Hydrogen sulfide engages catalytic zinc in HDAC6 to modulate an alternative deacetylation pathway
In the authors' words
Hydrogen sulfide (H₂S) is a gasotransmitter whose non-covalent effects on protein function remain incompletely understood. Here we show that H₂S-derived sulfur species engage the catalytic Zn²⁺ center of histone deacetylase 6 (HDAC6) and enhance deacetylase activity under defined conditions. Molecular dynamics simulations support access of HS⁻ to the CD2 active-site tunnel, whereas surface plasmon resonance and zinc-depletion experiments support reversible, zinc-dependent engagement. Quantum chemical calculations support a chemically feasible sulfur-associated deacetylation pathway that generates thioacetic acid, which we detect in cell-free reactions, cultured cells, mouse tissues and human serum. Cryo-electron microscopy defines the tandem organization of human HDAC6 catalytic domains and reveals distinct CD1 and CD2 tunnel architectures. HDAC6 loss blunts H₂S-induced endothelial migration and angiogenesis, and CD2 is required for these responses. These findings support HDAC6 as an H₂S-responsive Zn²⁺-dependent deacetylase and link zinc–sulfur coordination to altered deacetylation chemistry. Hydrogen sulfide is a gasotransmitter whose non-covalent effects on protein function remain incompletely understood. Here the authors show that hydrogen sulfide interacts with zinc in the enzyme HDAC6, changes how it removes acetyl groups from proteins, and contributes to blood-vessel growth.
Appeared: Friday, September 25. Nature Communications. Peer-reviewed journal.