Sulfide Oxidation by a Noncanonical Pathway in Red Blood Cells Generates Thiosulfate and Polysulfides

Victor Vitvitsky,Pramod K Yadav,Angelika Kurthen,Ruma Banerjee

doi:10.1074/jbc.m115.639831

Victor Vitvitsky, Pramod K Yadav + Show 2 more

Open Access

https://doi.org/10.1074/jbc.m115.639831

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Abstract

A cardioprotectant at low concentrations, H2S is a toxin at high concentrations and inhibits cytochrome c oxidase. A conundrum in H2S homeostasis is its fate in red blood cells (RBCs), which produce H2S but lack the canonical mitochondrial sulfide oxidation pathway for its clearance. The sheer abundance of RBCs in circulation enhances the metabolic significance of their clearance strategy for H2S, necessary to avoid systemic toxicity. In this study, we demonstrate that H2S generation by RBCs is catalyzed by mercaptopyruvate sulfurtransferase. Furthermore, we have discovered the locus of sulfide oxidation in RBCs and describe a new role for an old protein, hemoglobin, which in the ferric or methemoglobin state binds H2S and oxidizes it to a mixture of thiosulfate and hydropolysulfides. Our study reveals a previously undescribed route for the biogenesis of hydropolysulfides, which are increasingly considered important for H2S-based signaling, but their origin in mammalian cells is unknown. An NADPH/flavoprotein oxidoreductase system restores polysulfide-carrying hemoglobin derivatives to ferrous hemoglobin, thus completing the methemoglobin-dependent sulfide oxidation cycle. Methemoglobin-dependent sulfide oxidation in mammals is complex and has similarities to chemistry reported for the dissolution of iron oxides in sulfidic waters and during bioleaching of metal sulfides. The catalytic oxidation of H2S by hemoglobin explains how RBCs maintain low steady-state H2S levels in circulation, and suggests that additional hemeproteins might be involved in sulfide homeostasis in other tissues.

Highlights

red blood cells (RBCs) produce H2S but, lacking mitochondria, are devoid of the canonical sulfide oxidation pathway
A conundrum in H2S homeostasis is its fate in red blood cells (RBCs), which produce H2S but lack the canonical mitochondrial sulfide oxidation pathway for its clearance
We demonstrate that H2S generation by RBCs is catalyzed by mercaptopyruvate sulfurtransferase

Summary

Background

RBCs produce H2S but, lacking mitochondria, are devoid of the canonical sulfide oxidation pathway. The bacterially derived sulfide oxidation pathway that resides in mitochondria is missing in RBCs, which as producers of H2S must rely on an alternative strategy for its clearance This problem is magnified by the sheer abundance of RBCs in circulation, which in the absence of an H2S clearance mechanism, would lead to certain death due to the buildup of toxic levels of H2S and its facile permeation across lipid bilayers (2, 3). Spectroscopic and structural studies on Hb suggest that several factors control the reactivity of H2S with Hb including the orientation of side chains and the dielectric constant in the vicinity of the distal ligand (19) These observations provide evidence for heme-dependent sulfide chemistry, albeit a role for Hb in catalytic sulfide oxidation in higher organisms has not been considered. We report that sulfide homeostasis in RBCs involves its generation by MST and its oxidative removal by MetHb, resulting in the production of thiosulfate and hydropolysulfides (hereafter referred to as polysulfides)

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