Manganese Porphyrin-Based SOD Mimetics Produce Polysulfides from Hydrogen Sulfide

Abstract

Manganese-centered porphyrins (MnPs), MnTE-2-PyP⁵⁺ (MnTE), MnTnHex-2-PyP⁵⁺ (MnTnHex), and MnTnBuOE-2-PyP⁵⁺ (MnTnBuOE) have received considerable attention because of their ability to serve as superoxide dismutase (SOD) mimetics thereby producing hydrogen peroxide (H₂O₂), and oxidants of ascorbate and simple aminothiols or protein thiols. MnTE-2-PyP⁵⁺ and MnTnBuOE-2-PyP⁵⁺ are now in five Phase II clinical trials warranting further exploration of their rich redox-based biology. Previously, we reported that SOD is also a sulfide oxidase catalyzing the oxidation of hydrogen sulfide (H₂S) to hydrogen persulfide (H₂S₂) and longer-chain polysulfides (H₂S_n, <i>n</i> = 3-7). We hypothesized that MnPs may have similar actions on sulfide metabolism. H₂S and polysulfides were monitored in fluorimetric assays with 7-azido-4-methylcoumarin (AzMC) and 3',6'-di(O-thiosalicyl)fluorescein (SSP4), respectively, and specific polysulfides were further identified by mass spectrometry. MnPs concentration-dependently consumed H₂S and produced H₂S₂ and subsequently longer-chain polysulfides. This reaction appeared to be O₂-dependent. MnP absorbance spectra exhibited wavelength shifts in the Soret and Q bands characteristic of sulfide-mediated reduction of Mn. Taken together, our results suggest that MnPs can become efficacious activators of a variety of cytoprotective processes by acting as sulfide oxidation catalysts generating per/polysulfides.