Figure 14.

H₂S-mediated modulation of nitric oxide and carbon monoxide biosynthesis. Hydrogen sulfide produced by CBS, CSE, and MST, and the related per- and polysulfide species (RS_(n)H), can modulate NO and CO bioavailability through different mechanisms. Left, representation of sulfide-mediated enhanced eNOS activity: H₂S reduces VEGFR2 Cys₁₀₂₄-Cys₁₀₄₅ disulfide, resulting in activation of PI3K; the accumulated PIP3 increases Akt-mediated phosphorylation of eNOS at Ser₁₀₇₇ and/or Ser₁₀₇₉, enhancing its NO-synthesizing activity. Center, direct persulfidation of eNOS Cys₄₄₃ sustains the protein catalytic activity by competing with Cys₄₄₃s-nitrosation, which causes dissociation of the active dimeric into the inactive monomeric form. Right, modulation of CO biosynthesis through increased expression of HO-1, mediated by the Keap1/Nrf2 pathway. Persulfidation of Keap1 Cys₁₅₁, either by reaction of H₂S with oxidized Cys₁₅₁ or of reduced Cys₁₅₁ with H₂S-derived HS·, causes its dissociation from Nrf2, which can then translocate to the nucleus, where it enhances heme oxygenase HO-1 expression, thus resulting in higher CO levels that may become inhibitory for CBS.