱甘肽的降解形成。最近发现的 S-烷基半胱氨酸挽救途径使用两种黄素酶（CmoO 和 CmoJ）在土壤细菌中脱除这种代谢物的烷基。CmoO 催化立体特异性的磺氧化，而 CmoJ 催化未知机制的新反应中一个亚砜 C-S 键的断裂。在本文中，我们研究了 CmoJ 的机制。我们提供了排除碳负离子和自由基中间体的实验证据，并得出结论，反应通过前所未有的酶介导的修饰 Pummerer 重排进行。CmoJ 机制的阐明为含硫天然产物的黄素酶学增添了一个新的主题，并展示了酶催化 C-S 键断裂的新策略。
