Thiol Reactivity and Its Impact on the Ciliate Toxicity of α,β-Unsaturated Aldehydes, Ketones, and Esters

Böhme, Alexander; Thaens, Diana; Schramm, Franziska; Paschke, Albrecht; Schüürmann, Gerrit

doi:10.1021/tx100226n

Cited by 61 publications

(89 citation statements)

References 21 publications

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“…Therefore, we assume that spontaneous conjugation between MACR and GSH largely accounts for the formation of MACR-GSH in tomato leaves exposed to MACR vapor, and enzymatic formation via GST has little, if any, contribution. The second-order rate constant of MACR and GSH in phosphate buffer (pH 6.8) is as high as 203 L mol 21 min 21 (Böhme et al, 2010). This high reaction rate explains the quick formation of MACR-GSH adduct well, even without GST.…”

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confidence: 94%

Glutathionylation and reduction of methacrolein in tomato plants account for its absorption from the vapor phase

et al. 2015

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A large portion of the volatile organic compounds emitted by plants are oxygenated to yield reactive carbonyl species, which have a big impact on atmospheric chemistry. Deposition to vegetation driven by the absorption of reactive carbonyl species into plants plays a major role in cleansing the atmosphere, but the mechanisms supporting this absorption have been little examined.Here, we performed model experiments using methacrolein (MACR), one of the major reactive carbonyl species formed from isoprene, and tomato (Solanum lycopersicum) plants. Tomato shoots enclosed in a jar with MACR vapor efficiently absorbed MACR. The absorption efficiency was much higher than expected from the gas/liquid partition coefficient of MACR, indicating that MACR was likely metabolized in leaf tissues. Isobutyraldehyde, isobutyl alcohol, and methallyl alcohol (MAA) were detected in the headspace and inside tomato tissues treated with MACR vapor, suggesting that MACR was enzymatically reduced. Glutathione (GSH) conjugates of MACR (MACR-GSH) and MAA (MAA-GSH) were also detected. MACR-GSH was essentially formed through spontaneous conjugation between endogenous GSH and exogenous MACR, and reduction of MACR-GSH to MAA-GSH was likely catalyzed by an NADPH-dependent enzyme in tomato leaves. Glutathionylation was the metabolic pathway most responsible for the absorption of MACR, but when the amount of MACR exceeded the available GSH, MACR that accumulated reduced photosynthetic capacity. In an experiment simulating the natural environment using gas flow, MACR-GSH and MAA-GSH accumulation accounted for 30% to 40% of the MACR supplied. These results suggest that MACR metabolism, especially spontaneous glutathionylation, is an essential factor supporting MACR absorption from the atmosphere by tomato plants.

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confidence: 94%

Glutathionylation and reduction of methacrolein in tomato plants account for its absorption from the vapor phase

et al. 2015

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“…Analysis of the reactivity of ethyl vinyl ketone (EVK, 1-penten-3-one), which is well-known as a highly reactive electrophile, toward GSH was compared to that of biliatresone and DP in our conjugation assay. 5,9,10 The comparison of the EVK reactivity to those of DP and biliatresone provides an evaluation of our study compared to the previous kinetic assays of GSH reactivity. 9,10 This design provides valuable indirect evidence for the interaction between the plant toxin and various endogenous biological substances.…”

Section: Introductionmentioning

confidence: 99%

“…5,9,10 The comparison of the EVK reactivity to those of DP and biliatresone provides an evaluation of our study compared to the previous kinetic assays of GSH reactivity. 9,10 This design provides valuable indirect evidence for the interaction between the plant toxin and various endogenous biological substances. Through the study of the chemical reactivity of biliatresone with GSH, various amino acids (cysteine, glycine, glutamate, histidine, phenylalanine, and serine), a DNA base (adenine), derivatives of cysteine (D-NAC and L-NAC), and a imidazole moiety (histamine), we can infer toxic mechanisms or likely targets leading to the biliary toxicity that we have observed in vivo (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Reactivity of Biliatresone, a Natural Biliary Toxin, with Glutathione, Histamine, and Amino Acids

Koo

Waisbourd‐Zinman

Wells³

et al. 2016

Chem. Res. Toxicol.

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In our previous work, we identified a natural toxin, biliatresone, from Dysphania glomulifera and D. littoralis, endemic plants associated with outbreaks of biliary atresia in Australian neonatal livestock. Biliatresone is a very rare isoflavonoid with an α-methylene ketone between two phenyls, 1,2-diaryl-2-propenone, along with methylenedioxy, dimethoxyl, and hydroxyl functional groups, that causes extrahepatic biliary toxicity in zebrafish. The toxic core of biliatresone is a methylene in the α-position relative to the ketone of 1,2-diaryl-2-propenone that serves as an electrophilic Michael acceptor. The α-methylene of biliatresone spontaneously conjugated with water and methanol (MeOH), respectively, via Michael addition in a reverse phase high-performance liquid chromatography (RP-HPLC) analysis. We here report the reactivity of biliatresone toward glutathione (GSH), several amino acids, and other thiol- or imidazole-containing biomolecules. LC-MS and HPLC analysis of the conjugation reaction showed the reactivity of biliatresone to be in the order histidine > N-acetyl-d-cysteine (D-NAC) = N-acetyl-l-cysteine (L-NAC) > histamine > glutathione ≥ cysteine ≫ glycine > glutamate > phenylalanine, while serine and adenine had no reactivity due to intramolecular hydrogen bonding in the protic solvents. The reactivity of ethyl vinyl ketone (EVK, 1-penten-3-one), an example of a highly reactive α,ß-unsaturated ketone, toward GSH gave a 6.7-fold lower reaction rate constant than that of biliatresone. The reaction rate constant of synthetic 1,2-diaryl-2-propen-1-one (DP), a core structure of the toxic molecule, was 10-fold and 1.5-fold weaker in potency compared to the reaction rate constants of biliatresone and EVK, respectively. These results demostrated that the methylenedioxy, dimethoxyl, and hydroxyl functional groups of biliatresone contribute to the stronger reactivity of the Michael acceptor α-methylene ketone toward nucleophiles compared to that of DP and EVK.

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“…However, acetylenic ketones, aldehydes and alkyl propiolates and can be rather difficult to functionalize. 15 Most importantly, these substrates, particularly in the terminal alkyne form required for CuAAC, are too reactive as Michael acceptors 16 to be bioorthogonal. We regarded propiolamides as having a good combination of synthetic accessibility, electronic activation of the CuAAC process, and attenuated Michael reactivity.…”

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confidence: 99%

Relative Performance of Alkynes in Copper-Catalyzed Azide–Alkyne Cycloaddition

et al. 2013

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Copper-catalyzed azide–alkyne cycloaddition (CuAAC) has found numerous applications in a variety of fields. We report here only modest differences in the reactivity of various classes of terminal alkynes under typical bioconjugative and preparative organic conditions. Propargyl compounds represent an excellent combination of azide reactivity, ease of installation, and cost. Electronically activated propiolamides are slightly more reactive, at the expense of increased propensity for Michael addition. Certain alkynes, including tertiary propargyl carbamates, are not suitable for bioconjugation due to copper-induced fragmentation. A fluorogenic probe based on such reactivity is available in one step from rhodamine 110 and can be useful for optimization of CuAAC conditions.

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Thiol Reactivity and Its Impact on the Ciliate Toxicity of α,β-Unsaturated Aldehydes, Ketones, and Esters

Cited by 61 publications

References 21 publications

Glutathionylation and reduction of methacrolein in tomato plants account for its absorption from the vapor phase

Glutathionylation and reduction of methacrolein in tomato plants account for its absorption from the vapor phase

Reactivity of Biliatresone, a Natural Biliary Toxin, with Glutathione, Histamine, and Amino Acids

Relative Performance of Alkynes in Copper-Catalyzed Azide–Alkyne Cycloaddition

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