Characterization and Interaction Studies of Two Isoforms of the Dual Localized 3-Mercaptopyruvate Sulfurtransferase TUM1 from Humans

Fräsdorf, Benjamin; Radon, Christin; Leimkühler, Silke

doi:10.1074/jbc.m114.605733

Cited by 66 publications

(85 citation statements)

References 54 publications

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“…This agrees with previous data showing urmylation occurs in the absence of tRNA thiolation 45. These read-outs contrast sharply with those of tum1 ∆ cells lacking S-transferase Tum1 2245. As revealed by LC-MS/MS and EMSA, they are significantly reduced in tRNA thiolation and Ahp1 urmylation (Fig.…”

Section: Resultssupporting

confidence: 92%

Sulfur transfer and activation by ubiquitin-like modifier system Uba4•Urm1 link protein urmylation and tRNA thiolation in yeast

et al. 2016

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Urm1 is a unique dual-function member of the ubiquitin protein family and conserved from yeast to man. It acts both as a protein modifier in ubiquitin-like urmylation and as a sulfur donor for tRNA thiolation, which in concert with the Elongator pathway forms 5-methoxy-carbonyl-methyl-2-thio (mcm5s2) modified wobble uridines (U34) in anticodons. Using Saccharomyces cerevisiae as a model to study a relationship between these two functions, we examined whether cultivation temperature and sulfur supply previously implicated in the tRNA thiolation branch of the URM1 pathway also contribute to proper urmylation. Monitoring Urm1 conjugation, we found urmylation of the peroxiredoxin Ahp1 is suppressed either at elevated cultivation temperatures or under sulfur starvation. In line with this, mutants with sulfur transfer defects that are linked to enzymes (Tum1, Uba4) required for Urm1 activation by thiocarboxylation (Urm1-COSH) were found to maintain drastically reduced levels of Ahp1 urmylation and mcm5s2U34 modification. Moreover, as revealed by site specific mutagenesis, the S-transfer rhodanese domain (RHD) in the E1-like activator (Uba4) crucial for Urm1-COSH formation is critical but not essential for protein urmylation and tRNA thiolation. In sum, sulfur supply, transfer and activation chemically link protein urmylation and tRNA thiolation. These are features that distinguish the ubiquitin-like modifier system Uba4•Urm1 from canonical ubiquitin family members and will help elucidate whether, in addition to their mechanistic links, the protein and tRNA modification branches of the URM1 pathway may also relate in function to one another.

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Section: Resultssupporting

confidence: 92%

Sulfur transfer and activation by ubiquitin-like modifier system Uba4•Urm1 link protein urmylation and tRNA thiolation in yeast

et al. 2016

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“…Thus, we postulated that hydropersulfides created by SQR oxidize roGFP2 within the mitochondrial matrix. In addition, MST, which is dually localized to both cytosol and mitochondria (Frasdorf et al, 2014), is known to use 3MP to create hydropersulfides, which may either directly contribute to roGFP2 oxidation, or be reduced to yield H 2 S, and thereby contribute to SQR-mediated hydropersulfide production. In addition, some 3MP may also be converted back to Cys by cysteine aminotransferase (CTA) (Singh and Banerjee, 2011a), also fueling Cys-dependent H 2 S generation.…”

Section: Resultsmentioning

confidence: 99%

N-Acetyl Cysteine Functions as a Fast-Acting Antioxidant by Triggering Intracellular H2S and Sulfane Sulfur Production

Ezeriņa

Takano

Hanaoka

et al. 2018

Cell Chemical Biology

281

207

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The cysteine prodrug N-acetyl cysteine (NAC) is widely used as a pharmacological antioxidant and cytoprotectant. It has been reported to lower endogenous oxidant levels and to protect cells against a wide range of pro-oxidative insults. As NAC itself is a poor scavenger of oxidants, the molecular mechanisms behind the antioxidative effects of NAC have remained uncertain. Here we show that NAC-derived cysteine is desulfurated to generate hydrogen sulfide, which in turn is oxidized to sulfane sulfur species, predominantly within mitochondria. We provide evidence suggesting the possibility that sulfane sulfur species produced by 3-mercaptopyruvate sulfurtransferase and sulfide:quinone oxidoreductase are the actual mediators of the immediate antioxidative and cytoprotective effects provided by NAC.

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“…Moreover, MPST was confirmed to be evolutionarily related to TST via site‐directed mutagenesis of these amino acids, in which the catalytic ability of MPST was converted to that of TST and vice versa (Nagahara et al ., ; Nagahara and Nishino, ). In humans, two MPST isoforms, tRNA thiouridine modification proteins (TUMs) have been reported: one is associated with a 25‐amino acid mitochondrial‐targeting sequence at its N‐terminal region (isoform 1), and the other is 20 amino acids longer than isoform 1 at its N‐terminal region (isoform 2) (Frasdorf et al ., ).…”

Section: Molecular Characteristics Of Mpstmentioning

confidence: 97%

Multiple role of 3‐mercaptopyruvate sulfurtransferase: antioxidative function, H₂S and polysulfide production and possible SO_x production

Nagahara

2018

British J Pharmacology

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are on the enzyme surface. MPST is found in all tissues, particularly in the kidneys, although the localization of its activity differs in each tissue. In this review, four functions of MPST are reviewed: (i) antioxidative function: Cys 247 is redox-sensitive and serves as a redox-sensing switch. It is oxidized to cysteine sulfenate, which has a low redox potential, upon which the enzyme is inactivated. Then, reduced thioredoxin (Trx) with a reducing system (Trx reductase and NADPH) reduces the sulfenate to restore activity; meanwhile, Cys 154 and Cys 263 form an intermolecular disulfide bond, which serves as another redox-sensing switch. Consequently, Trx specifically cleaves the intermolecular disulfide bond by converting it from the inactive form (dimer) to the active form (monomer). (ii) Hydrogen sulfide and polysulfide production: hydrogen sulfide is produced via reduction of the persulfurated sulfur-acceptor substrate by reduced Trx or Trx with a reducing system; as an alternative process, stable polysulfurated or persulfurated Cys 247 as a reaction intermediate is reduced by Trx with a reducing system to release hydrogen sulfide and polysulfides. (iii) Possible sulfur oxide production: sulfur oxides (SO, SO 2 and SO 3 ) can be produced in the redox cycle of sulfane sulfur formed at the catalytic site Cys 247 (Cys-SO À , Cys-SO 2À and Cys-SO 3À ) as reaction intermediates and released by reduced Trx or Trx with a reducing system. (iv) Possible anxiolytic-like effects: MPST-knockout mice exhibited anxiolytic-like effects.Abbreviations MALDI-TOF-MS, matrix-assisted laser desorption/ionization time-of-flight MS; MPST, 3-mercaptopyruvate sulfurtransferase; NBD-Cl, 4-chloro-7-nitrobenzofurazan; Trx, thioredoxin; TST, thiosulfate sulfuransferase; TUM, tRNA thiouridine modification protein

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Characterization and Interaction Studies of Two Isoforms of the Dual Localized 3-Mercaptopyruvate Sulfurtransferase TUM1 from Humans

Cited by 66 publications

References 54 publications

Sulfur transfer and activation by ubiquitin-like modifier system Uba4•Urm1 link protein urmylation and tRNA thiolation in yeast

Sulfur transfer and activation by ubiquitin-like modifier system Uba4•Urm1 link protein urmylation and tRNA thiolation in yeast

N-Acetyl Cysteine Functions as a Fast-Acting Antioxidant by Triggering Intracellular H2S and Sulfane Sulfur Production

Multiple role of 3‐mercaptopyruvate sulfurtransferase: antioxidative function, H₂S and polysulfide production and possible SO_x production

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Characterization and Interaction Studies of Two Isoforms of the Dual Localized 3-Mercaptopyruvate Sulfurtransferase TUM1 from Humans

Cited by 66 publications

References 54 publications

Sulfur transfer and activation by ubiquitin-like modifier system Uba4•Urm1 link protein urmylation and tRNA thiolation in yeast

Sulfur transfer and activation by ubiquitin-like modifier system Uba4•Urm1 link protein urmylation and tRNA thiolation in yeast

N-Acetyl Cysteine Functions as a Fast-Acting Antioxidant by Triggering Intracellular H2S and Sulfane Sulfur Production

Multiple role of 3‐mercaptopyruvate sulfurtransferase: antioxidative function, H2S and polysulfide production and possible SOx production

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Multiple role of 3‐mercaptopyruvate sulfurtransferase: antioxidative function, H₂S and polysulfide production and possible SO_x production