-
1دورية أكاديمية
المؤلفون: Tossounian, Maria-Armineh, Zhao, Yuhan, Yu, Bess Yi Kun, Markey, Samuel A, Malanchuk, Oksana, Zhu, Yuejia, Cain, Amanda, Gout, Ivan
المصدر: Redox Biology , 71 , Article 103094. (2024)
مصطلحات موضوعية: Antioxidants, Defence mechanism, LMW thiols, Oxidative stress, Thiol transferases
الوصف: Low-molecular-weight (LMW) thiols are produced in all living cells in different forms and concentrations. Glutathione (GSH), coenzyme A (CoA), bacillithiol (BSH), mycothiol (MSH), ergothioneine (ET) and trypanothione T(SH)2 are the main LMW thiols in eukaryotes and prokaryotes. LMW thiols serve as electron donors for thiol-dependent enzymes in redox-mediated metabolic and signaling processes, protect cellular macromolecules from oxidative and xenobiotic stress, and participate in the reduction of oxidative modifications. The level and function of LMW thiols, their oxidized disulfides and mixed disulfide conjugates in cells and tissues is tightly controlled by dedicated oxidoreductases, such as peroxiredoxins, glutaredoxins, disulfide reductases and LMW thiol transferases. This review provides the first summary of the current knowledge of structural and functional diversity of transferases for LMW thiols, including GSH, BSH, MSH and T(SH)2. Their role in maintaining redox homeostasis in single-cell and multicellular organisms is discussed, focusing in particular on the conjugation of specific thiols to exogenous and endogenous electrophiles, or oxidized protein substrates. Advances in the development of new research tools, analytical methodologies, and genetic models for the analysis of known LMW thiol transferases will expand our knowledge and understanding of their function in cell growth and survival under oxidative stress, nutrient deprivation, and during the detoxification of xenobiotics and harmful metabolites. The antioxidant function of CoA has been recently discovered and the breakthrough in defining the identity and functional characteristics of CoA S-transferase(s) is soon expected.
وصف الملف: application/pdf
العلاقة: https://discovery.ucl.ac.uk/id/eprint/10189383/1/Gout_Low-molecular-weight%20thiol%20transferases%20in%20redox%20regulation%20and%20antioxidant%20defence_VoR.pdfTest; https://discovery.ucl.ac.uk/id/eprint/10189383Test/
-
2دورية أكاديمية
المؤلفون: Petrone, Olivia, Serafini, Steven, Yu, Bess Yi Kun, Filonenko, Valeriy, Gout, Ivan, O'Flaherty, Cristian
المصدر: International Journal of Molecular Sciences , 24 (15) , Article 12526. (2023)
مصطلحات موضوعية: Coenzyme A, antioxidants, peroxiredoxins, reactive oxygen species, sperm capacitation, sperm motility, sperm viability, spermatozoa, Humans, Male, Hydrogen Peroxide, Diamide, Semen, Oxidative Stress
الوصف: The spermatozoa have limited antioxidant defences, a high polyunsaturated fatty acids content and the impossibility of synthesizing proteins, thus being susceptible to oxidative stress. High levels of reactive oxygen species (ROS) harm human spermatozoa, promoting oxidative damage to sperm lipids, proteins and DNA, leading to infertility. Coenzyme A (CoA) is a key metabolic integrator in all living cells. Recently, CoA was shown to function as a major cellular antioxidant mediated by a covalent modification of surface-exposed cysteines by CoA (protein CoAlation) under oxidative or metabolic stresses. Here, the profile of protein CoAlation was examined in sperm capacitation and in human spermatozoa treated with different oxidizing agents (hydrogen peroxide, (H2O2), diamide and tert-butyl hydroperoxide (t-BHP). Sperm viability and motility were also investigated. We found that H2O2 and diamide produced the highest levels of protein CoAlation and the greatest reduction of sperm motility without impairing viability. Protein CoAlation levels are regulated by 2-Cys peroxiredoxins (PRDXs). Capacitated spermatozoa showed lower levels of protein CoAlation than non-capacitation cells. This study is the first to demonstrate that PRDXs regulate protein CoAlation, which is part of the antioxidant response of human spermatozoa and participates in the redox regulation associated with sperm capacitation.
وصف الملف: application/pdf
العلاقة: https://discovery.ucl.ac.uk/id/eprint/10175565/1/ijms-24-12526-v3.pdfTest; https://discovery.ucl.ac.uk/id/eprint/10175565Test/
-
3دورية أكاديمية
المؤلفون: Tossounian, Maria-Armineh, Hristov, Stefan Denchev, Semelak, Jonathan Alexis, Yu, Bess Yi Kun, Baczynska, Maria, Zhao, Yuhan, Estrin, Dario Ariel, Trujillo, Madia, Filonenko, Valeriy, Gouge, Jerome, Gout, Ivan
المصدر: International Journal of Molecular Sciences , 24 (11) , Article 9359. (2023)
مصطلحات موضوعية: metastasis suppressor, NME1, coenzyme A, CoAlation, NDPK-A structure, NM23-H1, nucleotide binding, molecular dynamics, X-ray crystallography, protein-metabolite regulation
الوصف: Coenzyme A (CoA) is a key cellular metabolite which participates in diverse metabolic pathways, regulation of gene expression and the antioxidant defense mechanism. Human NME1 (hNME1), which is a moonlighting protein, was identified as a major CoA-binding protein. Biochemical studies showed that hNME1 is regulated by CoA through both covalent and non-covalent binding, which leads to a decrease in the hNME1 nucleoside diphosphate kinase (NDPK) activity. In this study, we expanded the knowledge on previous findings by focusing on the non-covalent mode of CoA binding to the hNME1. With X-ray crystallography, we solved the CoA bound structure of hNME1 (hNME1-CoA) and determined the stabilization interactions CoA forms within the nucleotide-binding site of hNME1. A hydrophobic patch stabilizing the CoA adenine ring, while salt bridges and hydrogen bonds stabilizing the phosphate groups of CoA were observed. With molecular dynamics studies, we extended our structural analysis by characterizing the hNME1-CoA structure and elucidating possible orientations of the pantetheine tail, which is absent in the X-ray structure due to its flexibility. Crystallographic studies suggested the involvement of arginine 58 and threonine 94 in mediating specific interactions with CoA. Site-directed mutagenesis and CoA-based affinity purifications showed that arginine 58 mutation to glutamate (R58E) and threonine 94 mutation to aspartate (T94D) prevent hNME1 from binding to CoA. Overall, our results reveal a unique mode by which hNME1 binds CoA, which differs significantly from that of ADP binding: the α- and β-phosphates of CoA are oriented away from the nucleotide-binding site, while 3′-phosphate faces catalytic histidine 118 (H118). The interactions formed by the CoA adenine ring and phosphate groups contribute to the specific mode of CoA binding to hNME1.
وصف الملف: text
العلاقة: https://discovery.ucl.ac.uk/id/eprint/10171517/1/ijms-24-09359-v3.pdfTest; https://discovery.ucl.ac.uk/id/eprint/10171517Test/
-
4دورية أكاديمية
المؤلفون: Khalil, Mahmoud I, Ismail, Heba M, Panasyuk, Ganna, Bdzhola, Anna, Filonenko, Valeriy, Gout, Ivan, Pardo, Olivier E
المصدر: International Journal of Molecular Sciences , 24 (10) , Article 8806. (2023)
مصطلحات موضوعية: arginine methylation, serine/threonine kinases, AT-hook, methyltransferases, SCLC
الوصف: Ribosomal S6 kinases (S6Ks) are critical regulators of cell growth, homeostasis, and survival, with dysregulation of these kinases found to be associated with various malignancies. While S6K1 has been extensively studied, S6K2 has been neglected despite its clear involvement in cancer progression. Protein arginine methylation is a widespread post-translational modification regulating many biological processes in mammalian cells. Here, we report that p54-S6K2 is asymmetrically dimethylated at Arg-475 and Arg-477, two residues conserved amongst mammalian S6K2s and several AT-hook-containing proteins. We demonstrate that this methylation event results from the association of S6K2 with the methyltransferases PRMT1, PRMT3, and PRMT6 in vitro and in vivo and leads to nuclear the localisation of S6K2 that is essential to the pro-survival effects of this kinase to starvation-induced cell death. Taken together, our findings highlight a novel post-translational modification regulating the function of p54-S6K2 that may be particularly relevant to cancer progression where general Arg-methylation is often elevated.
وصف الملف: application/pdf
العلاقة: https://discovery.ucl.ac.uk/id/eprint/10170940/1/Gout_Asymmetric%20Dimethylation%20of%20Ribosomal%20S6%20Kinase%202%20Regulates%20Its%20Cellular%20Localisation%20and%20Pro-Survival%20Function_VoR.pdfTest; https://discovery.ucl.ac.uk/id/eprint/10170940Test/
-
5دورية أكاديمية
المؤلفون: Tossounian, Maria-Armineh, Baczynska, Maria, Dalton, William, Peak-Chew, Sew Yeu, Undzenas, Kipras, Korza, George, Filonenko, Valeriy, Skehel, Mark, Setlow, Peter, Gout, Ivan
المصدر: Antioxidants , 12 (4) , Article 938. (2023)
مصطلحات موضوعية: coenzyme A, protein CoAlation, protein deCoAlation, mixed disulfide, oxidative stress, Bacillus subtilis, Bacillus megaterium, antioxidant
الوصف: Coenzyme A (CoA) is an important cellular metabolite that is critical for metabolic processes and the regulation of gene expression. Recent discovery of the antioxidant function of CoA has highlighted its protective role that leads to the formation of a mixed disulfide bond with protein cysteines, which is termed protein CoAlation. To date, more than 2000 CoAlated bacterial and mammalian proteins have been identified in cellular responses to oxidative stress, with the majority being involved in metabolic pathways (60%). Studies have shown that protein CoAlation is a widespread post-translational modification which modulates the activity and conformation of the modified proteins. The induction of protein CoAlation by oxidative stress was found to be rapidly reversed after the removal of oxidizing agents from the medium of cultured cells. In this study, we developed an enzyme-linked immunosorbent assay (ELISA)-based deCoAlation assay to detect deCoAlation activity from Bacillus subtilis and Bacillus megaterium lysates. We then used a combination of ELISA-based assay and purification strategies to show that deCoAlation is an enzyme-driven mechanism. Using mass-spectrometry and deCoAlation assays, we identified B. subtilis YtpP (thioredoxin-like protein) and thioredoxin A (TrxA) as enzymes that can remove CoA from different substrates. With mutagenesis studies, we identified YtpP and TrxA catalytic cysteine residues and proposed a possible deCoAlation mechanism for CoAlated MsrA and PRDX5 proteins, which results in the release of both CoA and the reduced form of MsrA or PRDX5. Overall, this paper reveals the deCoAlation activity of YtpP and TrxA and opens doors to future studies on the CoA-mediated redox regulation of CoAlated proteins under various cellular stress conditions.
وصف الملف: text
العلاقة: https://discovery.ucl.ac.uk/id/eprint/10168608/1/antioxidants-12-00938-v2.pdfTest; https://discovery.ucl.ac.uk/id/eprint/10168608Test/
-
6دورية أكاديمية
المؤلفون: Filonenko, Valeriy, Gout, Ivan
المساهمون: Biotechnology and Biological Sciences Research Council, National Academy of Sciences of Ukraine
المصدر: BBA Advances ; volume 3, page 100075 ; ISSN 2667-1603
مصطلحات موضوعية: Biochemistry, Biophysics
الإتاحة: https://doi.org/10.1016/j.bbadva.2023.100075Test
https://api.elsevier.com/content/article/PII:S2667160323000042?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S2667160323000042?httpAccept=text/plainTest -
7دورية أكاديمية
المؤلفون: Tossounian, Maria-Armineh, Baczynska, Maria, Dalton, William, Newell, Charlie, Ma, Yilin, Das, Sayoni, Semelak, Jonathan Alexis, Estrin, Dario Ariel, Filonenko, Valeriy, Trujillo, Madia, Peak-Chew, Sew Yeu, Skehel, Mark, Fraternali, Franca, Orengo, Christine, Gout, Ivan
المصدر: Antioxidants , 11 (7) , Article 1362. (2022)
مصطلحات موضوعية: coenzyme A, CoAlation, thiolation, mixed-disulfide, CoA stabilization interactions, oxidative stress
الوصف: Coenzyme A (CoA) is a key cellular metabolite known for its diverse functions in metabolism and regulation of gene expression. CoA was recently shown to play an important antioxidant role under various cellular stress conditions by forming a disulfide bond with proteins, termed CoAlation. Using anti-CoA antibodies and liquid chromatography tandem mass spectrometry (LC-MS/MS) methodologies, CoAlated proteins were identified from various organisms/tissues/cell-lines under stress conditions. In this study, we integrated currently known CoAlated proteins into mammalian and bacterial datasets (CoAlomes), resulting in a total of 2093 CoAlated proteins (2862 CoAlation sites). Functional classification of these proteins showed that CoAlation is widespread among proteins involved in cellular metabolism, stress response and protein synthesis. Using 35 published CoAlated protein structures, we studied the stabilization interactions of each CoA segment (adenosine diphosphate (ADP) moiety and pantetheine tail) within the microenvironment of the modified cysteines. Alternating polar-non-polar residues, positively charged residues and hydrophobic interactions mainly stabilize the pantetheine tail, phosphate groups and the ADP moiety, respectively. A flexible nature of CoA is observed in examined structures, allowing it to adapt its conformation through interactions with residues surrounding the CoAlation site. Based on these findings, we propose three modes of CoA binding to proteins. Overall, this study summarizes currently available knowledge on CoAlated proteins, their functional distribution and CoA–protein stabilization interactions.
وصف الملف: text
العلاقة: https://discovery.ucl.ac.uk/id/eprint/10152726/1/antioxidants-11-01362-v2.pdfTest; https://discovery.ucl.ac.uk/id/eprint/10152726Test/
-
8دورية أكاديمية
المؤلفون: Tossounian, Maria Armineh, Baczynska, Maria, Dalton, William, Newell, Charlie, Ma, Yilin, Das, Sayoni, Semelak, Jonathan Alexis, Estrin, Dario Ariel, Filonenko, Valeriy, Trujillo, Madia, Peak-Chew, Sew Yeu, Skehel, Mark, Fraternali, Franca, Orengo, Christine, Gout, Ivan
المصدر: Tossounian , M A , Baczynska , M , Dalton , W , Newell , C , Ma , Y , Das , S , Semelak , J A , Estrin , D A , Filonenko , V , Trujillo , M , Peak-Chew , S Y , Skehel , M , Fraternali , F , Orengo , C & Gout , I 2022 , ' Profiling the Site of Protein CoAlation and Coenzyme A Stabilization Interactions ' , Antioxidants , vol. 11 , no. 7 , 1362 . https://doi.org/10.3390/antiox11071362Test
مصطلحات موضوعية: CoA stabilization interactions, CoAlation, coenzyme A, mixed-disulfide, oxidative stress, thiolation
الوصف: Coenzyme A (CoA) is a key cellular metabolite known for its diverse functions in metabolism and regulation of gene expression. CoA was recently shown to play an important antioxidant role under various cellular stress conditions by forming a disulfide bond with proteins, termed CoAlation. Using anti-CoA antibodies and liquid chromatography tandem mass spectrometry (LC-MS/MS) methodologies, CoAlated proteins were identified from various organisms/tissues/cell-lines under stress conditions. In this study, we integrated currently known CoAlated proteins into mammalian and bacterial datasets (CoAlomes), resulting in a total of 2093 CoAlated proteins (2862 CoAlation sites). Functional classification of these proteins showed that CoAlation is widespread among proteins involved in cellular metabolism, stress response and protein synthesis. Using 35 published CoAlated protein structures, we studied the stabilization interactions of each CoA segment (adenosine diphosphate (ADP) moiety and pantetheine tail) within the microenvironment of the modified cysteines. Alternating polar-non-polar residues, positively charged residues and hydrophobic interactions mainly stabilize the pantetheine tail, phosphate groups and the ADP moiety, respectively. A flexible nature of CoA is observed in examined structures, allowing it to adapt its conformation through interactions with residues surrounding the CoAlation site. Based on these findings, we propose three modes of CoA binding to proteins. Overall, this study summarizes currently available knowledge on CoAlated proteins, their functional distribution and CoA–protein stabilization interactions.
الإتاحة: https://doi.org/10.3390/antiox11071362Test
https://kclpure.kcl.ac.uk/portal/en/publications/7409ce86-d2b6-47cc-8e21-0547c1b3dd2fTest
http://www.scopus.com/inward/record.url?scp=85136406853&partnerID=8YFLogxKTest -
9دورية أكاديمية
المؤلفون: Lashley, Tammaryn, Tossounian, Maria Armineh, Costello Heaven, Neve, Wallworth, Samantha, Peak-Chew, Sew, Bradshaw, Aaron, Cooper, J. Mark, de Silva, Rohan, Srai, Surjit Kaila, Malanchuk, Oksana, Filonenko, Valeriy, Koopman, Margreet B., Rüdiger, Stefan G.D., Skehel, Mark, Gout, Ivan
المساهمون: Sub Cellular Protein Chemistry, Cellular Protein Chemistry
مصطلحات موضوعية: Alzheimer’s disease, Coenzyme A, neurodegeneration, oxidative stress, protein CoAlation, tau, Cellular and Molecular Neuroscience
الوصف: Alzheimer’s disease (AD) is a neurodegenerative disorder, accounting for at least two-thirds of dementia cases. A combination of genetic, epigenetic and environmental triggers is widely accepted to be responsible for the onset and development of AD. Accumulating evidence shows that oxidative stress and dysregulation of energy metabolism play an important role in AD pathogenesis, leading to neuronal dysfunction and death. Redox-induced protein modifications have been reported in the brain of AD patients, indicating excessive oxidative damage. Coenzyme A (CoA) is essential for diverse metabolic pathways, regulation of gene expression and biosynthesis of neurotransmitters. Dysregulation of CoA biosynthesis in animal models and inborn mutations in human genes involved in the CoA biosynthetic pathway have been associated with neurodegeneration. Recent studies have uncovered the antioxidant function of CoA, involving covalent protein modification by this cofactor (CoAlation) in cellular response to oxidative or metabolic stress. Protein CoAlation has been shown to both modulate the activity of modified proteins and protect cysteine residues from irreversible overoxidation. In this study, immunohistochemistry analysis with highly specific anti-CoA monoclonal antibody was used to reveal protein CoAlation across numerous neurodegenerative diseases, which appeared particularly frequent in AD. Furthermore, protein CoAlation consistently co-localized with tau-positive neurofibrillary tangles, underpinning one of the key pathological hallmarks of AD. Double immunihistochemical staining with tau and CoA antibodies in AD brain tissue revealed co-localization of the two immunoreactive signals. Further, recombinant 2N3R and 2N4R tau isoforms were found to be CoAlated in vitro and the site of CoAlation mapped by mass spectrometry to conserved cysteine 322, located in the microtubule binding region. We also report the reversible H2O2-induced dimerization of recombinant 2N3R, which is inhibited by CoAlation. Moreover, CoAlation of ...
وصف الملف: application/pdf
-
10دورية أكاديمية
المؤلفون: Gout, Ivan, Halliwell, Barry
المصدر: The Biochemist ; volume 43, issue 2, page 79-79 ; ISSN 0954-982X 1740-1194
مصطلحات موضوعية: General Biochemistry, Genetics and Molecular Biology
الإتاحة: https://doi.org/10.1042/bio_2021_110Test
https://portlandpress.com/biochemist/article-pdf/43/2/79/908002/bio_2021_110.pdfTest
النص الكامل