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Cited by 267Selenium in Biological SystemsOrganoselenium and organotellurium chemistryRedox biology and oxidative stress

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Role of Selenoproteins in Redox Regulation of Signaling and the Antioxidant System: A Review

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Zhang, Ying, Roh, Yeon Jin, Han, Seong-Jeong, Park, Iha, Lee, Hae Min, Ok, Yong Sik, Lee, Byung Cheon, Lee, Seung-Rock·2020·Antioxidants
DOI 10.3390/antiox9050383PMC PMC7278666
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Abstract

Selenium is a vital trace element present as selenocysteine (Sec) in proteins that are, thus, known as selenoproteins. Humans have 25 selenoproteins, most of which are functionally characterized as oxidoreductases, where the Sec residue plays a catalytic role in redox regulation and antioxidant activity. Glutathione peroxidase plays a pivotal role in scavenging and inactivating hydrogen and lipid peroxides, whereas thioredoxin reductase reduces oxidized thioredoxins as well as non-disulfide substrates, such as lipid hydroperoxides and hydrogen peroxide. Selenoprotein R protects the cell against oxidative damage by reducing methionine-R-sulfoxide back to methionine. Selenoprotein O regulates redox homeostasis with catalytic activity of protein AMPylation. Moreover, endoplasmic reticulum (ER) membrane selenoproteins (SelI, K, N, S, and Sel15) are involved in ER membrane stress regulation. Selenoproteins containing the CXXU motif (SelH, M, T, V, and W) are putative oxidoreductases that participate in various cellular processes depending on redox regulation. Herein, we review the recent studies on the role of selenoproteins in redox regulation and their physiological functions in humans, as well as their role in various diseases.

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Figures

Figure 1 Catalytic redox cycle of glutathione peroxidase. GR, glutathione reductase; GSH, glutathione (reduced form); GSSG, glutathione disulfide; GPx-SeOH, selenenic acid; GPx-SeSG, selenenyl sulfide; GPx-SeO2H, seleninic acid; ROOH, hydroperoxides (H2O2, peroxynitrite or aliphatic hydroperoxide); ROH, H2O or corresponding alcohol; NADPH, Nicotinamide adenine dinucleotide phosphate.
Figure 1 Catalytic redox cycle of glutathione peroxidase. GR, glutathione reductase; GSH, glutathione (reduced form); GSSG, glutathione disulfide; GPx-SeOH, selenenic acid; GPx-SeSG, selenenyl sulfide; GPx-SeO2H, seleninic acid; ROOH, hydroperoxides (H2O2, peroxynitrite or aliphatic hydroperoxide); ROH, H2O or corresponding alcohol; NADPH, Nicotinamide adenine dinucleotide phosphate.CC BY · PubMed Central
Figure 2 Catalytic redox cycle of the thioredoxin (Trx)/thioredoxin reductase (TrxR)/nicotinamide adenine dinucleotide phosphate (NADPH) system. FAD, flavin adenine dinucleotide.
Figure 2 Catalytic redox cycle of the thioredoxin (Trx)/thioredoxin reductase (TrxR)/nicotinamide adenine dinucleotide phosphate (NADPH) system. FAD, flavin adenine dinucleotide.CC BY · PubMed Central
Figure 3 Thioredoxin reductase (TrxR) as a novel target for cancer therapy. Gold compounds, nitrosoureas, arsenic trioxide, dinitrohalobenzenes, curcumin, flavonoids, quinones, and other cancer chemotherapeutics have been shown to be TrxR inhibitors. TrxR inhibition blocks thioredoxin (Trx)-mediated activity in various processes, such as defense against oxidative stress, DNA replication and repair, apoptosis inhibition, transcription control, and protein folding via different signaling pathways. Some inhibitors, such as 1-chloro-2,4-dinitrobenzene (DNCB) and curcumin, modify TrxR via the alkylation of Cys496 and redox-active Sec497 residues and induce nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, finally leading to reactive oxygen species (ROS) production.
Figure 3 Thioredoxin reductase (TrxR) as a novel target for cancer therapy. Gold compounds, nitrosoureas, arsenic trioxide, dinitrohalobenzenes, curcumin, flavonoids, quinones, and other cancer chemotherapeutics have been shown to be TrxR inhibitors. TrxR inhibition blocks thioredoxin (Trx)-mediated activity in various processes, such as defense against oxidative stress, DNA replication and repair, apoptosis inhibition, transcription control, and protein folding via different signaling pathways. Some inhibitors, such as 1-chloro-2,4-dinitrobenzene (DNCB) and curcumin, modify TrxR via the alkylation of Cys496 and redox-active Sec497 residues and induce nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, finally leading to reactive oxygen species (ROS) production.CC BY · PubMed Central
Figure 4 (A) Catalytic mechanism of SelR reducing methionine-R-sulfoxide (Met-R-SO). The catalytic selenocysteine (Sec) residue attacks Met-R-SO and forms the intermediate selenenic acid with Met release. The resolving cysteine (Cys) residue attacks the intermediate, resulting in the formation of intramolecular selenide–sulfide bond. The intramolecular selenide–sulfide bond of SelR is directly reduced by thioredoxin (Trx) system. (B) Role of SelR in various organs and cell types.
Figure 4 (A) Catalytic mechanism of SelR reducing methionine-R-sulfoxide (Met-R-SO). The catalytic selenocysteine (Sec) residue attacks Met-R-SO and forms the intermediate selenenic acid with Met release. The resolving cysteine (Cys) residue attacks the intermediate, resulting in the formation of intramolecular selenide–sulfide bond. The intramolecular selenide–sulfide bond of SelR is directly reduced by thioredoxin (Trx) system. (B) Role of SelR in various organs and cell types.CC BY · PubMed Central
Figure 5 Selenoprotein O (SelO) mediates protein AMPylation and protects the cell from oxidative stress.
Figure 5 Selenoprotein O (SelO) mediates protein AMPylation and protects the cell from oxidative stress.CC BY · PubMed Central

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Metadata

Authors
Zhang, Y., Roh, Y. J., Han, S.-J., Park, I., Lee, H. M., Ok, Y. S., Lee, B. C., & Lee, S.-R.
Affiliations
  • Chonnam National University (KR)
  • Korea University (KR)
  • COTDE Inc. 19-3, Ugakgol-gil, Susin-myeon, Cheonan-si, Chungcheongnam-do 330-882, Korea
Corresponding author
  • Lee, Byung Cheon
  • Lee, Seung-Rock
ORCID
Venue
Antioxidants
Publisher
MDPI AG
Published
2020-05-05
Volume
9
Issue
5
Pages
383
ISSN
2076-3921 (ISSN-L)
DOI
10.3390/antiox9050383
PMC
PMC7278666
OpenAlex
W3022351363
Cited by
267
References
162
Citations by year
2026: 52 · 2025: 55 · 2024: 51 · 2023: 40 · 2022: 43 · 2021: 16 · 2020: 9
FWCI
3.31
Type
journal article
Language
en
Open access
Licence
Locations
  • Antioxidants (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Research Foundation of Korea (2018R1D1A1B06051438, 2018M3A9F3055925, 2018R1A1A1A05079386)
Topics
  • Health Sciences › Nursing › Nutrition and Dietetics › Selenium in Biological Systems
  • Physical Sciences › Chemistry › Organic Chemistry › Organoselenium and organotellurium chemistry
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
Keywords
selenoproteins, selenocysteine, redox regulation, antioxidant defense, glutathione peroxidase, thioredoxin reductase, oxidative enzymes, redox homeostasis, oxidative stress

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