The SOD1 Inhibitor, LCS-1, Oxidizes H2S to Reactive Sulfur Species, Directly and Indirectly, through Conversion of SOD1 to an Oxidase

Authors

Kenneth R Olson
Tsuyoshi Takata
Kasey J Clear
Yan Gao
Zhilin Ma
Ella Pfaff
Karthik Mouli
Thomas A Kent
Prentiss Jones
Jon Fukuto
Gang Wu
Karl D Straub

Publication Date

8-15-2024

Journal

Antioxidants

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

DOI

10.3390/antiox13080991

PMID

39199236

PMCID

PMC11351665

PubMedCentral® Posted Date

8-15-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes