Investigations of metabolic pathways of Reactive Sulfur Species
Jurányi Eszter Petra
Molecular Medicine Division
Dr. Várnai Péter
Országos Onkológiai Intézet, Tanácsterem
2026-09-01 18:30:00
Cellular and Molecular Physiology
Dr. Hunyady László
Dr. Nagy Péter
Dr. Kardon Tamás
Dr. Jon Fukuto
Dr. Merkely Béla
Dr. Bödör Csaba
Dr. Kovácsné Dr. Bácskay Ildikó
Intracellular redox balance is essential for cellular viability, proliferation, and regulating processes such as energy metabolism, signal transduction, and stress adaptation. An imbalance in redox homeostasis results in oxidative or reductive stress, which can lead to different diseases. Reactive Sulfur Species (RSS) are vital for maintaining intracellular redox balance, but their detection is challenging due to their high reactivity, which makes them labile. To enable biological studies of RSS, we first optimize and re-evaluate alkylating protocols that preserve their speciation and capture labile persulfide species. The optimized method thereby enabled us to investigate low- and high-molecular weight (LMW and HMW) persulfide species in various biological matrices and to gain deeper, mechanistic insight into their metabolism and biological roles.
The HPE-IAM-based LMW and HMW persulfide detection protocol is widely used due to HPE-IAM's stabilizing effect on these species. We critically re-evaluated this persulfide detection method to improve the reliability and reproducibility of our analyses. Using the improved method with stable isotope-labeled fluxomic analyses, we examined two complex biological systems: a disulfide reductase-deficient mouse model and a pancreatic ductal adenocarcinoma model. We showed that, under disulfide reductase deficiency, a PLP-dependent, Cse-mediated C–S bond-cleaving pathway can be activated, bypassing NADPH-dependent disulfide reduction of CSSC and thereby maintaining CSH homeostasis. Our in vitro and in vivo stable-isotope-tracing studies provided the first evidence that this pathway is indeed biologically relevant; moreover, it highlighted the metabolic flexibility of sulfur metabolism.
Additionally, we linked the transsulfuration enzyme Cbs to metastasis formation in PDAC tumors through HMW persulfides and demonstrated that posttranslational protein pesulfidation can affect protein activity, thereby initiating epithelial-to-mesenchymal transformation and metastasis formation.
The research outlined in this thesis expands our comprehension of the metabolic pathways of sulfur metabolites and the adaptability of these pathways. We gained a deeper mechanistic understanding of the roles of LMW and HMW persulfide species in sulfur metabolism and redox homeostasis.
