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Current Medicinal Chemistry 2022Selenium (Se) has been known for its beneficial biological roles for several years, but interest in this trace element has seen a significant increase in the past couple... (Review)
Review
Selenium (Se) has been known for its beneficial biological roles for several years, but interest in this trace element has seen a significant increase in the past couple of decades. It has been reported to be a part of important bioactive organic compounds, such as selenoproteins and amino acids, including selenocysteine (SeCys), selenomethionine (SeMet), selenazolidine (SeAzo), and selenoneine. The traditional Se supplementations (primarily as selenite and selenomethionine), though have been shown to carry some benefits, also have associated toxicities, thereby paving the way for the organoselenium compounds, especially the selenoproteins and peptides (SePs/SePPs) that offer several health benefits beyond fulfilling the elementary nutritional Se needs. This review aims to showcase the applications of selenium-containing peptides that have been reported in recent decades. This article summarizes their bioactivities, including neuroprotective, antiinflammatory, anticancer, antioxidant, hepatoprotective, and immunomodulatory roles. This will offer the readers a sneak peek into the current advancements to invoke further developments in this emerging research area.
Topics: Humans; Selenium; Selenomethionine; Selenocysteine; Antioxidants; Trace Elements; Selenoproteins; Selenious Acid; Peptides
PubMed: 35156568
DOI: 10.2174/0929867329666220214104010 -
Free Radical Biology & Medicine Nov 2022Selenophosphate synthetases use selenium and ATP to synthesize selenophosphate. This is required for biological utilization of selenium, most notably for the synthesis... (Review)
Review
Selenophosphate synthetases use selenium and ATP to synthesize selenophosphate. This is required for biological utilization of selenium, most notably for the synthesis of the non-canonical amino acid selenocysteine (Sec). Therefore, selenophosphate synthetases underlie all functions of selenoproteins, which include redox homeostasis, protein quality control, hormone regulation, metabolism, and many others. This protein family comprises two groups, SelD/SPS2 and SPS1. The SelD/SPS2 group represent true selenophosphate synthetases, enzymes central to selenium metabolism which are present in all Sec-utilizing organisms across the tree of life. Notably, many SelD/SPS2 proteins contain Sec as catalytic residue in their N-terminal flexible selenium-binding loop, while others replace it with cysteine (Cys). The SPS1 group comprises proteins originated through gene duplications of SelD/SPS2 in metazoa in which the Sec/Cys-dependent catalysis was disrupted. SPS1 proteins do not synthesize selenophosphate and are not required for Sec synthesis. They have essential regulatory functions related to redox homeostasis and pyridoxal phosphate, which affect signaling pathways for growth and differentiation. In this review, we summarize the knowledge about the selenophosphate synthetase family acquired through decades of research, encompassing their structure, mechanism, function, and evolution.
Topics: Adenosine Triphosphate; Cysteine; Hormones; Ligases; Phosphates; Phosphotransferases; Pyridoxal Phosphate; Selenium; Selenium Compounds; Selenocysteine; Selenoproteins
PubMed: 36122644
DOI: 10.1016/j.freeradbiomed.2022.09.007 -
Annual Review of Pharmacology and... Jan 2022The cytosolic selenoprotein thioredoxin reductase 1 (TrxR1, TXNRD1), and to some extent mitochondrial TrxR2 (TXNRD2), can be inhibited by a wide range of electrophilic... (Review)
Review
The cytosolic selenoprotein thioredoxin reductase 1 (TrxR1, TXNRD1), and to some extent mitochondrial TrxR2 (TXNRD2), can be inhibited by a wide range of electrophilic compounds. Many such compounds also yield cytotoxicity toward cancer cells in culture or in mouse models, and most compounds are likely to irreversibly modify the easily accessible selenocysteine residue in TrxR1, thereby inhibiting its normal activity to reduce cytosolic thioredoxin (Trx1, TXN) and other substrates of the enzyme. This leads to an oxidative challenge. In some cases, the inhibited forms of TrxR1 are not catalytically inert and are instead converted to prooxidant NADPH oxidases, named SecTRAPs, thus further aggravating the oxidative stress, particularly in cells expressing higher levels of the enzyme. In this review, the possible molecular and cellular consequences of these effects are discussed in relation to cancer therapy, with a focus on outstanding questions that should be addressed if targeted TrxR1 inhibition is to be further developed for therapeutic use.
Topics: Animals; Humans; Mice; Mitochondria; Neoplasms; Oxidation-Reduction; Reactive Oxygen Species; Selenocysteine; Thioredoxin Reductase 1
PubMed: 34449246
DOI: 10.1146/annurev-pharmtox-052220-102509 -
International Journal of Molecular... Dec 2023Selenocysteine (Sec) was discovered as the 21st genetically encoded amino acid. In nature, site-directed incorporation of Sec into proteins requires specialized... (Review)
Review
Selenocysteine (Sec) was discovered as the 21st genetically encoded amino acid. In nature, site-directed incorporation of Sec into proteins requires specialized biosynthesis and recoding machinery that evolved distinctly in bacteria compared to archaea and eukaryotes. Many organisms, including higher plants and most fungi, lack the Sec-decoding trait. We review the discovery of Sec and its role in redox enzymes that are essential to human health and important targets in disease. We highlight recent genetic code expansion efforts to engineer site-directed incorporation of Sec in bacteria and yeast. We also review methods to produce selenoproteins with 21 or more amino acids and approaches to delivering recombinant selenoproteins to mammalian cells as new applications for selenoproteins in synthetic biology.
Topics: Humans; Animals; Selenoproteins; Amino Acids; Antifibrinolytic Agents; Archaea; Saccharomyces cerevisiae; Selenocysteine; Mammals
PubMed: 38203392
DOI: 10.3390/ijms25010223 -
Trends in Cancer Dec 2023In the past two decades significant progress has been made in uncovering the biological function of selenium. Selenium, an essential trace element, is required for the... (Review)
Review
In the past two decades significant progress has been made in uncovering the biological function of selenium. Selenium, an essential trace element, is required for the biogenesis of selenocysteine which is then incorporated into selenoproteins. These selenoproteins have emerged as central regulators of cellular antioxidant capacity and maintenance of redox homeostasis. This review provides a comprehensive examination of the multifaceted functions of selenoproteins with a particular emphasis on their contributions to cellular antioxidant capacity. Additionally, we highlight the promising potential of targeting selenoproteins and the biogenesis of selenocysteine as avenues for therapeutic intervention in cancer. By understanding the intricate relationship between selenium, selenoproteins, and reactive oxygen species (ROS), insights can be gained to develop therapies that exploit the inherent vulnerabilities of cancer cells.
Topics: Humans; Antioxidants; Selenium; Selenocysteine; Selenoproteins; Oxidation-Reduction; RNA, Transfer; Homeostasis; Neoplasms
PubMed: 37716885
DOI: 10.1016/j.trecan.2023.08.003 -
Mini Reviews in Medicinal Chemistry 2023Selenium (Se), a semi-metallic element, has chemical properties similar to sulfur; however, it has comparatively low electronegativity as well as a large atomic radius... (Review)
Review
Selenium (Se), a semi-metallic element, has chemical properties similar to sulfur; however, it has comparatively low electronegativity as well as a large atomic radius than sulfur. These features bestow selenium-containing compounds with extraordinary reactivity, sensitivity, and potential for several applications like chemical alteration, protein engineering, chemical (semi)synthesis, etc. Organoselenium chemistry is emerging fastly, however, examples of effective incorporation of Se into the peptides are relatively scarce. Providentially, there has been a drastic interest in synthesizing and applying selenoproteins and selenium-containing peptides over the last few decades. In this minireview, the synthetic methodologies of selenium-containing peptides and a brief description of their chemistry and biological activities are summarized. These methodologies enable access to various natural and unnatural selenium-containing peptides that have been used in a range of applications, from modulating protein characteristics to structure-activity relationship (SAR) studies for applications in nutraceuticals and drug development. This review aims at the audience interested in learning about the synthesis as well as will open new dimensions for their future research by aiding in the design of biologically interesting selenium-containing peptides.
Topics: Selenium Compounds; Peptides; Humans; Animals; Sulfur; Solutions
PubMed: 36029080
DOI: 10.2174/1389557522666220826140910 -
Essays in Biochemistry Feb 2020Selenocysteine (Sec), the sulfur-to-selenium substituted variant of cysteine (Cys), is the defining entity of selenoproteins. These are naturally expressed in many... (Review)
Review
Selenocysteine (Sec), the sulfur-to-selenium substituted variant of cysteine (Cys), is the defining entity of selenoproteins. These are naturally expressed in many diverse organisms and constitute a unique class of proteins. As a result of the physicochemical characteristics of selenium when compared with sulfur, Sec is typically more reactive than Cys while participating in similar reactions, and there are also some qualitative differences in the reactivities between the two amino acids. This minireview discusses the types of modifications of Sec in selenoproteins that have thus far been experimentally validated. These modifications include direct covalent binding through the Se atom of Sec to other chalcogen atoms (S, O and Se) as present in redox active molecular motifs, derivatization of Sec via the direct covalent binding to non-chalcogen elements (Ni, Mb, N, Au and C), and the loss of Se from Sec resulting in formation of dehydroalanine. To understand the nature of these Sec modifications is crucial for an understanding of selenoprotein reactivities in biological, physiological and pathophysiological contexts.
Topics: Animals; Humans; Protein Processing, Post-Translational; Selenocysteine; Selenoproteins
PubMed: 31867620
DOI: 10.1042/EBC20190051 -
Frontiers in Microbiology 2022Archaea constitute the third domain of life, distinct from bacteria and eukaryotes given their ability to tolerate extreme environments. To survive these harsh... (Review)
Review
Archaea constitute the third domain of life, distinct from bacteria and eukaryotes given their ability to tolerate extreme environments. To survive these harsh conditions, certain archaeal lineages possess unique genetic code systems to encode either selenocysteine or pyrrolysine, rare amino acids not found in all organisms. Furthermore, archaea utilize alternate tRNA-dependent pathways to biosynthesize and incorporate members of the 20 canonical amino acids. Recent discoveries of new archaeal species have revealed the co-occurrence of these genetic code systems within a single lineage. This review discusses the diverse genetic code systems of archaea, while detailing the associated biochemical elements and molecular mechanisms.
PubMed: 36160229
DOI: 10.3389/fmicb.2022.1007832 -
Pharmacological Research Dec 2021Thioredoxin reductases (TrxRs) belong to the pyridine nucleotide disulfide oxidoreductase family enzymes that reduce thioredoxin (Trx). The couple TrxR and Trx is one of... (Review)
Review
Thioredoxin reductases (TrxRs) belong to the pyridine nucleotide disulfide oxidoreductase family enzymes that reduce thioredoxin (Trx). The couple TrxR and Trx is one of the major antioxidant systems that control the redox homeostasis in cells. The thioredoxin system, comprised of TrxR, Trx and NADPH, exerts its activities via a disulfide-dithiol exchange reaction. Inhibition of TrxR is an important clinical goal in all conditions in which the redox state is perturbed. The present review focuses on the most critical aspects of the cellular functions of TrxRs and their inhibition mechanisms by metal ions or chemicals, through direct targeting of TrxRs or their substrates or protein interactors. To update the involvement of overactivation/dysfunction of TrxRs in various pathological conditions, human diseases associated with TrxRs genes were critically summarized by publicly available genome-wide association study (GWAS) catalogs and literature. The pieces of evidence presented here justify why TrxR is recognized as one of the most critical clinical targets and the growing current interest in developing molecules capable of interfering with the functions of TrxR enzymes.
Topics: Amino Acid Sequence; Animals; Antioxidants; Biomarkers; Enzyme Inhibitors; Genome-Wide Association Study; Humans; NADP; Oxidation-Reduction; Oxidative Stress; Protein Binding; Selenocysteine; Thioredoxin-Disulfide Reductase; Thioredoxins
PubMed: 34455077
DOI: 10.1016/j.phrs.2021.105854 -
Molecules (Basel, Switzerland) Apr 2023In recent years, researchers have been exploring the potential of incorporating selenium into peptides, as this element possesses unique properties that can enhance the... (Review)
Review
In recent years, researchers have been exploring the potential of incorporating selenium into peptides, as this element possesses unique properties that can enhance the reactivity of these compounds. Selenium is a non-metallic element that has a similar electronic configuration to sulfur. However, due to its larger atomic size and lower electronegativity, it is more nucleophilic than sulfur. This property makes selenium more reactive toward electrophiles. One of the most significant differences between selenium and sulfur is the dissociation of the Se-H bond. The Se-H bond is more easily dissociated than the S-H bond, leading to higher acidity of selenocysteine (Sec) compared to cysteine (Cys). This difference in acidity can be exploited to selectively modify the reactivity of peptides containing Sec. Furthermore, Se-H bonds in selenium-containing peptides are more susceptible to oxidation than their sulfur analogs. This property can be used to selectively modify the peptides by introducing new functional groups, such as disulfide bonds, which are important for protein folding and stability. These unique properties of selenium-containing peptides have found numerous applications in the field of chemical biology. For instance, selenium-containing peptides have been used in native chemical ligation (NCL). In addition, the reactivity of Sec can be harnessed to create cyclic and stapled peptides. Other chemical modifications, such as oxidation, reduction, and photochemical reactions, have also been applied to selenium-containing peptides to create novel molecules with unique biological properties.
Topics: Selenium; Peptides; Sulfur; Selenocysteine; Cysteine
PubMed: 37049961
DOI: 10.3390/molecules28073198