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Structure, Function and Biosynthesis of Mammalian Selenoproteins

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A special issue of Antioxidants (ISSN 2076-3921). This special issue belongs to the section "ROS, RNS and RSS".

Deadline for manuscript submissions: closed (20 November 2022) | Viewed by 27098

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Dr. Jianqiang Xu

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School of Chemical Enginnering, Ocean Technology and Life Science (CEOTLS), Dalian University of Technology, Panjin 124221, China
Interests: thioredoxin reductase; selenoprotein; inflammation; tumor drug resistance; small molecule inhibitor; ferroptosis; oxidative stress; disulfide stress
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Prof. Dr. Jun Lu

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Guest Editor

College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China
Interests: thioredoxin; selenium; thiol; drug target; inflammation; nonalcoholic fatty liver disease; inflammatory bowel disease; cancer; antibacterial agent
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Dear Colleagues,

As is well known, selenoproteins play important roles in mammalian health and diseases, and some selenoproteins have become targets in drug design and development. In humans, twenty-five selenoproteins have been identified, including thioredoxin reductase (TXNRD1, TXNRD2, and TXNRD3), glutathione peroxidase (GPX1, GPX2, GPX3, GPX4, and GPX6), iodothyronine deiodinase (DIO1, DIO2, and DIO3), MSR1, SEPHS2, and other selenoproteins (selenoprotein F, H, I, K, M, N, O, P, S, T, V, W). Many studies have shown that selenoproteins participate in various cellular processes, such as antioxidation, proliferation, and signaling transduction, and consequently play critical roles in human diseases, including cancer, diabetes, cardiovascular diseases, neurodegenerative diseases, and so on.

However, the catalytic mechanisms of many selenoenzymes are obscure, while the specific functions of many selenoproteins are still unknown. Additionally, the structures of many selenoproteins have not been defined up to date, which dramatically limits the development and application of drugs targeting selenoproteins. What is more, selenocysteine is encoded by an in-frame opal codon (UGA) and requires many cis and trans factors in cells, making the biosynthesis of selenoprotein difficult. For this reason, it is essential to investigate the mechanism of selenocysteine insertion machinery and develop novel methods for selenocysteine insertion.

To solve scientific issues correlated with human health and diseases, mammalian selenoproteins have been recruited and utilized by researchers for numerous studies. The structural information, drug targeting and biological properties, physiological and pathological functions, and biosynthesis of mammalian selenoproteins are working out in many ongoing in-depth investigations. Thus, in this Special Issue, we aim to collect all the latest review articles and original research articles on topics including but not limited to:

Crystal structure and structural analysis of selenoproteins;
Catalytic mechanism of Sec-containing oxidoreductases;
New substrates of Sec-containing oxidoreductases;
Biological functions of selenoproteins;
Regulation of intracellular roles of selenoproteins;
Mechanisms of eukaryote/prokaryote selenocysteine insertion machinery;
Biomacromolecules’ interaction in selenocysteine insertion machinery;
Biosynthesis and efficient purification of selenoproteins;
Pharmacological effects of selenium-containing compounds.

Dr. Jianqiang Xu
Prof. Dr. Jun Lu
Guest Editors

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Keywords

mammalian selenoproteins
characterization of selenoenzymes
crystal structure of selenoproteins
structural analysis of selenoproteins
functions of selenoproteins
drug–selenoprotein interactions
cellular signaling pathways
selenoprotein biosynthesis

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Published Papers (9 papers)

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Research

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18 pages, 4000 KiB

Open AccessArticle

Selenoprotein F Knockout Caused Glucose Metabolism Disorder in Young Mice by Disrupting Redox Homeostasis

by Min Li, Yun Zhang, Jun Zhou and Hongmei Liu

Antioxidants 2022, 11(11), 2105; https://doi.org/10.3390/antiox11112105 - 25 Oct 2022

Cited by 10 | Viewed by 2491

Abstract

Selenoprotein F (SELENOF) might play an important role in maintaining human health since an increasing number of studies have linked SELENOF deficiency to various pathologies such as cancer and neurodegeneration. We have previously reported on glucose metabolism disorders in SELENOF knockout mice, which imply a novel biological function of SELENOF in glucose metabolism. However, the underlying mechanism and whether the effect of SELENOF on glucose metabolism is age-dependent remain unknown. In the present study, we compare the metabolic phenotype in more detail as well as the oxidative stress parameters in SELENOF knockout mice (C57BL/6J background) and naïve C57BL/6J mice of different ages (12, 16 and 21 weeks old). The results showed that SELENOF knockout caused glucose metabolism disorders only in young mice, especially in 12-week-old mice, characterized by hyperglycemia, serum insulin reduction, impaired glucose tolerance, decreased insulin sensitivity, decreased glucose catabolism, increased gluconeogenesis and impaired insulin signaling pathway. These abnormalities gradually improved with age and disappeared in knockout mice at 21 weeks old. Furthermore, before 16 weeks old, SELENOF knockout mice showed increased lipid peroxidation and decreased glutathione/glutathione disulfide ratio and glutathione peroxidase activity in the serum and liver. Furthermore, the expression of glutathione peroxidase 1 significantly reduced in the liver and pancreas. Our findings suggest that SELENOF knockout might cause glucose metabolism disorders in young mice via the disruption of redox homeostasis. Full article

(This article belongs to the Special Issue Structure, Function and Biosynthesis of Mammalian Selenoproteins)

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14 pages, 3886 KiB

Open AccessArticle

Ebselen Interferes with Alzheimer’s Disease by Regulating Mitochondrial Function

by Xuexia Li, Qingqing Shi, Hao Xu, Yufang Xiong, Chao Wang, Linfeng Le, Junliang Lian, Guoli Wu, Feiyuan Peng, Qiong Liu and Xiubo Du

Antioxidants 2022, 11(7), 1350; https://doi.org/10.3390/antiox11071350 - 11 Jul 2022

Cited by 12 | Viewed by 2490

Abstract

(1) Background: With unknown causes and no effective treatment available, Alzheimer’s disease (AD) places enormous pressure on families and society. Our previous study had shown that Ebselen at a high concentration (10.94 μM) improved the cognition of triple-transgenic AD (3×Tg-AD) mice and alleviated the related pathological indicators but showed toxicity to the mice. Here, we dedicated to study the therapeutic effect and molecular mechanism of Ebselen at a much lower concentration on 3×Tg-AD mice. (2) Methods: Various behavioral experiments were applied to detect the behavioral ability of mice. Western blot, thioflavin T staining and a transmission electron microscope were used to evaluate the pathology of AD mice. The mitochondrial membrane potential and respiration were assessed with the corresponding assay kit. (3) Results: Ebselen remarkably increased cognitive ability of AD mice, eliminated β-Amyloid (Aβ) oligomers and recovered the synaptic damage in AD mice brain. In addition, the destroyed mitochondrial morphologies and function were repaired by Ebselen through ameliorating mitochondrial energy metabolism, mitochondrial biogenesis and mitochondrial fusion/fission balance in N2a-SW cells and brain tissues of AD mice. (4) Conclusions: This research indicated that Ebselen might exert its therapeutic effect via protecting mitochondria in AD. Full article

(This article belongs to the Special Issue Structure, Function and Biosynthesis of Mammalian Selenoproteins)

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14 pages, 3783 KiB

Open AccessArticle

Selenoprotein K Is Essential for the Migration and Phagocytosis of Immature Dendritic Cells

by Huan Xia, Yongmei Wang, Jie Dai, Xin Zhang, Jun Zhou, Zhu Zeng and Yi Jia

Antioxidants 2022, 11(7), 1264; https://doi.org/10.3390/antiox11071264 - 27 Jun 2022

Cited by 10 | Viewed by 2452

Abstract

Selenoprotein K (SELENOK) is an endoplasmic reticulum stress (ERS)-regulated protein required for the calcium (Ca²⁺) flux-mediated migration of T cells and neutrophils, and the migration and phagocytosis of macrophages and microglia. However, the effect of SELENOK on the regulation of the immune function of dendritic cells (DCs), including immature DCs (imDCs) and mature DCs (mDCs), is still unclear. In this study, imDCs prepared from SELENOK knockout mice were used to evaluate the effect of SELENOK on the migration and phagocytosis of imDCs. The results showed that ERS-induced downregulation of imDCs phenotypic markers led to a reduction in Ras homolog gene family member A (RhoA)-dependent migration and enhanced Ca²⁺/CD205-mediated phagocytosis. SELENOK deficiency-induced upregulation of selenoprotein S (SELENOS) attenuated ERS levels in imDCs. An increase in Ca²⁺ levels resulted in increased migration and decreased phagocytosis with or without ERS conditions. The migration was RhoA-dependent, and Ca²⁺ or CD205 was associated with regulating phagocytosis in imDCs. Our study found that SELENOK is required for imDC migration and phagocytosis. Full article

(This article belongs to the Special Issue Structure, Function and Biosynthesis of Mammalian Selenoproteins)

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13 pages, 2558 KiB

Open AccessArticle

Selenium Status in Diet Affects Nephrotoxicity Induced by Cisplatin in Mice

by Shuang Liu, Xing Wen, Qihan Huang, Minghui Zhu and Jun Lu

Antioxidants 2022, 11(6), 1141; https://doi.org/10.3390/antiox11061141 - 10 Jun 2022

Cited by 6 | Viewed by 2052

Abstract

Cisplatin is one of the most active chemotherapy drugs to treat solid tumors. However, it also causes various side effects, especially nephrotoxicity, in which oxidative stress plays critical roles. Our previous studies found that cisplatin selectively inhibited selenoenzyme thioredoxin reductase1 (TrxR1) in the kidney at an early stage and, subsequently, induced the activation of Nrf2. However, the effects of selenium on cisplatin-induced nephrotoxicity are still unclear. In this study, we established mice models with different selenium intake levels to explore the effects of selenoenzyme activity changes on cisplatin-induced nephrotoxicity. Results showed that feeding with a selenium-deficient diet sensitize the mice to cisplatin-induced damage, whereas selenium supplementation increased the activities of selenoenzymes TrxR and glutathione peroxidase (GPx), changed the renal cellular redox environment to a reduced state, and exhibited protective effects. These results demonstrated the correlation of selenoenzymes with cisplatin-induced side effects and provided a basis for the potential approach to alleviate cisplatin-induced renal injury. Full article

(This article belongs to the Special Issue Structure, Function and Biosynthesis of Mammalian Selenoproteins)

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14 pages, 4048 KiB

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Reactive Human Plasma Glutathione Peroxidase Mutant with Diselenide Bond Succeeds in Tetramer Formation

by Zhenlin Fan, Qi Yan, Jian Song and Jingyan Wei

Antioxidants 2022, 11(6), 1083; https://doi.org/10.3390/antiox11061083 - 29 May 2022

Cited by 3 | Viewed by 1835

Abstract

Plasma glutathione peroxidase (GPx3) belongs to the GPx superfamily, and it is the only known secreted selenocysteine (Sec)−containing GPx in humans. It exists as a glycosylated homotetramer and catalyzes the reduction of hydrogen peroxide and lipid peroxides, depending on the Sec in its active center. In this study, a previously reported chimeric tRNA^UTuT6 was used for the incorporation of Sec at the UAG amber codon, and the mature form of human GPx3 (hGPx3) without the signal peptide was expressed in amber−less E. coli C321.ΔA.exp. Reactive Sec−hGPx3, able to reduce H₂O₂ and tert−butyl hydroperoxide (t−BuOOH), was produced with high purity and yield. Study of the quaternary structure suggested that the recombinant Sec−hGPx3 contained an intra−molecular disulfide bridge but failed to form tetramer. Mutational and structural analysis of the mutants with three Cys residues, individually or jointly replaced with Ser, indicated that the formation of intra−molecular disulfide bridges involved structure conformational changes. The secondary structure containing Cys77 and Cys132 was flexible and could form a disulfide bond, or form a sulfhydryl–selenyl bond with Sec49 in relative mutants. Mutation of Cys8 and Cys132 to Sec8 and Sec132 could fix the oligomerization loop through the formation of diselenide bond, which, in turn, facilitated tetramer formation and noticeably improved the GPx activity. This research provides an important foundation for the further catalysis and functional study of hGPx3. Full article

(This article belongs to the Special Issue Structure, Function and Biosynthesis of Mammalian Selenoproteins)

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21 pages, 2915 KiB

Open AccessArticle

Comparative Proteomic Analysis Reveals the Effect of Selenoprotein W Deficiency on Oligodendrogenesis in Fear Memory

by Jiaxin Situ, Xuelian Huang, Mingyang Zuo, Yingying Huang, Bingyu Ren and Qiong Liu

Antioxidants 2022, 11(5), 999; https://doi.org/10.3390/antiox11050999 - 19 May 2022

Cited by 7 | Viewed by 2428

Abstract

The essential trace element selenium plays an important role in maintaining brain function. Selenoprotein W (SELENOW), the smallest selenoprotein that has been identified in mammals, is sensitive to selenium levels and abundantly expressed in the brain. However, its biological role in the brain remains to be clarified. Here, we studied the morphological and functional changes in the brain caused by SELENOW deficiency using its gene knockout (KO) mouse models. Histomorphological alterations of the amygdala and hippocampus, specifically in the female SELENOW KO mice, were observed, ultimately resulting in less anxiety-like behavior and impaired contextual fear memory. Fear conditioning (FC) provokes rapidly intricate responses involving neuroplasticity and oligodendrogenesis. During this process, the females generally show stronger contextual FC than males. To characterize the effect of SELENOW deletion on FC, specifically in the female mice, a Tandem mass tag (TMT)-based comparative proteomic approach was applied. Notably, compared to the wildtype (WT) no shock (NS) mice, the female SELENOW KO NS mice shared lots of common differentially expressed proteins (DEPs) with the WT FC mice in the hippocampus, enriched in the biological process of ensheathment and oligodendrocyte differentiation. Immunostaining and Western blotting analyses further confirmed the proteomic results. Our work may provide a holistic perspective of gender-specific SELENOW function in the brain and highlighted its role in oligodendrogenesis during fear memory. Full article

(This article belongs to the Special Issue Structure, Function and Biosynthesis of Mammalian Selenoproteins)

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19 pages, 2830 KiB

Open AccessArticle

Reversal of Lipid Metabolism Dysregulation by Selenium and Folic Acid Co-Supplementation to Mitigate Pathology in Alzheimer’s Disease

by Zhong-Hao Zhang, Xian-Chun Cao, Jia-Ying Peng, Shao-Ling Huang, Chen Chen, Shi-Zheng Jia, Jia-Zuan Ni and Guo-Li Song

Antioxidants 2022, 11(5), 829; https://doi.org/10.3390/antiox11050829 - 24 Apr 2022

Cited by 36 | Viewed by 3482

Abstract

Aberrant lipid metabolism is reported to be closely related to the pathogenesis of neurodegenerative diseases, such as Alzheimer’s disease (AD). Selenium (Se) and folate are two ideal and safe nutritional supplements, whose biological effects include regulating redox and homocysteine (Hcy) homeostasis in vivo. Here, to achieve effective multitarget therapy for AD, we combined Se and folic acid in a co-supplementation regimen (Se-FA) to study the therapeutic potential and exact mechanism in two transgenic mouse models of AD (APP/Tau/PSEN and APP/PS1). In addition to a reduction in Aβ generation and tau hyperphosphorylation, a restoration of synaptic plasticity and cognitive ability was observed in AD mice upon Se-FA administration. Importantly, by using untargeted metabolomics, we found that these improvements were dependent on the modulation of brain lipid metabolism, which may be associated with an antioxidant effect and the promotion of Hcy metabolism. Thus, from mechanism to effects, this study systematically investigated Se-FA as an intervention for AD, providing important mechanistic insights to inform its potential use in clinical trials. Full article

(This article belongs to the Special Issue Structure, Function and Biosynthesis of Mammalian Selenoproteins)

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15 pages, 2323 KiB

Open AccessArticle

Piperlongumine Inhibits Thioredoxin Reductase 1 by Targeting Selenocysteine Residues and Sensitizes Cancer Cells to Erastin

by Yijia Yang, Shibo Sun, Weiping Xu, Yue Zhang, Rui Yang, Kun Ma, Jie Zhang and Jianqiang Xu

Antioxidants 2022, 11(4), 710; https://doi.org/10.3390/antiox11040710 - 4 Apr 2022

Cited by 32 | Viewed by 4117

Abstract

Piperlongumine, a natural alkaloid substance extracted from the fruit of the long pepper (Piper longum Linn.), is known to inhibit the cytosolic thioredoxin reductase (TXNRD1 or TrxR1) and selectively kill cancer cells. However, the details and mechanism of the inhibition by piperlongumine against TXNRD1 remain unclear. In this study, based on the classical DTNB reducing assay, irreversible inhibition of recombinant TXNRD1 by piperlongumine was found and showed an apparent k_inact value of 0.206 × 10⁻³ µM⁻¹ min⁻¹. Meanwhile, compared with the wild-type TXNRD1 (-GCUG), the UGA-truncated form (-GC) of TXNRD1 was resistant to piperlongumine, suggesting the preferential target of piperlongumine is the selenol (-SeH) at the C-terminal redox motif of the enzyme. Interestingly, the high concentration of piperlongumine-inhibited TXNRD1 showed that its Sec-dependent activity is decayed but its intrinsic NADPH oxidase activity is retained. Furthermore, piperlongumine did not induce ferroptosis in HCT116 cells at 10 µM, whereas significantly promoted erastin-induced lipid oxidation, which could be alleviated by supplying glutathione (GSH) or N-acetyl L-cysteine (NAC). However, restricting GSH synthesis by inhibiting glutaminase (GLS) using the small molecule inhibitor CB-839 only slightly enhanced erastin-induced cell death. Taken together, this study elucidates the molecular mechanism of the antitumor capacity of piperlongumine by targeting TXNRD1 and reveals the potential possibility of inhibiting TXNRD1 to strengthen cancer cells’ ferroptosis. Full article

(This article belongs to the Special Issue Structure, Function and Biosynthesis of Mammalian Selenoproteins)

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Review

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15 pages, 1591 KiB

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The Role and Mechanism of Essential Selenoproteins for Homeostasis

by Ruihua Ye, Jiaqiang Huang, Zixu Wang, Yaoxing Chen and Yulan Dong

Antioxidants 2022, 11(5), 973; https://doi.org/10.3390/antiox11050973 - 15 May 2022

Cited by 47 | Viewed by 4444

Abstract

Selenium (Se) is one of the essential trace elements that plays a biological role in the body, mainly in the form of selenoproteins. Selenoproteins can be involved in the regulation of oxidative stress, endoplasmic reticulum (ER) stress, antioxidant defense, immune and inflammatory responses and other biological processes, including antioxidant, anti-inflammation, anti-apoptosis, the regulation of immune response and other functions. Over-loading or lack of Se causes certain damage to the body. Se deficiency can reduce the expression and activity of selenoproteins, disrupt the normal physiological function of cells and affect the body in antioxidant, immunity, toxin antagonism, signaling pathways and other aspects, thus causing different degrees of damage to the body. Se intake is mainly in the form of dietary supplements. Due to the important role of Se, people pay increasingly more attention to Se-enriched foods, which also lays a foundation for better research on the mechanism of selenoproteins in the future. In this paper, the synthesis and mechanism of selenoproteins, as well as the role and mechanism of selenoproteins in the regulation of diseases, are reviewed. Meanwhile, the future development of Se-enriched products is prospected, which is of great significance to further understand the role of Se. Full article

(This article belongs to the Special Issue Structure, Function and Biosynthesis of Mammalian Selenoproteins)

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