Hydrogen Sulfide Oxidation by Myoglobin

Bostelaar, Trever; Vitvitsky, Victor; Kumutima, Jacques; Lewis, B. A.; Yadav, Pramod Kumar; Brunold, Thomas C.; Filipović, Miloš R.; Lehnert, Nicolai; Stemmler, Timothy L.; Banerjee, Ruma

doi:10.1021/jacs.6b03456

Cited by 141 publications

(160 citation statements)

References 67 publications

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“…thiosulfate and polysulfides) were detected, albeit in lower amounts with neuroglobin ( Fig. 4A) than seen with myoglobin and hemoglobin (27,28). These results suggest that sulfide oxidation and oxygenation products can be formed even in the absence of direct coordination of the sulfur to the heme.…”

Section: Discussionmentioning

confidence: 74%

“…A similar band at ϳ360 cm Ϫ1 was observed in sulfide-treated ferric myoglobin (28). The D 2 O insensitivity of this band, however, indicates that it does not represent an Fe-SH (or Fe-SH 2 ) vibration, although it could correspond to an Fe-S bond vibration in a hydropolysulfide derivative.…”

mentioning

confidence: 56%

“…Recently, we have described a hemeprotein-dependent alternative to the mitochondrial pathway for catalytic H 2 S oxidation. Both ferric myoglobin and ferric hemoglobin oxidize sulfide to thiosulfate and to hydropolysulfides (27,28). H 2 S functions as a neuromodulator (29) and also protects neurons from oxidative stress (30).…”

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confidence: 99%

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A distal ligand mutes the interaction of hydrogen sulfide with human neuroglobin

Ruetz

Kumutima

Lewis

et al. 2017

Journal of Biological Chemistry

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Edited by Norma AllewellHydrogen sulfide is a critical signaling molecule, but high concentrations cause cellular toxicity. A four-enzyme pathway in the mitochondrion detoxifies H 2 S by converting it to thiosulfate and sulfate. Recent studies have shown that globins like hemoglobin and myoglobin can also oxidize H 2 S to thiosulfate and hydropolysulfides. Neuroglobin, a globin enriched in the brain, was reported to bind H 2 S tightly and was postulated to play a role in modulating neuronal sensitivity to H 2 S in conditions such as stroke. However, the H 2 S reactivity of the coordinately saturated heme in neuroglobin is expected a priori to be substantially lower than that of the 5-coordinate hemes present in myoglobin and hemoglobin. To resolve this discrepancy, we explored the role of the distal histidine residue in muting the reactivity of human neuroglobin toward H 2 S. Ferric neuroglobin is slowly reduced by H 2 S and catalyzes its inefficient oxidative conversion to thiosulfate. Mutation of the distal His 64 residue to alanine promotes rapid binding of H 2 S and its efficient conversion to oxidized products. X-ray absorption, EPR, and resonance Raman spectroscopy highlight the chemically different reaction options influenced by the distal histidine ligand. This study provides mechanistic insights into how the distal heme ligand in neuroglobin caps its reactivity toward H 2 S and identifies by cryo-mass spectrometry a range of sulfide oxidation products with 2-6 catenated sulfur atoms with or without oxygen insertion, which accumulate in the absence of the His 64 ligand.Neuroglobin is a member of the globin family (1) that is expressed primarily in neuronal tissues (2) but also in other metabolically highly active endocrine tissues, such as the adrenal gland and the pancreatic islets of Langerhans (3, 4). Although the physiological role of neuroglobin is still elusive, early studies suggested that it might be involved in oxygen supply (1, 5). However, neuroglobin is generally expressed at low levels and exhibits a high autoxidation rate, producing reactive oxygen species, which makes its role as an O 2 carrier unlikely (6). Neuroglobin can also scavenge reactive oxygen species and reduce nitrite to NO under hypoxic conditions (7-9).In contrast to hemoglobin and myoglobin, two histidine residues coordinate the heme cofactor in neuroglobin in the ferrous and ferric states (Fig. 1A). The crystal structure of neuroglobin reveals a high structural similarity to myoglobin, despite Ͻ25% amino acid sequence similarity between the proteins. The structure reveals a large hydrophobic cavity, which connects the proximal and distal sides of the heme (7). His 64 and His 96 coordinate the heme on the distal and proximal sides, respectively (10). Exogenous ligands like O 2 , CO, and NO bind to ferrous neuroglobin (Fe II -Ngb) 2 on the distal side, and binding is limited by dissociation of His 64 , which is slow (6,(11)(12)(13)(14). Limited characterization of the binding of sulfide to ferric neuroglobin (Fe III -Ngb) has...

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Section: Discussionmentioning

confidence: 74%

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confidence: 56%

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A distal ligand mutes the interaction of hydrogen sulfide with human neuroglobin

Ruetz

Kumutima

Lewis

et al. 2017

Journal of Biological Chemistry

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“…Alternatively or additionally, increased H 2 S could stimulate its oxidation by heme proteins. We have shown that globins like hemoglobin, myoglobin and neuroglobin catalyze oxidation of H 2 S to thiosulfate (26)(27)(28)(29).…”

Section: Discussionmentioning

confidence: 99%

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

Kabil

Motl

Strack

et al. 2018

Journal of Biological Chemistry

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Hydrogen sulfide (H 2 S) is a signaling molecule with many beneficial effects. However, its cellular concentration is strictly regulated to avoid toxicity. Persulfide dioxygenase (PDO or ETHE1) is a mononuclear non-heme ironcontaining protein in the sulfide oxidation pathway catalyzing the conversion of glutathione persulfide (GSSH) to sulfite and glutathione. PDO mutations result in the autosomal recessive disorder, ethylmalonic encephalopathy (EE). Here, we developed γ-glutamyl-homocysteinyl-glycine (GHcySH) in which the cysteinyl moiety in glutathione is substituted with homocysteine, as a mechanismbased PDO inhibitor. Human PDO used GHcySH as an alternate substrate and converted it to GHcy-SO 2 H, mimicking GS-SO 2 H, the putative oxygenated intermediate formed with the natural substrate. Since GHcy-SO 2 H contains a C-S bond rather than an S-S bond in GS-SO 2 H, it failed to undergo the final hydrolysis step in the catalytic cycle, leading to PDO inhibition. We also characterized the biochemical penalties incurred by the L55P, T136A, C161Y and R163W mutations reported in EE patients. The variants displayed lower iron content (1.4-to 11-fold) and lower thermal stability (1.2-to 1.7-fold) than wild-type PDO. They also exhibited varying degrees of catalytic impairment; the k cat /K m values for R163W, L55P and C161Y PDOs were 18-, 42-and 65-fold lower, respectively and the T136A variant was most affected with a 200-fold lower k cat /K m . Like wild-type enzyme, these variants were inhibited by GHcySH. This study provides the first characterization of an intermediate in the PDO-catalyzed reaction and reports on deficits associated with EE-linked mutations that are distal from the active site.Ethylmalonic encephalopathy (EE) 1 is an autosomal recessive disorder that is associated with pathological effects in the brain, gastrointestinal tract and peripheral vessels (1-3). It results in acrocyanosis, petechiae, hemorrhagic diarrhea, developmental delay and progressive neurological failure leading to necrotic lesions in the deep gray matter of the brain. Patients with EE usually succumb to the disease within the first decade of life (4). The clinical profile of EE includes elevated ethylmalonic acid in urine, C4 and C5 acrylcarnitines in blood and a deficiency of cytochrome c oxidase in brain and muscle (5). 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). PDO catalyzes the second step in the pathway, i.e. the oxidation of glutathione persulfide (GSSH) to sulfite (Eq. 1) (12). Sulfite is either oxidized b...

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“…RBCs play an important role in regulation of vascular tone by regulating local H 2 S levels. H 2 S, whether generated in RBCs by 3-MST or diffused into RBCs from blood, binds to hemoglobin and is oxidized to thiosulfate and hydropolysulfides [108]; myoglobin shows a similar capacity for H 2 S oxidation [109]. …”

Section: H2s and No Synthesis In Vasculaturementioning

confidence: 99%

Regulation of vascular tone homeostasis by NO and H2S: Implications in hypertension

Gheibi

Jeddi

Kashfi

et al. 2018

Biochemical Pharmacology

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Nitric oxide (NO) and hydrogen sulfide (HS) are two gasotransmitters that are produced in the vasculature and contribute to the regulation of vascular tone. NO and HS are synthesized in both vascular smooth muscle and endothelial cells; NO functions primarily through the sGC/cGMP pathway, and HS mainly through activation of the ATP-dependent potassium channels; both leading to relaxation of vascular smooth muscle cells. A deficit in the NO/HS homeostasis is involved in the pathogenesis of various cardiovascular diseases, especially hypertension. It is now becoming increasingly clear that there are important interactions between NO and HS and that have a profound impact on vascular tone and this may provide insights into the new therapeutic interventions. The aim of this review is to provide a better understanding of individual and interactive roles of NO and HS in vascular biology. Overall, available data indicate that both NO and HS contribute to vascular (patho)physiology and in regulating blood pressure. In addition, boosting NO and HS using various dietary sources or donors could be a hopeful therapeutic strategy in the management of hypertension.

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Hydrogen Sulfide Oxidation by Myoglobin

Cited by 141 publications

References 67 publications

A distal ligand mutes the interaction of hydrogen sulfide with human neuroglobin

A distal ligand mutes the interaction of hydrogen sulfide with human neuroglobin

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

Regulation of vascular tone homeostasis by NO and H2S: Implications in hypertension

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