An uncommon redox behavior sheds light on the cellular antioxidant properties of ergothioneine

Servillo, Luigi; Castaldo, Domenico; Casale, Rosario; D’Onofrio, Nunzia; Giovane, Alfonso; Cautela, Domenico; Balestrieri, Maria Luisa

doi:10.1016/j.freeradbiomed.2014.11.017

Cited by 71 publications

(82 citation statements)

References 33 publications

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“…It is logical to think that s 2 c 5 Ura is oxidized by the same pathway. This agrees with the proposed mechanism of the oxidation of ergothioneine, a thiourea-containing compound related to thiouracil [37], although the direct oxidation pathway (red) could not be ruled out for ergothioneine and it cannot be ruled out here either. Oxidation of the parent compound to the sulfenic/selenenic acid is the first step in all three pathways shown in Figure 13.…”

Section: Discussionsupporting

confidence: 86%

“…Sulfenic and selenenic acids are unstable species [38, 39] and are susceptible to disproportionation [40–43], which is a third route by which the sulfinic/seleninic acid can form. We note that we are proposing that s 2 c 5 Ura is desulfurized when it is converted to the sulfonic acid, which is different from the desulfurization mechanism proposed for ergothioneine [37]. …”

Section: Discussionmentioning

confidence: 96%

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Comparison of the redox chemistry of sulfur- and selenium-containing analogs of uracil

Payne¹,

Geissler²,

Button³

et al. 2017

Free Radical Biology and Medicine

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Selenium is present in proteins in the form of selenocysteine, where this amino acid serves catalytic oxidoreductase functions. The use of selenocysteine in nature is strongly associated with redox catalysis. However, selenium is also found in a 2-selenouridine moiety at the wobble position of tRNAGlu, tRNAGln and tRNALys. It is thought that the modifications of the wobble position of the tRNA improves the selectivity of the codon-anticodon pair as a result of the physico-chemical changes that result from substitution of sulfur and selenium for oxygen. Both selenocysteine and 2-selenouridine have widespread analogs, cysteine and thiouridine, where sulfur is used instead. To examine the role of selenium in 2-selenouridine, we comparatively analyzed the oxidation reactions of sulfur-containing 2-thiouracil-5-carboxylic acid (s2c5Ura) and its selenium analog 2-selenouracil-5-carboxylic acid (se2c5Ura) using 1H-NMR spectroscopy, 77Se-NMR spectroscopy, and liquid chromatography-mass spectrometry. Treatment of s2c5Ura with hydrogen peroxide led to oxidized intermediates, followed by irreversible desulfurization to form uracil-5-carboxylic acid (c5Ura). In contrast, se2c5Ura oxidation resulted in a diselenide intermediate, followed by conversion to the seleninic acid, both of which could be readily reduced by ascorbate and glutathione. Glutathione and ascorbate only minimally prevented desulfurization of s2c5Ura, whereas very little deselenization of se2c5Ura occurred in the presence of the same antioxidants. In addition, se2c5Ura but not s2c5Ura showed glutathione peroxidase activity, further suggesting that oxidation of se2c5Ura is readily reversible, while oxidation of s2c5Ura is not. The results of the study of these model nucleobases suggest that the use of 2-selenouridine is related to resistance to oxidative inactivation that otherwise characterizes 2-thiouridine. As the use of selenocysteine in proteins also confers resistance to oxidation, our findings suggest a common mechanism for the use of selenium in biology.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 96%

Comparison of the redox chemistry of sulfur- and selenium-containing analogs of uracil

Payne¹,

Geissler²,

Button³

et al. 2017

Free Radical Biology and Medicine

View full text Add to dashboard Cite

show abstract

“…Recently, Servillio et al [27] reported that oxidation of ESH with hypochlorite, peroxynitrite and hydrogen peroxide resulted in the sulfonated form (ESO 3 H), and hercynine, the desulfurated form of ESH indicating that this thiol, like cysteine and MSH, is oxidized irreversibly during oxidative stress. Moreover, Sao-Emani et al (2013) reported that a double mutant lacking both ESH and MSH is significantly more sensitive to the peroxides than either of the single mutants lacking either ESH or MSH.…”

Section: Discussionmentioning

confidence: 99%

Lack of mycothiol and ergothioneine induces different protective mechanisms in Mycobacterium smegmatis

Singh

Strankman

Orkusyan

et al. 2016

Biochemistry and Biophysics Reports

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Mycobacterium smegmatis contains the low molecular weight thiols, mycothiol (MSH) and ergothioneine (ESH). Examination of transposon mutants disrupted in mshC and egtA, involved in the biosynthesis of MSH and ESH respectively, demonstrated that both mutants were sensitive to oxidative, alkylating, and metal stress. However, the mshC mutant exhibited significantly more protein carbonylation and lipid peroxidation than wildtype, while the egtA mutant had less protein and lipid damage than wildtype. We further show that Ohr, KatN, and AhpC, involved in protection against oxidative stress, are upregulated in the egtA mutant. In the mshC mutant, an Usp and a putative thiol peroxidase are upregulated. In addition, mutants lacking MSH also contained higher levels of Coenzyme F420 as compared to wildtype and two Coenzyme F420 dependent enzymes were found to be upregulated. These results indicate that lack of MSH and ESH result in induction of different mechanisms for protecting against oxidative stress.

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“…In this regard, among the natural dietary compounds able to modulate SIRT1 and SIRT6, ergothioneine, the 2-mercapto-l-histidine betaine, has been shown to prevent the high-glucose-induced endothelial senescence through modulation of SIRT1/p66 shc and SIRT6/NF-jB pathways (41,156,157).…”

Section: Sirt1 and Sirt6 Pharmacological Modulators In The Preclinicamentioning

confidence: 99%

SIRT1 and SIRT6 Signaling Pathways in Cardiovascular Disease Protection

D’Onofrio¹,

Servillo²,

Balestrieri³

2018

Antioxidants & Redox Signaling

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296

238

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Significance: Oxidative stress represents the common hallmark of pathological conditions associated with cardiovascular disease (CVD), including atherosclerosis, heart failure, hypertension, aging, diabetes, and other vascular system-related diseases. The sirtuin (SIRT) family, comprising seven proteins (SIRT1-SIRT7) sharing a highly conserved nicotinamide adenine dinucleotide (NAD + )-binding catalytic domain, attracted a great attention for the past few years as stress adaptor and epigenetic enzymes involved in the cellular events controlling aging-related disorder, cancer, and CVD. Recent Advances: Among sirtuins, SIRT1 and SIRT6 are the best characterized for their protective roles against inflammation, vascular aging, heart disease, and atherosclerotic plaque development. This latest role has been only recently unveiled for SIRT6. Of interest, in recent years, complex signaling networks controlled by SIRT1 and SIRT6 common to stress resistance, vascular aging, and CVD have emerged. Critical Issues: We provide a comprehensive overview of recent developments on the molecular signaling pathways controlled by SIRT1 and SIRT6, two post-translational modifiers proven to be valuable tools to dampen inflammation and oxidative stress at the cardiovascular level. Future Directions: A deeper understanding of the epigenetic mechanisms through which SIRT1 and SIRT6 act in the signalings responsible for onset and development CVD is a prime scientific endeavor of the upcoming years. Multiple ''omic'' technologies will have widespread implications in understanding such mechanisms, speeding up the achievement of selective and efficient pharmacological modulation of sirtuins for future applications in the prevention and treatment of CVD. Antioxid. Redox Signal. 28, 711-732.

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An uncommon redox behavior sheds light on the cellular antioxidant properties of ergothioneine

Cited by 71 publications

References 33 publications

Comparison of the redox chemistry of sulfur- and selenium-containing analogs of uracil

Comparison of the redox chemistry of sulfur- and selenium-containing analogs of uracil

Lack of mycothiol and ergothioneine induces different protective mechanisms in Mycobacterium smegmatis

SIRT1 and SIRT6 Signaling Pathways in Cardiovascular Disease Protection

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