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TitleAllosteric activators of cystathionine γ lyase to augment endogenous hydrogen sulfide and inhibit pathologic calcification.
Journal, issue, pagesPharmacol Res, Vol. 219, Page 107869, Year 2025
Publish dateJul 26, 2025
AuthorsSonia Nasi / Driss Ehirchiou / Cindy Blatter / Veronique Chobaz / Stefan Germann / Alexandra Brandenberger / Elias Bommeli / Emiko Uchikawa / Giuseppe Cirino / Rainer Riedl / Alexander So / Nathalie Busso /
PubMed AbstractHydrogen sulfide (H₂S), a gasotransmitter naturally produced in the body by enzymes such as cystathionine γ lyase (CSE), helps reduce inflammation, oxidative stress, and abnormal tissue ...Hydrogen sulfide (H₂S), a gasotransmitter naturally produced in the body by enzymes such as cystathionine γ lyase (CSE), helps reduce inflammation, oxidative stress, and abnormal tissue calcification. We present a novel strategy to boost endogenous H₂S production via CSE allosteric activation. Two CSE positive allosteric modulators (CSE-PAMs) were identified. Despite moderate binding affinity, both compounds induced a strong allosteric effect, increasing H₂S production by approximately 200 %. Cryo-electron microscopy and proteomics identified a distinct allosteric binding pocket on recombinant human CSE. In cellular assays, both compounds elevated H₂S levels. This correlated with inhibition of calcification. In chondrocytes, CSE-PAMs reduced alkaline phosphatase activity, inflammatory cytokine secretion, and oxidative stress, while enhancing protein persulfidation. These results highlight CSE-PAMs as promising therapeutic agents for conditions involving pathological calcification and inflammation, such as osteoarthritis. Additionally, they serve as valuable tools for investigating CSE-derived H₂S biology, previously limited by a lack of specific modulators.
External linksPharmacol Res / PubMed:40716475
MethodsEM (single particle)
Resolution2.06 - 2.52 Å
Structure data

EMDB-52956: Structure of Cystathionine gamma-lyase with ZHAWOC24000
Method: EM (single particle) / Resolution: 2.52 Å

EMDB-52957: Structure of Cystathionine gamma-lyase
Method: EM (single particle) / Resolution: 2.06 Å

Source
  • Homo sapiens (human)

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