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Selenium, diabetes, and their intricate sex-specific relationship.
Demircan, K, Chillon, TS, Bang, J, Gladyshev, VN, Schomburg, L
Trends in endocrinology and metabolism: TEM. 2024
Abstract
Selenium (Se) is an essential trace element, which is inserted as selenocysteine (Sec) into selenoproteins during biosynthesis, orchestrating their expression and activity. Se is associated with both beneficial and detrimental health effects; deficient supply or uncontrolled supplementation raises concerns. In particular, Se was associated with an increased incidence of type 2 diabetes (T2D) in a secondary analysis of a randomized controlled trial (RCT). In this review, we discuss the intricate relationship between Se and diabetes and the limitations of the available clinical and experimental studies. Recent evidence points to sexual dimorphism and an association of Se deficiency with gestational diabetes mellitus (GDM). We highlight the emerging evidence linking high Se status with improved prognosis in patients with T2D and lower risk of macrovascular complications.
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2.
ARDD 2020: from aging mechanisms to interventions.
Mkrtchyan, GV, Abdelmohsen, K, Andreux, P, Bagdonaite, I, Barzilai, N, Brunak, S, Cabreiro, F, de Cabo, R, Campisi, J, Cuervo, AM, et al
Aging. 2020;(24):24484-24503
Abstract
Aging is emerging as a druggable target with growing interest from academia, industry and investors. New technologies such as artificial intelligence and advanced screening techniques, as well as a strong influence from the industry sector may lead to novel discoveries to treat age-related diseases. The present review summarizes presentations from the 7th Annual Aging Research and Drug Discovery (ARDD) meeting, held online on the 1st to 4th of September 2020. The meeting covered topics related to new methodologies to study aging, knowledge about basic mechanisms of longevity, latest interventional strategies to target the aging process as well as discussions about the impact of aging research on society and economy. More than 2000 participants and 65 speakers joined the meeting and we already look forward to an even larger meeting next year. Please mark your calendars for the 8th ARDD meeting that is scheduled for the 31st of August to 3rd of September, 2021, at Columbia University, USA.
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3.
The conundrum of human immune system "senescence".
Pawelec, G, Bronikowski, A, Cunnane, SC, Ferrucci, L, Franceschi, C, Fülöp, T, Gaudreau, P, Gladyshev, VN, Gonos, ES, Gorbunova, V, et al
Mechanisms of ageing and development. 2020;:111357
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Abstract
There is a great deal of debate on the question of whether or not we know what ageing is (Ref. Cohen et al., 2020). Here, we consider what we believe to be the especially confused and confusing case of the ageing of the human immune system, commonly referred to as "immunosenescence". But what exactly is meant by this term? It has been used loosely in the literature, resulting in a certain degree of confusion as to its definition and implications. Here, we argue that only those differences in immune parameters between younger and older adults that are associated in some definitive manner with detrimental health outcomes and/or impaired survival prospects should be classed as indicators of immunosenescence in the strictest sense of the word, and that in humans we know remarkably little about their identity. Such biomarkers of immunosenescence may nonetheless indicate beneficial effects in other contexts, consistent with the notion of antagonistic pleiotropy. Identifying what could be true immunosenescence in this respect requires examining: (1) what appears to correlate with age, though generality across human populations is not yet confirmed; (2) what clearly is part of a suite of canonical changes in the immune system that happen with age; (3) which subset of those changes accelerates rather than slows aging; and (4) all changes, potentially population-specific, that accelerate agig. This remains an immense challenge. These questions acquire an added urgency in the current SARS-CoV-2 pandemic, given the clearly greater susceptibility of older adults to COVID-19.
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4.
Genome-wide association study of selenium concentrations.
Cornelis, MC, Fornage, M, Foy, M, Xun, P, Gladyshev, VN, Morris, S, Chasman, DI, Hu, FB, Rimm, EB, Kraft, P, et al
Human molecular genetics. 2015;(5):1469-77
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Abstract
Selenium (Se) is an essential trace element in human nutrition, but its role in certain health conditions, particularly among Se sufficient populations, is controversial. A genome-wide association study (GWAS) of blood Se concentrations previously identified a locus at 5q14 near BHMT. We performed a GW meta-analysis of toenail Se concentrations, which reflect a longer duration of exposure than blood Se concentrations, including 4162 European descendants from four US cohorts. Toenail Se was measured using neutron activation analysis. We identified a GW-significant locus at 5q14 (P < 1 × 10(-16)), the same locus identified in the published GWAS of blood Se based on independent cohorts. The lead single-nucleotide polymorphism (SNP) explained ∼1% of the variance in toenail Se concentrations. Using GW-summary statistics from both toenail and blood Se, we observed statistical evidence of polygenic overlap (P < 0.001) and meta-analysis of results from studies of either trait (n = 9639) yielded a second GW-significant locus at 21q22.3, harboring CBS (P < 4 × 10(-8)). Proteins encoded by genes at 5q14 and 21q22.3 function in homocysteine (Hcy) metabolism, and index SNPs for each have previously been associated with betaine and Hcy levels in GWAS. Our findings show evidence of a genetic link between Se and Hcy pathways, both involved in cardiometabolic disease.
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5.
Selenocysteine in thiol/disulfide-like exchange reactions.
Hondal, RJ, Marino, SM, Gladyshev, VN
Antioxidants & redox signaling. 2013;(13):1675-89
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Abstract
SIGNIFICANCE Among trace elements used as cofactors in enzymes, selenium is unique in that it is incorporated into proteins co-translationally in the form of an amino acid, selenocysteine (Sec). Sec differs from cysteine (Cys) by only one atom (selenium versus sulfur), yet this switch dramatically influences important aspects of enzyme reactivity. RECENT ADVANCES The main focus of this review is an updated and critical discussion on how Sec might be used to accelerate thiol/disulfide-like exchange reactions in natural selenoenzymes, compared with their Cys-containing homologs. CRITICAL ISSUES We discuss in detail three major aspects associated with thiol/disulfide exchange reactions: (i) nucleophilicity of the attacking thiolate (or selenolate); (ii) electrophilicity of the center sulfur (or selenium) atom; and (iii) stability of the leaving group (sulfur or selenium). In all these cases, we analyze the benefits that selenium might provide in these types of reactions. FUTURE DIRECTIONS It is the biological thiol oxidoreductase-like function that benefits from the use of Sec, since Sec functions to chemically accelerate the rate of these reactions. We review various hypotheses that could help explain why Sec is used in enzymes, particularly with regard to competitive chemical advantages provided by the presence of the selenium atom in enzymes. Ultimately, these chemical advantages must be connected to biological functions of Sec.
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Comparative genomics analysis of the metallomes.
Gladyshev, VN, Zhang, Y
Metal ions in life sciences. 2013;:529-80
Abstract
Biological trace metals are needed in small quantities, but used by all living organisms. They are employed in key cellular functions in a variety of biological processes, resulting in the various degree of dependence of organisms on metals. Most effort in the field has been placed on experimental studies of metal utilization pathways and metal-dependent proteins. On the other hand, systemic level analyses of metalloproteomes (or metallomes) have been limited for most metals. In this chapter, we focus on the recent advances in comparative genomics, which provides many insights into evolution and function of metal utilization. These studies suggested that iron and zinc are widely used in biology (presumably by all organisms), whereas some other metals such as copper, molybdenum, nickel, and cobalt, show scattered occurrence in various groups of organisms. For these metals, most user proteins are well characterized and their dependence on a specific element is evolutionarily conserved. We also discuss evolutionary dynamics of the dependence of user proteins on different metals. Overall, comparative genomics analysis of metallomes provides a foundation for the systemic level understanding of metal utilization as well as for investigating the general features, functions, and evolutionary dynamics of metal use in the three domains of life.
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Recharging oxidative protein repair: catalysis by methionine sulfoxide reductases towards their amino acid, protein, and model substrates.
Tarrago, L, Gladyshev, VN
Biochemistry. Biokhimiia. 2012;(10):1097-107
Abstract
The sulfur-containing amino acid methionine (Met) in its free and amino acid residue forms can be readily oxidized to the R and S diastereomers of methionine sulfoxide (MetO). Methionine sulfoxide reductases A (MSRA) and B (MSRB) reduce MetO back to Met in a stereospecific manner, acting on the S and R forms, respectively. A third MSR type, fRMSR, reduces the R form of free MetO. MSRA and MSRB are spread across the three domains of life, whereas fRMSR is restricted to bacteria and unicellular eukaryotes. These enzymes protect against abiotic and biotic stresses and regulate lifespan. MSRs are thiol oxidoreductases containing catalytic redox-active cysteine or selenocysteine residues, which become oxidized by the substrate, requiring regeneration for the next catalytic cycle. These enzymes can be classified according to the number of redox-active cysteines (selenocysteines) and the strategies to regenerate their active forms by thioredoxin and glutaredoxin systems. For each MSR type, we review catalytic parameters for the reduction of free MetO, low molecular weight MetO-containing compounds, and oxidized proteins. Analysis of these data reinforces the concept that MSRAs reduce various types of MetO-containing substrates with similar efficiency, whereas MSRBs are specialized for the reduction of MetO in proteins.
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Functional diversity of cysteine residues in proteins and unique features of catalytic redox-active cysteines in thiol oxidoreductases.
Fomenko, DE, Marino, SM, Gladyshev, VN
Molecules and cells. 2008;(3):228-35
Abstract
Thiol-dependent redox systems are involved in regulation of diverse biological processes, such as response to stress, signal transduction, and protein folding. The thiol-based redox control is provided by mechanistically similar, but structurally distinct families of enzymes known as thiol oxidoreductases. Many such enzymes have been characterized, but identities and functions of the entire sets of thiol oxidoreductases in organisms are not known. Extreme sequence and structural divergence makes identification of these proteins difficult. Thiol oxidoreductases contain a redox-active cysteine residue, or its functional analog selenocysteine, in their active sites. Here, we describe computational methods for in silico prediction of thiol oxidoreductases in nucleotide and protein sequence databases and identification of their redox-active cysteines. We discuss different functional categories of cysteine residues, describe methods for discrimination between catalytic and noncatalytic and between redox and non-redox cysteine residues and highlight unique properties of the redox-active cysteines based on evolutionary conservation, secondary and three-dimensional structures, and sporadic replacement of cysteines with catalytically superior selenocysteine residues.
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SelenoDB 1.0 : a database of selenoprotein genes, proteins and SECIS elements.
Castellano, S, Gladyshev, VN, Guigó, R, Berry, MJ
Nucleic acids research. 2008;(Database issue):D332-8
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Abstract
Selenoproteins are a diverse group of proteins usually misidentified and misannotated in sequence databases. The presence of an in-frame UGA (stop) codon in the coding sequence of selenoprotein genes precludes their identification and correct annotation. The in-frame UGA codons are recoded to cotranslationally incorporate selenocysteine, a rare selenium-containing amino acid. The development of ad hoc experimental and, more recently, computational approaches have allowed the efficient identification and characterization of the selenoproteomes of a growing number of species. Today, dozens of selenoprotein families have been described and more are being discovered in recently sequenced species, but the correct genomic annotation is not available for the majority of these genes. SelenoDB is a long-term project that aims to provide, through the collaborative effort of experimental and computational researchers, automatic and manually curated annotations of selenoprotein genes, proteins and SECIS elements. Version 1.0 of the database includes an initial set of eukaryotic genomic annotations, with special emphasis on the human selenoproteome, for immediate inspection by selenium researchers or incorporation into more general databases. SelenoDB is freely available at http://www.selenodb.org.
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Comparison of selenium-containing molybdoenzymes.
Gladyshev, VN
Metal ions in biological systems. 2002;:655-72