{"doi":"10.3390/antiox13080991","title":"The SOD1 Inhibitor, LCS-1, Oxidizes H2S to Reactive Sulfur Species, Directly and Indirectly, through Conversion of SOD1 to an Oxidase","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.","journal":"Antioxidants","year":2024,"id":466178,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9635,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":245016,"name":"Tsuyoshi Takata","orcid":"0000-0002-6691-2569","position":1,"is_corresponding":false},{"id":912214,"name":"Kasey J. Clear","orcid":"0000-0001-8628-681X","position":2,"is_corresponding":false},{"id":812569,"name":"Yan Gao","orcid":"0000-0002-6541-8577","position":3,"is_corresponding":false},{"id":912215,"name":"Zhilin Ma","orcid":"0000-0003-2493-0889","position":4,"is_corresponding":false},{"id":950305,"name":"Ella Pfaff","orcid":"0000-0001-7634-0114","position":5,"is_corresponding":false},{"id":678015,"name":"K. Chandra Mouli","orcid":"0000-0002-1671-5727","position":6,"is_corresponding":false},{"id":475096,"name":"Thomas A. Kent","orcid":"0000-0002-9877-7584","position":7,"is_corresponding":false},{"id":1298403,"name":"Prentiss Jones","orcid":null,"position":8,"is_corresponding":false},{"id":245021,"name":"Jon M. Fukuto","orcid":"0000-0002-0014-160X","position":9,"is_corresponding":false},{"id":306816,"name":"Gang Wu","orcid":"0000-0001-6803-0853","position":10,"is_corresponding":false},{"id":912706,"name":"Karl D. Straub","orcid":null,"position":11,"is_corresponding":false},{"id":425905,"name":"Kenneth R. Olson","orcid":"0000-0003-0178-2203","position":0,"is_corresponding":true}],"reference_count":36,"raw_metadata":null,"created_at":"2026-07-19T02:04:54.606394Z","pmid":"39199236","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}