Three enzymatic activities catalyze the oxidation of sulfide to thiosulfate in mammalian and invertebrate mitochondria

Abstract

Hydrogen sulfide was known as a toxic pollutant long before its physiological functions became apparent. The main effects of sulfide poisoning are the loss of central respiratory drive due to lesions in the brain stem, and inhibition of cytochrome oxidase, leading to impaired aerobic energy metabolism [1]. Sulfide-rich environments occur naturally in the sediments and grass marshes of the intertidal zone, in deep-sea hydrothermal vents, and in the hypolimneon of eutrophic lakes [2]. Moreover, mammalian as well as invertebrate tissues, such as the body wall of the lugworm Arenicola marina, enzymatically produce sulfide [3,4].In mammals, H 2 S acts as a gaseous transmitter and regulates several physiological processes [5]. Altered sulfide metabolism is associated with a number of disorders, such as Alzheimer's disease, Down's syndrome and ulcerative colitis [6][7][8]. Within a narrow concentration range, the effects of sulfide change from physiological to highly toxic, and therefore regulatory mechanisms are necessary to control endogenous sulfide levels within the physiological range.Sulfide is catabolized mainly by oxidation to nontoxic sulfur compounds. Mammals rapidly oxidize sublethal concentrations of sulfide to sulfate and excrete it in the urine [1,9]. The main sites of sulfide oxidation are liver and colon tissues, and the enzyme activity is present in the mitochondria [10,11]. Thiosulfate is produced as an obligate intermediate by a putative sulfide oxidase, which has not yet been identified [12].A mitochondrial pathway also catalyzes sulfide oxidation in many sulfide-adapted invertebrates including polychaetes, crustaceans and bivalves [2]. The lugworm A. marina is often used to study strategies of sulfide tolerance, because it is highly abundant in sandy to muddy intertidal flats, where high micromolar concentrations of sulfide regularly occur [2]. Hydrogen sulfide is a potent toxin of aerobic respiration, but also has physiological functions as a signalling molecule and as a substrate for ATP production. A mitochondrial pathway catalyzing sulfide oxidation to thiosulfate in three consecutive reactions has been identified in rat liver as well as in the body-wall tissue of the lugworm, Arenicola marina. A membranebound sulfide : quinone oxidoreductase converts sulfide to persulfides and transfers the electrons to the ubiquinone pool. Subsequently, a putative sulfur dioxygenase in the mitochondrial matrix oxidizes one persulfide molecule to sulfite, consuming molecular oxygen. The final reaction is catalyzed by a sulfur transferase, which adds a second persulfide from the sulfide : quinone oxidoreductase to sulfite, resulting in the final product thiosulfate. This role in sulfide oxidation is an additional physiological function of the mitochondrial sulfur transferase, rhodanese.Abbreviations GSH, glutathione; GSSH, glutathione persulfide; SQR, sulfide : quinone oxidoreductase.

Hydrogen sulfide as an oxygen sensor

“…One electron from each of the two H 2 S are fed via the quinone pool (Q) into the respiratory chain (98) and they ultimately reduce O 2 at complex IV. SQR is bound to the inner mitochondrial membrane, and it is believed that sulfur is shuttled from SQR by an as-yet unidentified mobile carrier, possibly glutathione (GSH), dihydrolipoate, Trx, or sulfite (59,63,165). SQR is found in all tissues except the brain (58,82,89) (but see ''2.…”

Mechanism-based inhibition of human persulfide dioxygenase by γ-glutamyl-homocysteinyl-glycine

“…Homolytic cleavage of the O-O bond results in a sulfoxy-cation and an Fe(II)-activated oxygen [6]. Recombination [7] followed by hydrolysis yields the products, sulfite and GSH [8], and restore the enzyme to its resting state [1]. B, Structures of GSSH, GHcySH and glutathione (GSH).…”

“…Recombination of the superoxo and sulfur radical species yields a cyclic peroxo intermediate [5], followed by homolytic cleavage of the O-O bond resulting in a sulfoxy-cation intermediate and an Fe(II)-bound activated oxygen [6]. Recombination of the activated oxygen and the sulfoxy-cation yields the GSSO 2 -intermediate [7], which is hydrolyzed to give the products, sulfite and GSH [8]. The postulated intermediates form transiently and are reactive.…”

“…PDO is a mitochondrial matrix protein that participates in the mitochondrial sulfide oxidation pathway, which converts H 2 S to the end products, thiosulfate and sulfate (7,8). In addition to PDO, the other enzymes involved in the mitochondrial sulfur oxidation pathway are sulfide quinone oxidoreductase (9), rhodanese (10), and sulfite oxidase (11).…”

“…EE is caused by mutations in the ethe1 gene that encodes persulfide dioxygenase (PDO or ETHE1). Over 20 mutations have been described in the ethe1 gene, of which a subset represents missense mutations (3,4,6).PDO is a mitochondrial matrix protein that participates in the mitochondrial sulfide oxidation pathway, which converts H 2 S to the end products, thiosulfate and sulfate (7,8). In addition to PDO, the other enzymes involved in the mitochondrial sulfur oxidation pathway are sulfide quinone oxidoreductase (9), rhodanese (10), and sulfite oxidase (11).…”