1. The SOD1 Inhibitor, LCS-1, Oxidizes H2S to Reactive Sulfur Species, Directly and Indirectly, through Conversion of SOD1 to an Oxidase.
- Author
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Olson, Kenneth R., Takata, Tsuyoshi, Clear, Kasey J., Gao, Yan, Ma, Zhilin, Pfaff, Ella, Mouli, Karthik, Kent, Thomas A., Jones Jr., Prentiss, Fukuto, Jon, Wu, Gang, and Straub, Karl D.
- Abstract
LCS-1, a putative selective inhibitor of SOD1, is a substituted pyridazinone with rudimentary similarity to quinones and naphthoquinones. As quinones catalytically oxidize H
2 S to biologically active reactive sulfur species (RSS), we hypothesized LCS-1 might have similar attributes. Here, we examine LCS-1 reactions with H2 S and SOD1 using thiol-specific fluorophores, liquid chromatography–mass spectrometry, electron paramagnetic resonance (EPR), UV–vis spectrometry, and oxygen consumption. We show that LCS-1 catalytically oxidizes H2 S in buffer solutions to form RSS, namely per- and polyhydrosulfides (H2 Sn , n = 2–6). These reactions consume oxygen and produce hydrogen peroxide, but they do not have an EPR signature, nor do they affect the UV–vis spectrum. Surprisingly, LCS-1 synergizes with SOD1, but not SOD2, to oxidize H2 S to H2 S3-6 . LCS-1 forms monothiol adducts with H2 S, glutathione (GSH), and cysteine (Cys), but not with oxidized glutathione or cystine; both thiol adducts inhibit LCS-1-SOD1 synergism. We propose that LCS-1 forms an adduct with SOD1 that disrupts the intramolecular Cys57 -Cys146 disulfide bond and transforms SOD1 from a dismutase to an oxidase. This would increase cellular ROS and polysulfides, the latter potentially affecting cellular signaling and/or cytoprotection. [ABSTRACT FROM AUTHOR]- Published
- 2024
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