Faculty, Staff and Student Publications
Language
English
Publication Date
8-15-2024
Journal
Antioxidants
DOI
10.3390/antiox13080991
PMID
39199236
PMCID
PMC11351665
PubMedCentral® Posted Date
8-15-2024
PubMedCentral® Full Text Version
Post-print
Abstract
LCS-1, a putative selective inhibitor of SOD1, is a substituted pyridazinone with rudimentary similarity to quinones and naphthoquinones. As quinones catalytically oxidize H2S to biologically active reactive sulfur species (RSS), we hypothesized LCS-1 might have similar attributes. Here, we examine LCS-1 reactions with H2S 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 H2S in buffer solutions to form RSS, namely per- and polyhydrosulfides (H2Sn, 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 H2S to H2S3-6. LCS-1 forms monothiol adducts with H2S, 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.
Keywords
reactive sulfur species, reactive oxygen species, antioxidants, SOD1, SOD2
Published Open-Access
yes
Recommended Citation
Olson, Kenneth R; Takata, Tsuyoshi; Clear, Kasey J; et al., "The SOD1 Inhibitor, LCS-1, Oxidizes H2S to Reactive Sulfur Species, Directly and Indirectly, through Conversion of SOD1 to an Oxidase" (2024). Faculty, Staff and Student Publications. 3040.
https://digitalcommons.library.tmc.edu/uthmed_docs/3040