- Comparative inhibition of yeast glutathione reductase by arsenicals and arsenothiols
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Tri(γ-glutamylcysteinylglycinyl)trithioarsenite (As(III)(GS)3) is formed in cells and is a more potent mixed-type inhibitor of the reduction of glutathione disulfide (GSSG) by yeast glutathione (GSH) reductase than either arsenite (As(III)) or GSH. The present work examines the effects of valence and complexation of arsenicals with GSH or L-cysteine (Cys) upon potency as competitive inhibitors of the reduction of GSH disulfide (GSSG) by yeast GSH reductase. Trivalent arsenicals were more potent inhibitors than their pentavalent analogs, and methylated trivalent arsenicals were more potent inhibitors than was inorganic trivalent As. Complexation of either inorganic trivalent As or methylarsonous diiodide (CH3As(III)I2) with Cys or GSH produced inhibitors of GSH reductase that were severalfold more potent than the parent arsenicals. In contrast, dimethylarsinous iodide ((CH3)2As(III)I) was a more potent inhibitor than its complexes with either GSH or Cys. Complexes of CH3As(III) with GSH (CH3-As(III)(GS)2) or with Cys (CH3As(III)(Cys)2) were the most potent inhibitors, with K(i)'s of 0.009 and 0.018 mM, respectively. Inhibition of GSH reductase by arsenicals or arsenothiols was prevented by addition of meso-2,3-dimercaptosuccinic acid (DMSA) to a mixture of enzyme, GSSG, and inhibitor before addition of NADPH. DMSA added to the reaction mixture after NADPH reversed inhibition by (CH3)2As(III)I but had little effect on inhibition by CH3As(III)I2, CH3As(III)(GS)2, CH3As(III)(Cys)2, or As(III)(GS)3. Partial redox inactivation of the enzyme with NADPH increased the inhibitory potency of CH3As(III)I2 and (CH3)2As(III)I and changed the mode of inhibition for CH3As(III)I2 from competitive to noncompetitive. The greater potency of methylated trivalent arsenicals and arsenothiols than of inorganic trivalent As suggests that biomethylation of As could yield species that inhibit reduction of GSSG and alter the redox status of cells.
- Styblo, Miroslav,Serves, Spiros V.,Cullen, William R.,Thomas, David J.
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- Characterization and Mechanistic Study of the Radical SAM Enzyme ArsS Involved in Arsenosugar Biosynthesis
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Arsenosugars are a group of arsenic-containing ribosides that are found predominantly in marine algae but also in terrestrial organisms. It has been proposed that arsenosugar biosynthesis involves a key intermediate 5′-deoxy-5′-dimethylarsinoyl-adenosine (DDMAA), but how DDMAA is produced remains elusive. Now, we report characterization of ArsS as a DDMAA synthase, which catalyzes a radical S-adenosylmethionine (SAM)-mediated alkylation (adenosylation) of dimethylarsenite (DMAsIII) to produce DDMAA. This radical-mediated reaction is redox neutral, and multiple turnover can be achieved without external reductant. Phylogenomic and biochemical analyses revealed that DDMAA synthases are widespread in distinct bacterial phyla with similar catalytic efficiencies; these enzymes likely originated from cyanobacteria. This study reveals a key step in arsenosugar biosynthesis and also a new paradigm in radical SAM chemistry, highlighting the catalytic diversity of this superfamily of enzymes.
- Cheng, Jinduo,Ji, Wenjuan,Ma, Suze,Ji, Xinjian,Deng, Zixin,Ding, Wei,Zhang, Qi
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supporting information
p. 7570 - 7575
(2021/03/01)
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- Facile access to arsenic-containing triacylglycerides
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The previously unknown arsenic-containing triacylglycerides (AsTAGs) 3-((15-(dimethylarsinoyl)pentadecanoyl)oxy)propane-1,2-diyl dipalmitate 1 and 2-((15-(dimethylarsinoyl)pentadecanoyl)oxy)propane-1,3-diyl dipalmitate 2 have been synthesized. They will serve as model compounds in the search for naturally occurring AsTAGs, recently proposed natural constituents of fish oils.
- Guttenberger, Nikolaus,Sagmeister, Peter,Glabonjat, Ronald A.,Hirner, Stefan,Francesconi, Kevin A.
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supporting information
p. 362 - 364
(2017/01/03)
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- The Reaction of Bunsen's Cacodyl Disulfide, Me2As(S)-S-AsMe2, with Iodine: Preparation and Properties of Dimethylarsinosulfenyl Iodide, Me2As-S-I
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Bunsen's cacodyl disulfide, Me2As(S)-S-AsMe2 (1), reacted with iodine giving the novel dimethylarsinosulfenyl iodide, Me2As-S-I (3) although theoretical calculations indicated that the AsV compound Me2As(S)-I (4) was more stable in the gas phase. The oily product was stable neat and as a solution in CDCl3 at +4 °C and -20 °C for at least 15 d. Light, H2O, H2O2, and Zn dust, but not NaI or Ag, decomposed it. Compound 3 did not interact with Ph3N, with Ph2NH and PhNH2 it interacted but not reacted. 3 was decomposed by piperidine, with pyridine and 4-dimethylaminopyridine it interacted and produced Me2As-SS-AsMe2 (2) and I2 that formed charge transfer complexes Base·I2, whereas Et3N decomposed 3, and 3Et3N·2I2 was isolated. 3 was desulfurized by Ph3P and (Me2N)3P completely, and by (PhO)3P and (PhS)3P partially. The reactions of 3 with (Me2N)3P, (PhS)3P, and (EtO)3P were complicated. From the AsIII nucleophiles, only Ph3As was bound, while (PhS)3As reacted slowly in a complicated manner with 3. No interaction of 3 with MeOH or PhOH was observed but NaOH, Ag2O, and PhONa decomposed it. Thiophenol produced traces of Me2As-SPh (10) and sodium thiophenolate attacked mainly at AsIII of 3. Thus, externally stabilized sulfenium ions of the type Me2As-S-Nu+I- were not obtained.
- Ioannou, Panayiotis V.,Vachliotis, Dimitris G.,Chrissanthopoulos, Athanassios
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p. 1340 - 1346
(2015/06/30)
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- Synthesis of trimethylated phosphonium and arsonium analogues of the osmoprotectant glycine betaine; contrasted biological activities in two bacterial species
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Phosphoniobetaine and arsenobetaine, the P and As analogues of glycine betaine (trimethylammonioacetate) were synthesized and assayed for activity in bacterial osmoprotection biotests, using Escherichia coli and Rhizobium meliloti as model organisms. The P- and As-betaines displayed similar osmoprotective activities in E. coli, but were highly toxic in the betaine- demethylating bacterium R. meliloti.
- Pichereau, Vianney,Cosquer, Anne,Gaumont, Annie-Claude,Bernard, Theophile
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p. 2893 - 2896
(2007/10/03)
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