Reactive Sulfur Species-Mediated Activation of the Keap1-Nrf2 Pathway by 1,2-Naphthoquinone through Sulfenic Acids Formation under Oxidative Stress

Yasuhiro Shinkai, Yumi Abiko, Tomoaki Ida, Takashi Miura, Hidenao Kakehashi, Isao Ishii, Motohiro Nishida, Tomohiro Sawa, Takaaki Akaike, Yoshito Kumagai

Research output: Contribution to journalArticle

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Abstract

Sulfhydration by a hydrogen sulfide anion and electrophile thiolation by reactive sulfur species (RSS) such as persulfides/polysulfides (e.g., R-S-SH/R-S-S<inf>n</inf>-H(R)) are unique reactions in electrophilic signaling. Using 1,2-dihydroxynaphthalene-4-thioacetate (1,2-NQH<inf>2</inf>-SAc) as a precursor to 1,2-dihydroxynaphthalene-4-thiol (1,2-NQH<inf>2</inf>-SH) and a generator of reactive oxygen species (ROS), we demonstrate that protein thiols can be modified by a reactive sulfenic acid to form disulfide adducts that undergo rapid cleavage in the presence of glutathione (GSH). As expected, 1,2-NQH<inf>2</inf>-SAc is rapidly hydrolyzed and partially oxidized to yield 1,2-NQ-SH, resulting in a redox cycling reaction that produces ROS through a chemical disproportionation reaction. The sulfenic acid forms of 1,2-NQ-SH and 1,2-NQH<inf>2</inf>-SH were detected by derivatization experiments with dimedone. 1,2-NQH<inf>2</inf>-SOH modified Keap1 at Cys171 to produce a Keap1-S-S-1,2-NQH<inf>2</inf> adduct. Subsequent exposure of A431 cells to 1,2-NQ or 1,2-NQH<inf>2</inf>-SAc caused an extensive chemical modification of cellular proteins in both cases. Protein adduction by 1,2-NQ through a thio ether (C-S-C) bond slowly declined through a GSH-dependent S-transarylation reaction, whereas that originating from 1,2-NQH<inf>2</inf>-SAc through a disulfide (C-S-S-C) bond was rapidly restored to the free protein thiol in the cells. Under these conditions, 1,2-NQH<inf>2</inf>-SAc activated Nrf2 and upregulated its target genes, which were enhanced by pretreatment with buthionine sulfoximine (BSO), to deplete cellular GSH. Pretreatment of catalase conjugated with poly(ethylene glycol) suppressed Nrf2 activation by 1,2-NQH<inf>2</inf>-SAc. These results suggest that RSS-mediated reversible electrophilic signaling takes place through sulfenic acids formation under oxidative stress.

Original languageEnglish
Pages (from-to)838-847
Number of pages10
JournalChemical Research in Toxicology
Volume28
Issue number5
DOIs
Publication statusPublished - 2015 May 18

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Sulfenic Acids
Oxidative stress
Sulfur
Oxidative Stress
Chemical activation
Sulfhydryl Compounds
Disulfides
Reactive Oxygen Species
Proteins
Buthionine Sulfoximine
Hydrogen Sulfide
Ethylene Glycol
Chemical modification
Ether
Catalase
Polyethylene glycols
Oxidation-Reduction
Anions
Glutathione
Chemical reactions

ASJC Scopus subject areas

  • Toxicology

Cite this

Reactive Sulfur Species-Mediated Activation of the Keap1-Nrf2 Pathway by 1,2-Naphthoquinone through Sulfenic Acids Formation under Oxidative Stress. / Shinkai, Yasuhiro; Abiko, Yumi; Ida, Tomoaki; Miura, Takashi; Kakehashi, Hidenao; Ishii, Isao; Nishida, Motohiro; Sawa, Tomohiro; Akaike, Takaaki; Kumagai, Yoshito.

In: Chemical Research in Toxicology, Vol. 28, No. 5, 18.05.2015, p. 838-847.

Research output: Contribution to journalArticle

Shinkai, Y, Abiko, Y, Ida, T, Miura, T, Kakehashi, H, Ishii, I, Nishida, M, Sawa, T, Akaike, T & Kumagai, Y 2015, 'Reactive Sulfur Species-Mediated Activation of the Keap1-Nrf2 Pathway by 1,2-Naphthoquinone through Sulfenic Acids Formation under Oxidative Stress', Chemical Research in Toxicology, vol. 28, no. 5, pp. 838-847. https://doi.org/10.1021/tx500416y
Shinkai, Yasuhiro ; Abiko, Yumi ; Ida, Tomoaki ; Miura, Takashi ; Kakehashi, Hidenao ; Ishii, Isao ; Nishida, Motohiro ; Sawa, Tomohiro ; Akaike, Takaaki ; Kumagai, Yoshito. / Reactive Sulfur Species-Mediated Activation of the Keap1-Nrf2 Pathway by 1,2-Naphthoquinone through Sulfenic Acids Formation under Oxidative Stress. In: Chemical Research in Toxicology. 2015 ; Vol. 28, No. 5. pp. 838-847.
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AU - Abiko, Yumi

AU - Ida, Tomoaki

AU - Miura, Takashi

AU - Kakehashi, Hidenao

AU - Ishii, Isao

AU - Nishida, Motohiro

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AU - Akaike, Takaaki

AU - Kumagai, Yoshito

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N2 - Sulfhydration by a hydrogen sulfide anion and electrophile thiolation by reactive sulfur species (RSS) such as persulfides/polysulfides (e.g., R-S-SH/R-S-Sn-H(R)) are unique reactions in electrophilic signaling. Using 1,2-dihydroxynaphthalene-4-thioacetate (1,2-NQH2-SAc) as a precursor to 1,2-dihydroxynaphthalene-4-thiol (1,2-NQH2-SH) and a generator of reactive oxygen species (ROS), we demonstrate that protein thiols can be modified by a reactive sulfenic acid to form disulfide adducts that undergo rapid cleavage in the presence of glutathione (GSH). As expected, 1,2-NQH2-SAc is rapidly hydrolyzed and partially oxidized to yield 1,2-NQ-SH, resulting in a redox cycling reaction that produces ROS through a chemical disproportionation reaction. The sulfenic acid forms of 1,2-NQ-SH and 1,2-NQH2-SH were detected by derivatization experiments with dimedone. 1,2-NQH2-SOH modified Keap1 at Cys171 to produce a Keap1-S-S-1,2-NQH2 adduct. Subsequent exposure of A431 cells to 1,2-NQ or 1,2-NQH2-SAc caused an extensive chemical modification of cellular proteins in both cases. Protein adduction by 1,2-NQ through a thio ether (C-S-C) bond slowly declined through a GSH-dependent S-transarylation reaction, whereas that originating from 1,2-NQH2-SAc through a disulfide (C-S-S-C) bond was rapidly restored to the free protein thiol in the cells. Under these conditions, 1,2-NQH2-SAc activated Nrf2 and upregulated its target genes, which were enhanced by pretreatment with buthionine sulfoximine (BSO), to deplete cellular GSH. Pretreatment of catalase conjugated with poly(ethylene glycol) suppressed Nrf2 activation by 1,2-NQH2-SAc. These results suggest that RSS-mediated reversible electrophilic signaling takes place through sulfenic acids formation under oxidative stress.

AB - Sulfhydration by a hydrogen sulfide anion and electrophile thiolation by reactive sulfur species (RSS) such as persulfides/polysulfides (e.g., R-S-SH/R-S-Sn-H(R)) are unique reactions in electrophilic signaling. Using 1,2-dihydroxynaphthalene-4-thioacetate (1,2-NQH2-SAc) as a precursor to 1,2-dihydroxynaphthalene-4-thiol (1,2-NQH2-SH) and a generator of reactive oxygen species (ROS), we demonstrate that protein thiols can be modified by a reactive sulfenic acid to form disulfide adducts that undergo rapid cleavage in the presence of glutathione (GSH). As expected, 1,2-NQH2-SAc is rapidly hydrolyzed and partially oxidized to yield 1,2-NQ-SH, resulting in a redox cycling reaction that produces ROS through a chemical disproportionation reaction. The sulfenic acid forms of 1,2-NQ-SH and 1,2-NQH2-SH were detected by derivatization experiments with dimedone. 1,2-NQH2-SOH modified Keap1 at Cys171 to produce a Keap1-S-S-1,2-NQH2 adduct. Subsequent exposure of A431 cells to 1,2-NQ or 1,2-NQH2-SAc caused an extensive chemical modification of cellular proteins in both cases. Protein adduction by 1,2-NQ through a thio ether (C-S-C) bond slowly declined through a GSH-dependent S-transarylation reaction, whereas that originating from 1,2-NQH2-SAc through a disulfide (C-S-S-C) bond was rapidly restored to the free protein thiol in the cells. Under these conditions, 1,2-NQH2-SAc activated Nrf2 and upregulated its target genes, which were enhanced by pretreatment with buthionine sulfoximine (BSO), to deplete cellular GSH. Pretreatment of catalase conjugated with poly(ethylene glycol) suppressed Nrf2 activation by 1,2-NQH2-SAc. These results suggest that RSS-mediated reversible electrophilic signaling takes place through sulfenic acids formation under oxidative stress.

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