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 (H2Sn, n = 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.
Highlights
The key component of many enzymes and respiratory pigments is a porphyrin ring that stabilizes a reactive metal, often iron, in its center
We previously showed that porphyrins and porphyrin-containing proteins optically interfere with excitation/emission of fluorophores at lower wavelengths (~300–550 nm) [30]
To determine if the effects of Manganese-centered porphyrins (MnPs) were on polysulfide production or due to physical interference with fluorescence itself, we compared the effects of MnPs on fluorescence produced by 1 μM fluorescein at 90 min to the 90 min SSP4 fluorescence samples of MnPs reacting with 100 μM hydrogen sulfide (H2 S)
Summary
The key component of many enzymes and respiratory pigments is a porphyrin ring that stabilizes a reactive metal, often iron, in its center. Most notable are three MnPs; MnTE-2-PyP5+ (MnTE, AEOL10113, BMX-010), MnTnHex-2-PyP5+ (MnHex), and MnTnBuOE-2-PyP5+ (MnBuOE, BMX-001), that closely mimic the reduction potential (E 1 ) of the endogenous antioxidant enzyme, superoxide dismutase (SOD; ~+300 mV vs the normal hydrogen electrode (NHE)) [10,11]. These MnPs are excellent SOD mimetics, they lack the tertiary structure that enables the high specificity of SOD toward superoxide and they react with other compounds such as peroxynitrite, carbonate radical, nitric oxide, peroxide, small aminothiols or protein thiols, and hypochlorite [12,13]
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