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Selenocysteine: Synthesis, Function, and Evolution of the 21st Amino Acid

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A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Biomacromolecules: Proteins".

Deadline for manuscript submissions: closed (31 October 2023) | Viewed by 17171

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Special Issue Editor

Dr. Marco Mariotti

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Guest Editor

Group Leader, Ramon y Cajal FellowInstitute of Biomedicine, Department of Genetics, Microbiology and Statistics, Universitat de Barcelona, Barcelona, Spain
Interests: comparative genomics; bioinformatics; evolution; functional genomics; protein synthesis; gene expression; selenium; selenocysteine; recoding; readthrough; aging

Special Issue Information

Dear Colleagues,

Selenocysteine (Sec), the 21^st amino acid, is found in enzymes known as selenoproteins, typically located in their active site. Sec is inserted by an expansion of the genetic code, wherein the UGA codon (normally a stop) is recoded for Sec insertion, through a highly regulated process involving various cis-signals and trans-factors. Some 46 years after the discovery of Sec, our understanding of this intriguing amino acid has greatly advanced, but many aspects remain obscure.

In this Special Issue, we seek manuscripts from the diverse branches of molecular biology that take on the study of Sec. Submissions may cover the processes of its biosynthesis and peculiar insertion, the function and regulation of specific selenoproteins, their role in human health and disease, the evolution and phylogenetic distribution of Sec, and the biochemical nature of its catalytic benefit. We welcome both original research articles and reviews, and encourage you to contact us for preliminary inquiries.

Dr. Marco Mariotti
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

selenocysteine
selenium
recoding

Published Papers (6 papers)

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Research

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22 pages, 6215 KiB

Open AccessArticle

High-Resolution Ribosome Profiling Reveals Gene-Specific Details of UGA Re-Coding in Selenoprotein Biosynthesis

by Simon Bohleber, Noelia Fradejas-Villar, Wenchao Zhao, Uschi Reuter and Ulrich Schweizer

Biomolecules 2022, 12(10), 1504; https://doi.org/10.3390/biom12101504 - 17 Oct 2022

Viewed by 1729

Abstract

Co-translational incorporation of selenocysteine (Sec) into selenoproteins occurs at UGA codons in a process in which translational elongation competes with translational termination. Selenocysteine insertion sequence-binding protein 2 (SECISBP2) greatly enhances Sec incorporation into selenoproteins by interacting with the mRNA, ribosome, and elongation factor Sec (EFSEC). Ribosomal profiling allows to study the process of UGA re-coding in the physiological context of the cell and at the same time for all individual selenoproteins expressed in that cell. Using HAP1 cells expressing a mutant SECISBP2, we show here that high-resolution ribosomal profiling can be used to assess read-through efficiency at the UGA in all selenoproteins, including those with Sec close to the C-terminus. Analysis of ribosomes with UGA either at the A-site or the P-site revealed, in a transcript-specific manner, that SECISBP2 helps to recruit tRNA^Sec and stabilize the mRNA. We propose to assess the effect of any perturbation of UGA read-through by determining the proportion of ribosomes carrying UGA in the P-site, pUGA. An additional, new observation is frameshifting that occurred 3′ of the UGA/Sec codon in SELENOF and SELENOW in SECISBP2-mutant HAP1 cells, a finding corroborated by reanalysis of neuron-specific Secisbp2^R543Q-mutant brains. Full article

(This article belongs to the Special Issue Selenocysteine: Synthesis, Function, and Evolution of the 21st Amino Acid)

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16 pages, 3989 KiB

Open AccessArticle

eIF3 Interacts with Selenoprotein mRNAs

by Hassan Hayek, Gilbert Eriani and Christine Allmang

Biomolecules 2022, 12(9), 1268; https://doi.org/10.3390/biom12091268 - 9 Sep 2022

Cited by 3 | Viewed by 2127

Abstract

The synthesis of selenoproteins requires the co-translational recoding of an in-frame UGASec codon. Interactions between the Selenocysteine Insertion Sequence (SECIS) and the SECIS binding protein 2 (SBP2) in the 3′untranslated region (3′UTR) of selenoprotein mRNAs enable the recruitment of the selenocysteine insertion machinery. Several selenoprotein mRNAs undergo unusual cap hypermethylation and are not recognized by the translation initiation factor 4E (eIF4E) but nevertheless translated. The human eukaryotic translation initiation factor 3 (eIF3), composed of 13 subunits (a-m), can selectively recruit several cellular mRNAs and plays roles in specialized translation initiation. Here, we analyzed the ability of eIF3 to interact with selenoprotein mRNAs. By combining ribonucleoprotein immunoprecipitation (RNP IP) in vivo and in vitro with cross-linking experiments, we found interactions between eIF3 and a subgroup of selenoprotein mRNAs. We showed that eIF3 preferentially interacts with hypermethylated capped selenoprotein mRNAs rather than m⁷G-capped mRNAs. We identified direct contacts between GPx1 mRNA and eIF3 c, d, and e subunits and showed the existence of common interaction patterns for all hypermethylated capped selenoprotein mRNAs. Differential interactions of eIF3 with selenoprotein mRNAs may trigger specific translation pathways independent of eIF4E. eIF3 could represent a new player in the translation regulation and hierarchy of selenoprotein expression. Full article

(This article belongs to the Special Issue Selenocysteine: Synthesis, Function, and Evolution of the 21st Amino Acid)

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13 pages, 2105 KiB

Open AccessEditor’s ChoiceArticle

Selenocysteine Machinery Primarily Supports TXNRD1 and GPX4 Functions and Together They Are Functionally Linked with SCD and PRDX6

by Didac Santesmasses and Vadim N. Gladyshev

Biomolecules 2022, 12(8), 1049; https://doi.org/10.3390/biom12081049 - 28 Jul 2022

Cited by 9 | Viewed by 2703

Abstract

The human genome has 25 genes coding for selenocysteine (Sec)-containing proteins, whose synthesis is supported by specialized Sec machinery proteins. Here, we carried out an analysis of the co-essentiality network to identify functional partners of selenoproteins and Sec machinery. One outstanding cluster included all seven known Sec machinery proteins and two critical selenoproteins, GPX4 and TXNRD1. Additionally, these nine genes were further positively associated with PRDX6 and negatively with SCD, linking the latter two genes to the essential role of selenium. We analyzed the essentiality scores of gene knockouts in this cluster across one thousand cancer cell lines and found that Sec metabolism genes are strongly selective for a subset of primary tissues, suggesting that certain cancer cell lineages are particularly dependent on selenium. A separate outstanding cluster included selenophosphate synthetase SEPHS1, which was linked to a group of transcription factors, whereas the remaining selenoproteins were linked neither to these clusters nor among themselves. The data suggest that key components of Sec machinery have already been identified and that their primary role is to support the functions of GPX4 and TXNRD1, with further functional links to PRDX6 and SCD. Full article

(This article belongs to the Special Issue Selenocysteine: Synthesis, Function, and Evolution of the 21st Amino Acid)

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Review

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11 pages, 681 KiB

Open AccessEditor’s ChoiceReview

Distinct Roles of SELENOF in Different Human Cancers

by Brenna Flowers, Oliwia Bochnacka, Allison Poles, Alan M. Diamond and Irida Kastrati

Biomolecules 2023, 13(3), 486; https://doi.org/10.3390/biom13030486 - 6 Mar 2023

Cited by 3 | Viewed by 1862

Abstract

SELENOF, previously known as SEP15, is a selenoprotein that contains selenium in the form of the amino acid selenocysteine. Like other selenoproteins, the role for SELENOF in carcinogenesis has been investigated due to its altered expression compared to the corresponding normal tissue, its molecular function, and the association of genetic variations in the SELENOF gene to cancer risk or outcome. This review summarizes SELENOF’s discovery, structure, cellular localization, and expression. SELENOF belongs to a new family of thioredoxin-like proteins. Published data summarized here indicate a likely role for SELENOF in redox protein quality control, and in the regulation of lipids, glucose, and energy metabolism. Current evidence indicates that loss of SELENOF contributes to the development of prostate and breast cancer, while its loss may be protective against colon cancer. Additional investigation into SELENOF’s molecular mechanisms and its impact on cancer is warranted. Full article

(This article belongs to the Special Issue Selenocysteine: Synthesis, Function, and Evolution of the 21st Amino Acid)

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20 pages, 1021 KiB

Open AccessReview

Metabolism of Selenium, Selenocysteine, and Selenoproteins in Ferroptosis in Solid Tumor Cancers

by Briana K. Shimada, Sydonie Swanson, Pamela Toh and Lucia A. Seale

Biomolecules 2022, 12(11), 1581; https://doi.org/10.3390/biom12111581 - 28 Oct 2022

Cited by 13 | Viewed by 4273

Abstract

A potential target of precision nutrition in cancer therapeutics is the micronutrient selenium (Se). Se is metabolized and incorporated as the amino acid selenocysteine (Sec) into 25 human selenoproteins, including glutathione peroxidases (GPXs) and thioredoxin reductases (TXNRDs), among others. Both the processes of Se and Sec metabolism for the production of selenoproteins and the action of selenoproteins are utilized by cancer cells from solid tumors as a protective mechanism against oxidative damage and to resist ferroptosis, an iron-dependent cell death mechanism. Protection against ferroptosis in cancer cells requires sustained production of the selenoprotein GPX4, which involves increasing the uptake of Se, potentially activating Se metabolic pathways such as the trans-selenation pathway and the TXNRD1-dependent decomposition of inorganic selenocompounds to sustain GPX4 synthesis. Additionally, endoplasmic reticulum-resident selenoproteins also affect apoptotic responses in the presence of selenocompounds. Selenoproteins may also help cancer cells adapting against increased oxidative damage and the challenges of a modified nutrient metabolism that result from the Warburg switch. Finally, cancer cells may also rewire the selenoprotein hierarchy and use Se-related machinery to prioritize selenoproteins that are essential to the adaptations against ferroptosis and oxidative damage. In this review, we discuss both the evidence and the gaps in knowledge on how cancer cells from solid tumors use Se, Sec, selenoproteins, and the Se-related machinery to promote their survival particularly via resistance to ferroptosis. Full article

(This article belongs to the Special Issue Selenocysteine: Synthesis, Function, and Evolution of the 21st Amino Acid)

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14 pages, 903 KiB

Open AccessReview

Selenium Metabolism and Selenoproteins in Prokaryotes: A Bioinformatics Perspective

by Yan Zhang, Jiao Jin, Biyan Huang, Huimin Ying, Jie He and Liang Jiang

Biomolecules 2022, 12(7), 917; https://doi.org/10.3390/biom12070917 - 29 Jun 2022

Cited by 10 | Viewed by 2925

Abstract

Selenium (Se) is an important trace element that mainly occurs in the form of selenocysteine in selected proteins. In prokaryotes, Se is also required for the synthesis of selenouridine and Se-containing cofactor. A large number of selenoprotein families have been identified in diverse prokaryotic organisms, most of which are thought to be involved in various redox reactions. In the last decade or two, computational prediction of selenoprotein genes and comparative genomics of Se metabolic pathways and selenoproteomes have arisen, providing new insights into the metabolism and function of Se and their evolutionary trends in bacteria and archaea. This review aims to offer an overview of recent advances in bioinformatics analysis of Se utilization in prokaryotes. We describe current computational strategies for the identification of selenoprotein genes and generate the most comprehensive list of prokaryotic selenoproteins reported to date. Furthermore, we highlight the latest research progress in comparative genomics and metagenomics of Se utilization in prokaryotes, which demonstrates the divergent and dynamic evolutionary patterns of different Se metabolic pathways, selenoprotein families, and selenoproteomes in sequenced organisms and environmental samples. Overall, bioinformatics analyses of Se utilization, function, and evolution may contribute to a systematic understanding of how this micronutrient is used in nature. Full article

(This article belongs to the Special Issue Selenocysteine: Synthesis, Function, and Evolution of the 21st Amino Acid)

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