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Artykuły w czasopismach na temat "Enzymes de modifications N-terminales"
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Pessatti, Tomás, Hernán Terenzi i Jean Bertoldo. "Protein Modifications: From Chemoselective Probes to Novel Biocatalysts". Catalysts 11, nr 12 (30.11.2021): 1466. http://dx.doi.org/10.3390/catal11121466.
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Chemical reactions can be performed to covalently modify specific residues in proteins. When applied to native enzymes, these chemical modifications can greatly expand the available set of building blocks for the development of biocatalysts. Nucleophilic canonical amino acid sidechains are the most readily accessible targets for such endeavors. A rich history of attempts to design enhanced or novel enzymes, from various protein scaffolds, has paved the way for a rapidly developing field with growing scientific, industrial, and biomedical applications. A major challenge is to devise reactions that are compatible with native proteins and can selectively modify specific residues. Cysteine, lysine, N-terminus, and carboxylate residues comprise the most widespread naturally occurring targets for enzyme modifications. In this review, chemical methods for selective modification of enzymes will be discussed, alongside with examples of reported applications. We aim to highlight the potential of such strategies to enhance enzyme function and create novel semisynthetic biocatalysts, as well as provide a perspective in a fast-evolving topic.
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Jarrell, Ken F., Gareth M. Jones, Lina Kandiba, Divya B. Nair i Jerry Eichler. "S-Layer Glycoproteins and Flagellins: Reporters of Archaeal Posttranslational Modifications". Archaea 2010 (2010): 1–13. http://dx.doi.org/10.1155/2010/612948.
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Many archaeal proteins undergo posttranslational modifications. S-layer proteins and flagellins have been used successfully to study a variety of these modifications, including N-linked glycosylation, signal peptide removal and lipid modification. Use of these well-characterized reporter proteins in the genetically tractable model organisms,Haloferax volcanii, Methanococcus voltaeandMethanococcus maripaludis,has allowed dissection of the pathways and characterization of many of the enzymes responsible for these modifications. Such studies have identified archaeal-specific variations in signal peptidase activity not found in the other domains of life, as well as the enzymes responsible for assembly and biosynthesis of novel N-linked glycans. In vitro assays for some of these enzymes have already been developed. N-linked glycosylation is not essential for eitherHfx. volcaniior theMethanococcusspecies, an observation that allowed researchers to analyze the role played by glycosylation in the function of both S-layers and flagellins, by generating mutants possessing these reporters with only partial attached glycans or lacking glycan altogether. In future studies, it will be possible to consider questions related to the heterogeneity associated with given modifications, such as differential or modulated glycosylation.
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Chang, Yie-Hwa. "Impact of Protein Nα-Modifications on Cellular Functions and Human Health". Life 13, nr 7 (24.07.2023): 1613. http://dx.doi.org/10.3390/life13071613.
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Most human proteins are modified by enzymes that act on the α-amino group of a newly synthesized polypeptide. Methionine aminopeptidases can remove the initiator methionine and expose the second amino acid for further modification by enzymes responsible for myristoylation, acetylation, methylation, or other chemical reactions. Specific acetyltransferases can also modify the initiator methionine and sometimes the acetylated methionine can be removed, followed by further modifications. These modifications at the protein N-termini play critical roles in cellular protein localization, protein-protein interaction, protein-DNA interaction, and protein stability. Consequently, the dysregulation of these modifications could significantly change the development and progression status of certain human diseases. The focus of this review is to highlight recent progress in our understanding of the roles of these modifications in regulating protein functions and how these enzymes have been used as potential novel therapeutic targets for various human diseases.
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Sheeran, Freya L., i Salvatore Pepe. "Posttranslational modifications and dysfunction of mitochondrial enzymes in human heart failure". American Journal of Physiology-Endocrinology and Metabolism 311, nr 2 (1.08.2016): E449—E460. http://dx.doi.org/10.1152/ajpendo.00127.2016.
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Deficiency of energy supply is a major complication contributing to the syndrome of heart failure (HF). Because the concurrent activity profile of mitochondrial bioenergetic enzymes has not been studied collectively in human HF, our aim was to examine the mitochondrial enzyme defects in left ventricular myocardium obtained from explanted end-stage failing hearts. Compared with nonfailing donor hearts, activity rates of complexes I and IV and the Krebs cycle enzymes isocitrate dehydrogenase, malate dehydrogenase, and aconitase were lower in HF, as determined spectrophotometrically. However, activity rates of complexes II and III and citrate synthase did not differ significantly between the two groups. Protein expression, determined by Western blotting, did not differ between the groups, implying posttranslational perturbation. In the face of diminished total glutathione and coenzyme Q10levels, oxidative modification was explored as an underlying cause of enzyme dysfunction. Of the three oxidative modifications measured, protein carbonylation was increased significantly by 31% in HF ( P < 0.01; n = 18), whereas levels of 4-hydroxynonenal and protein nitration, although elevated, did not differ. Isolation of complexes I and IV and F1FoATP synthase by immunocapture revealed that proteins containing iron-sulphur or heme redox centers were targets of oxidative modification. Energy deficiency in end-stage failing human left ventricle involves impaired activity of key electron transport chain and Krebs cycle enzymes without altered expression of protein levels. Augmented oxidative modification of crucial enzyme subunit structures implicates dysfunction due to diminished capacity for management of mitochondrial reactive oxygen species, thus contributing further to reduced bioenergetics in human HF.
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Bond, Michelle R., i John A. Hanover. "A little sugar goes a long way: The cell biology of O-GlcNAc". Journal of Cell Biology 208, nr 7 (30.03.2015): 869–80. http://dx.doi.org/10.1083/jcb.201501101.
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Unlike the complex glycans decorating the cell surface, the O-linked β-N-acetyl glucosamine (O-GlcNAc) modification is a simple intracellular Ser/Thr-linked monosaccharide that is important for disease-relevant signaling and enzyme regulation. O-GlcNAcylation requires uridine diphosphate–GlcNAc, a precursor responsive to nutrient status and other environmental cues. Alternative splicing of the genes encoding the O-GlcNAc cycling enzymes O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) yields isoforms targeted to discrete sites in the nucleus, cytoplasm, and mitochondria. OGT and OGA also partner with cellular effectors and act in tandem with other posttranslational modifications. The enzymes of O-GlcNAc cycling act preferentially on intrinsically disordered domains of target proteins impacting transcription, metabolism, apoptosis, organelle biogenesis, and transport.
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Pauli, Cornelius, Michael Kienhöfer, Stefanie Göllner i Carsten Müller-Tidow. "Epitranscriptomic modifications in acute myeloid leukemia: m6A and 2′-O-methylation as targets for novel therapeutic strategies". Biological Chemistry 402, nr 12 (11.10.2021): 1531–46. http://dx.doi.org/10.1515/hsz-2021-0286.
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Abstract Modifications of RNA commonly occur in all species. Multiple enzymes are involved as writers, erasers and readers of these modifications. Many RNA modifications or the respective enzymes are associated with human disease and especially cancer. Currently, the mechanisms how RNA modifications impact on a large number of intracellular processes are emerging and knowledge about the pathogenetic role of RNA modifications increases. In Acute Myeloid Leukemia (AML), the N 6-methyladenosine (m6A) modification has emerged as an important modulator of leukemogenesis. The writer proteins METTL3 and METTL14 are both involved in AML pathogenesis and might be suitable therapeutic targets. Recently, close links between 2′-O-methylation (2′-O-me) of ribosomal RNA and leukemogenesis were discovered. The AML1-ETO oncofusion protein which specifically occurs in a subset of AML was found to depend on induction of snoRNAs and 2′-O-me for leukemogenesis. Also, NPM1, an important tumor suppressor in AML, was associated with altered snoRNAs and 2′-O-me. These findings point toward novel pathogenetic mechanisms and potential therapeutic interventions. The current knowledge and the implications are the topic of this review.
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Xiang, Meiyi, Wensu Liu, Wei Tian, Abin You i Dajun Deng. "RNA N-6-methyladenosine enzymes and resistance of cancer cells to chemotherapy and radiotherapy". Epigenomics 12, nr 9 (maj 2020): 801–9. http://dx.doi.org/10.2217/epi-2019-0358.
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Aim: As one of the early adaptive mechanisms by which cells respond to environmental changes, RNA modification appears to be a very promising target for cancer treatment. Results: RNA modifications are currently a hot topic in epigenetic research. Emerging experimental studies show that expression alterations of multiple m6A enzymes, including demethylase FTO, methyltransferase METTL3 and WTAP, mediate the development of resistance of cancer cells to various treatments. A set of small molecular chemical drugs targeted to these m6A enzymes are under development. Intervention of RNA m6A methylation is a possible therapeutic strategy to overcome drug resistance. Conclusions: RNA m6A methylation may play a crucial role in drug resistance development and intervention in cancer cells.
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van den Homberg, Daphne A. L., Reginald V. C. T. van der Kwast, Paul H. A. Quax i A. Yaël Nossent. "N-6-Methyladenosine in Vasoactive microRNAs during Hypoxia; A Novel Role for METTL4". International Journal of Molecular Sciences 23, nr 3 (19.01.2022): 1057. http://dx.doi.org/10.3390/ijms23031057.
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N-6-methyladenosine (m6A) is the most prevalent post-transcriptional RNA modification in eukaryotic cells. The modification is reversible and can be dynamically regulated by writer and eraser enzymes. Alteration in the levels of these enzymes can lead to changes in mRNA stability, alternative splicing or microRNA processing, depending on the m6A-binding proteins. Dynamic regulation of mRNA m6A methylation after ischemia and hypoxia influences mRNA stability, alternative splicing and translation, contributing to heart failure. In this study, we studied vasoactive microRNA m6A methylation in fibroblasts and examined the effect of hypoxia on microRNAs methylation using m6A immunoprecipitation. Of the 19 microRNAs investigated, at least 16 contained m6A in both primary human fibroblasts and a human fibroblast cell line, suggesting vasoactive microRNAs are commonly m6A methylated in fibroblasts. More importantly, we found that mature microRNA m6A levels increased upon subjecting cells to hypoxia. By silencing different m6A writer and eraser enzymes followed by m6A immunoprecipitation, we identified METTL4, an snRNA m6A methyltransferase, to be predominantly responsible for the increase in m6A modification. Moreover, by using m6A-methylated microRNA mimics, we found that microRNA m6A directly affects downstream target mRNA repression efficacy. Our findings highlight the regulatory potential of the emerging field of microRNA modifications.
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Roll-Mecak, Antonina, Agnieszka Szyk i Vasilisa Kormendi. "Microtubule chemical complexity: mechanism of tubulin modification enzymes". Acta Crystallographica Section A Foundations and Advances 70, a1 (5.08.2014): C1286. http://dx.doi.org/10.1107/s2053273314087130.
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Tubulin is subject to an abundant and diverse set of post-translational modifications that include phosphorylation, acetylation, poly-glutamylation, poly-glycylation and tyrosination. The highest density and variety of post-translational modifications are found in especially complex microtubule arrays like those of neurons or cilia. Not surprisingly, tubulin modification enzymes have been linked to human diseases including cancers and neurodegenerative disorders. I will present recent data from my lab on the mechanism of action of two tubulin modification enzymes that illustrate two divergent paradigms of tubulin recognition. Tubulin tyrosine ligase (TTL) adds a C-terminal Tyr to the exposed C-terminus of alpha-tubulin as part of a tyrosination/detyrosination cycle present in most eukaryotic cells. We solved the first crystal structure of tubulin tyrosine ligase that revealed how the TTL scaffold supported the expansion of the repertory of tubulin post-translational modification enzymes of the TTL like family that recognize either alpha- or beta-tubulin C-terminal tails. In addition to modifying tubulin, TTL also prevents tubulin from incorporating into microtubules by recognizing a tubulin dimer interface that would otherwise be involved in microtubule lattice interactions. I will also present recent work from my group on the structure and mechanism of action of tubulin acetyltransferase (TAT). TAT acetylates Lys-40 on alpha-tubulin in the microtubule lumen. We solved the 2.7Å structure of TAT bound to its ac-coA substrate as well as the 2.45Å structure of a catalytic inactive TAT mutant that reveals a domain swapped dimer in which the functionally essential N-terminus shows evidence of unprecedented structural plasticity. Implications for catalysis and microtubule stimulation of TAT activity will be discussed.
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Souza, G. M., D. P. Mehta, M. Lammertz, J. Rodriguez-Paris, R. Wu, J. A. Cardelli i H. H. Freeze. "Dictyostelium lysosomal proteins with different sugar modifications sort to functionally distinct compartments". Journal of Cell Science 110, nr 18 (15.09.1997): 2239–48. http://dx.doi.org/10.1242/jcs.110.18.2239.
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Many Dictyostelium lysosomal enzymes contain mannose-6-phosphate (Man-6-P) in their N-linked oligosaccharide chains. We have now characterized a new group of lysosomal proteins that contain N-acetylglucosamine-1-phosphate (GlcNAc-1-P) linked to serine residues. GlcNAc-1-P-containing proteins, which include papain-like cysteine proteinases, cofractionate with the lysosomal markers and are in functional vesicles of the endosomal/lysosomal pathway. Immunoblots probed with reagents specific for each carbohydrate modification indicate that the lysosomal proteins are modified either by Man-6-P or GlcNAc-1-P, but not by both. Confocal microscopy shows that the two sets of proteins reside in physically and functionally distinct compartments. Vesicles with GlcNAc-1-P fuse with nascent bacteria-loaded phagosomes less than 3 minutes after ingestion, while those with Man-6-P do not participate in bacterial digestion until about 15 minutes after phagocytosis. Even though both types of vesicles fuse with phagosomes, GlcNAc-1-P- and Man-6-P-bearing proteins rarely colocalize. Since both lysosomal enzymes and their bound carbohydrate modifications are stable in lysosomes, a targeting or retrieval mechanism based on these carbohydrate modifications probably establishes and/or maintains segregation.
Rozprawy doktorskie na temat "Enzymes de modifications N-terminales"
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El, Barbry Houssam. "Découverte du rôle crucial du résidu en position 2 des séquences MTS d’adressage mitochondrial". Electronic Thesis or Diss., Sorbonne université, 2023. http://www.theses.fr/2023SORUS035.
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Les mitochondries sont des organites complexes impliquant un millier de protéines, la plupart codées dans le génome nucléaire. Leur biogenèse a nécessité au cours de l’évolution la mise en place de systèmes efficaces d’adressage et d’import protéique, et des défaillances de ces systèmes sont associées à des pathologies graves, neuropathies, troubles cardiovasculaires, myopathies, maladies neurodégénératives ainsi que cancers. De nombreuses protéines mitochondriales possèdent en N-terminal une séquence d’adressage appelée MTS (Mitochondrial Targeting sequence) qui forme une hélice alpha amphiphile essentielle pour leur import mitochondrial. La séquence des divers MTSs est néanmoins très variables et leur caractéristiques critiques ne sont pas encore bien comprises. Le point de départ de ma thèse est la découverte, chez les levures, d’une surreprésentation en position 2 des séquences MTSs de 4 acides aminés hydrophobes (F, L, I, W). Au cours de mes années de thèse, j’ai pu confirmer, par des expériences de mutagenèse dirigée, le rôle critique de la nature du résidu en position 2 des MTSs. En effet, grâce au développement d’un système novateur de criblage des défauts d’import basé sur le sauvetage fonctionnel de la toxicité d’une protéine mitochondriale, j’ai pu observer que seuls les résidus surreprésentés en position 2 des protéines mitochondriales permettaient un import efficace. Mon travail a ainsi démontré l'existence de fortes contraintes évolutives s’exerçant au niveau de la position 2 des MTSs dont la compréhension pourrait à terme être utile pour optimiser l’adressage mitochondrial de protéines thérapeutiques chez des patients atteints de maladies mitochondrialesMitochondria are complex organelles involving a thousand proteins, most of which are encoded in the nuclear genome. Their biogenesis has required the evolutionary development of efficient protein addressing and import systems, and failures of these systems are associated with serious pathologies, neuropathies, cardiovascular disorders, myopathies, neurodegenerative diseases and cancers.Many mitochondrial proteins have an N-terminal addressing sequence called MTS (Mitochondrial Targeting Sequence) which forms an amphiphilic alpha helix essential for their mitochondrial import. However, the sequence of the various MTSs is highly variable and their critical characteristics are not yet well understood. The starting point of my thesis was the discovery in yeast of an overrepresentation of 4 hydrophobic amino acids (F, L, I, W) at position 2 of the MTSs sequences. During my thesis, I was able to confirm the critical role of the nature of the residue in position 2 of the MTSs through directed mutagenesis experiments. Indeed, thanks to the development of an innovative system for screening import defects based on the functional rescue of the toxicity of a mitochondrial protein, I was able to observe that only residues overrepresented at position 2 of mitochondrial proteins allowed efficient import. My work has thus demonstrated the existence of strong evolutionary constraints at position 2 of MTSs, the understanding of which could ultimately be useful for optimising the mitochondrial addressing of therapeutic proteins in patients suffering from mitochondrial diseases
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Martinez, Aude. "Modifications N-terminales des protéines : approche multi-échelles et signification biologique". Paris 11, 2010. http://www.theses.fr/2010PA112081.
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Les modifications co- et post-traductionnelles affectant le N-terminal des protéines, conditionnent fortement leur capacité à réaliser leur activité biologique. Quatre modifications de ce type sont au centre de ce projet. : l’excision de la première méthionine des protéines (NME), la N-myristoylation (MYR), la N--acétylation (NAA) et la S-palmitoylation. Dans un premier temps l’exploitation de données expérimentales couvrant différents organismes et différents Règnes a permis d’élaborer des motifs de prédiction de la NME et la NAA. En parallèle, des analyses expérimentales concernant la MYR ont été menées avec deux NMTs d’origine animale et végétale sur un jeu de 288 peptides modèles. Environ 30% de ces peptides sont potentiellement positifs à la MYR. Mes données indiquent des différences de spécificité de substrat entre ces deux enzymes. Ces données n’ont pas permis d’aboutir à une prédiction plus fine de la MYR que celle utilisant des motifs. Enfin, des observations de l’impact de certains de ces peptides sur la localisation subcellulaire de la GFP, ont été effectuées. Ces analyses confirment que la MYR de la plupart des peptides efficacement modifiés in vitro se concrétise par une localisation à membrane de la protéine in vivo. Cette étude conforte mon approche in vitro et permet de mieux cerner les seuils relatifs à la capacité de telle ou telle protéine de subir ou non la MYR. L’ensemble de ces études de spécificité des quatre familles d’enzymes m’a permis d’élaborer une plateforme de prédiction : TermiNator (http://www. Isv. Cnrs-gif. Fr/terminator3/) permettant à tout protéome d’e��tre annoté aisément pour chacune de ces quatre modifications N-terminalesCo- and post-translational modifications strongly affect proteins final functionality. Among those, the most frequents are early modifications affecting the N-terminus of the protein. This work deals with four such : N-terminal methionine excision (NME), N-myristoylation (MYR), N--acetylation (NAA) and S-palmitoylation. On one side, my work consisted in managing some experimental data for different organisms coming from different kingdoms and elaborating predictive patterns for NME and NAA. On the other side, I performed experiments about MYR with two NMTs originating from the animal and plant kingdom on a 288 peptides set expected to sample the proteome diversity. About 30% were identified as potential MYR substrates. My data reveal specificity differences between the two enzymes. In the end, it was not possible to elaborate a more accurate predictive motif than the one already elaborated. In order to complete this work, I investigated the MYR impact on the subcellular localisation of some of those peptides. It could confirm that efficient MYR as evidenced in vitro induce in vivo localisation of the the protein in the membranes. Those in vivo results reinforce the significance of our in vitro analyse and help understanding myristoylation status of our different peptides. Specificity features of each of those modifications were used to elaborate the predictive platform TermiNator (http://www. Isv. Cnrs-gif. Fr/terminator3/). TermiNator is available for all the scientist community. Any proteome can be annotated for those four N-terminal modifications with this unique tool
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Boisson, Bertrand. "Caractérisation et fonction de la N-myristoylation du protéome d'Arabidopsis thaliana". Paris 6, 2003. http://www.theses.fr/2003PA066367.
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Ayoub, Daniel. "Vers une étude approfondie des protéomes : caractérisation des extrémités N-terminales des protéines". Phd thesis, Université de Strasbourg, 2012. http://tel.archives-ouvertes.fr/tel-00855301.
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Dans ce travail de thèse, nous avons développé et optimisé une stratégie originale pour la caractérisation des extrémités N-terminales des protéines et des sites de clivages protéolytiques. Elle s'appuie sur la dérivation chimique spécifique des amines N-terminales et nous l'avons adapté à différents types d'échantillons biologiques. L'application de cette stratégie dans des études en biologie nous a permis d'apporter plusieurs éléments de réponse à différentes problématiques. Nous avons ainsi caractérisé les peptides de transit des protéines mitochondriales humaines et ainsi validé/corrigé expérimentalement leurs prédictions dans les banques de données. Nous avons aussi appliqué cette stratégie à l'étude du protéome du parasite P. falciparum. La mise au point de la dérivation N-terminale de protéines immobilisées dans un gel SDS PAGE nous a permis d'étudier le mécanisme d'export des protéines de ce parasite vers sa cellule hôte et de déterminer le rôle des acides aminés impliqués dans cet export. Un réactif de dérivation marqué aux isotopes stables permet d'effectuer des études différentielles des processus protéolytiques que subissent les protéines. Cette stratégie quantitative a été appliquée à l'étude du protéome hépatique du rat soumis au jeûne expérimental. D'autres applications de l'analyse protéomique en biologie sont aussi présentées dans ce manuscrit.
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Sunde, Margaret. "N-terminal modification of S-adenosylmethionine decarboxylase". Thesis, University of Cambridge, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.318198.
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Dedieu, Alain. "Exploration des modifications post-traductionnelles des protéines : nouvelles approches et nouveaux modèles biologiques". Thesis, Montpellier 1, 2014. http://www.theses.fr/2014MON13516/document.
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L'étude des modifications post-traductionnelles a connu au cours des dernières années un regain d'intérêt notable. Tout d'abord car elle s'effectue aujourd'hui au travers d'approches basées sur la spectrométrie de masse, technique qui pendant cette période a connu de profonds bouleversements, conduisant à des études plus aisées et systématiques.Mais aussi car tant par leur variété que par le rôle qu'elles jouent dans la vie et la régulation cellulaire, ces modifications ne peuvent plus être négligées. Par ailleurs au cours de ces quinze dernières années, nous avons assisté concernant les procaryotes à un changement total de paradigme. En effet à la fin des années 90, l'idée dominante était que ces modifications pouvaient exister chez ceux-ci mais de façon très partielle et/ou très particulière.Dans ce travail, les divers degrés d'iodation de la tyrosine ont été sondés par une approche de type «shotgun » sur un organe entier, la thyroïde de souris. L'efficacité de ce type d'approche démontrée, les modifications post-traductionnelles potentiellement présentes dans des organismes modèles radiorésistants, la bactérie Deinococcus deserti et l'archée Thermococcus gammatolerans ont été analysées. Dans le premier cas, les données de protéomique montrent que de nombreuses acétylations N-terminales portent sur un motif spécifique (essentiellement des thréonines et sérines), cas très atypique pour une bactérie. Chez Thermococcus gammatolerans les acétylations N-terminales sont rares, mais la présence d'acétylations sur les chaînes latérales des lysines est notable. La présence de phosphorylations sur ces mêmes protéines, laisse entrevoir un possible phénomène de « cross talk » entre les lysines acétylées et les sérines et/ou thréonines phosphorylées.Ici, nous démontrons que la complexité du protéome chez les procaryotes par le biais des MPT est bien réelle et que de possibles interdépendances entre MPT mériteraient un regard nouveauRecently, the study of post-translational modifications has greatly evolved, mainly because of crucial progresses in mass spectrometry methodology which have allowed high-throughput, high resolution analysis. Their variety and their role in the regulation of key molecular mechanisms are increasingly documented. In this work, the different degrees of iodination of tyrosine were probed with a "shotgun" approach carried out from an entire organ, the mice thyroid. Post-translational modifications present in two radioresistant organism models, the bacterium Deinococcus deserti and the archaeon Thermococcus gammatolerans, were analyzed. The large scale exploration of N-terminal acetylation in D. deserti indicates a specific pattern of this modification on serine and threonine, as well as an atypical, high propension to acetylation with 50% of modified N-termini. In T. gammatolerans, N-terminal acetylation is rare, but the presence of acetylation on lysine side chains is significant. The presence of phosphorylation on these proteins suggests a potential "cross talk" between the acetylated lysine and phosphorylated serine or threonine residues. This work demonstrates that the complexity of the proteome in prokaryotes through post-translational modifications is higher than expected when extremophiles are scrutinized compared to classical prokaryote models. Interdependencies between post-translational modifications definitively deserve a fresher look
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Kshetri, Man B. "N-TERMINAL DOMAIN OF rRNA METHYLTRANSFERASE ENZYME RsmC IS IMPORTANT FOR ITS BINDING TO RNA AND RNA CHAPERON ACTIVITY". Kent State University Honors College / OhioLINK, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=ksuhonors1621007414429417.
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Yamamoto, Keisuke. "Modification and application of glycosidases to create homogeneous glycoconjugates". Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:59d1917c-345d-4fe3-ace4-67dd3c8bc017.
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In the post-genomic era, recognition of the importance of sugars is increasing in biological research. For the precise analysis of their functions, homogeneous materials are required. Chemical synthesis is a powerful tool for preparation of homogeneous oligosaccharides and glycoconjugates. Glycosidases are potent catalysts for this purpose because they realize high stereo- and regio- selectivities under conditions benign to biomolecules without repetitive protection/deprotection procedures. A glycosynthase is an aritificial enzyme which is derived from a glycosidase and is devised for glycosylation reaction. To suppress the mechanistically inherent oligomerization side reaction of this class of biocatalysts, a glycosidase with plastic substrate recognition was engineered to afford the first α-mannosynthase. This novel biocatalyst showed low occurrence of oligomerized products as designed and was applied to prepare a wide range of oligosaccharides. Glycosidases are also valuable tools for glycan engineering of glycoconjugates, which is a pivotal issue in the development of pharmaceutical agents, including immunoglobulin G (IgG)-based drugs. EndoS, an endo-β-N-acetylglucosaminidase from Streptococcus pyogenes, natively cleaves N-glycans on IgG specifically. When the latent glycosylation activity of this enzyme was applied, the N-glycan remodelling of full-length IgG was successfully achieved for the first time and a highly pure glycoform was obtained using the chemically synthesized oxazoline tetrasaccharide as glycosyl donor. This biocatalytic reaction allows development of a novel type of antibody-drug conjugates (ADCs) in which drug molecules are linked to N-glycans site-specifically. For this purpose, glycans with bioorthogonal reaction handles were synthesized and conjugated to IgG. A model reaction using a dye compound as reaction partner worked successfully and the synthetic method for this newly designed ADC was validated. Glycan trimming of glycoproteins expressed from Pichia pastoris was performed using exoglycosidases to derive homogeneous glycoform. Jack Bean α-mannosidase (JBM) trimmed native N-glycans down to the core trisaccharide structure but some of the glycoforms were discovered to be resistant to the JBM activity. Enzymatic analyses using exoglycosidases suggested that the JBM-resistant factor was likely to be β-mannoside. In summary, this work advanced application of modified glycosidases for preparation of oligosaccharides and also demonstrated biocatalytic utility of glycosidases to produce biologically relevant glycoconjugates with homogeneous glycoforms.
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Walbott, Hélène. "Etude biochimique et structurale de deux pyrimidine-c5 méthyltransférases des arn de transfert". Paris 11, 2007. http://www.theses.fr/2007PA112159.
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Dans la cellule, l’ARNt est une molécule-clé de la traduction génétique. Pour être fonctionnel, il doit subir différentes étapes de maturation post-transcriptionnelle, au cours desquelles certains de ses nucléotides sont modifiés chimiquement grâce à des enzymes dites de modification. Mon sujet de thèse a porté sur l’étude biochimique et structurale de deux pyrimidine-C5 méthyltransférases (MTases) des ARNt. Une première partie de mon travail a consisté en la caractérisation biochimique de la cytosine-C5 MTase de S. Cerevisiae, Trm4. L’analyse de son mécanisme catalytique et de son organisation modulaire a ainsi été réalisée. Une seconde partie de mon travail a contribué à l’identification de la m5U54 MTase d’ARNt de P. Abyssi, PabTrmU54, et a conduit à la résolution de sa structure tridimensionnelle en complexe avec la S-adénosyl-L-homocystéine, par cristallographie aux rayons X. L’ensemble de ces résultats a permis d’améliorer nos connaissances sur le mode de reconnaissance spécifique du substrat ARN par les enzymes de modificationIn the cell, tRNA is a key molecule of genetic translation. To become functional, it undergoes different steps of post-transcriptional maturation. During this process, some of its nucleosides are chemically modified by modification enzymes. My thesis project focused on the biochemical and structural study of two tRNA C5-pyrimidine methyltransferases (MTases). The first part of my work consisted in the biochemical characterization of the S. Cerevisiae C5-cytosine MTase, Trm4. The analysis of its catalytic mechanism and of its modular organization was then realized. The second part of my work contributed to the identification of the P. Abyssi tRNA m5U54 MTase, PabTrmU54, and led to the resolution of its crystal structure in complex with S-adenosyl-L-homocysteine, by X-ray crystallography. Finally, all these results participated in the improvement of our knowledge about the specific mode of RNA recognition by modification enzymes
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Piontek, Alexander. "Deciphering the Catalytic Mechanism of the Zn Enzyme Glutaminyl Cyclase and the Deduction of Transition-State Analog Inhibitors". Doctoral thesis, 2014. http://hdl.handle.net/11858/00-1735-0000-0022-605A-C.
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Pawar, Shubhangi H., Vishal S. Gulecha, Manoj S. Mahajan, Aman B. Upaganiawar i Chandrashekhar D. Upasani. "Cellular Cysteine Network and Neurodegeneration". W Quality Control of Cellular Protein in Neurodegenerative Disorders, 303–25. IGI Global, 2020. http://dx.doi.org/10.4018/978-1-7998-1317-0.ch012.
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Oxidative stress is strongly linked to neurodegeneration and oxidative species can modify many amino acids and proteins in the brain. Cysteine amino acid is most susceptible to oxidative post-translational modifications (PTMs). Reversible or irreversible cysteine PTMs can cause dyshomeostasis, which further continued to cellular damage. Many cysteine dependent proteins and many non-proteins using cysteine as their structural components are affected by oxidative stress. Several cysteine dependent enzymes are acting as antioxidants. Cysteine is a major contributor to glutathione (GSH) and superoxide dismutase (SOD) synthesis. Cysteine precursor N-acetylcysteine (NAC) supplementation is proven as a potent free radical scavenger and increase brain antioxidants and subsequently potentiates the natural antioxidant cellular defense mechanism. Thus, in this chapter, the authors explore the linkage of cellular cysteine networks and neurodegenerative disorders.
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Stenitzer, David, i Friedrich Altmann. "Protein Glycosylation in Bryophytes Differs Subtly from That in Vascular Plants". W Bryophytes - The State of Knowledge in a World Under Climate Change [Working Title]. IntechOpen, 2022. http://dx.doi.org/10.5772/intechopen.107035.
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Glycosylation substantially contributes to the physicochemical properties of proteins, and hence also cell walls. Moreover, they are key factors for the recognition of free or cell-bound glycoproteins by internal and external interaction partners. Green plants get by with a highly conserved, limited number of modifications of the pan-eukaryotic basic N-glycan structure. In detail, these are fucosylation of the innermost N-acetylglucosamine residue in 3-position, which renders plant glycoproteins immunogenic to mammals; xylosylation of the branching mannose; frequent occurrence of small N-glycans terminating with mannose or decoration of the antennae with Lewis A determinants. Bryophytes share all these features, but some mosses additionally display two peculiarities not seen in vascular plants. Many mosses exhibit 2,6-di-O-methylated mannose on the 6-arm and some mosses contain modified Lewis A termini with an as yet unspecified methyl pentose. Neither the responsible enzymes nor the function of these novel glycan features is currently known. Targeted glycoengineering of the moss Physcomitrella patens (Hedw.) Bruch & Schimp can allow the production of biopharmaceutical glycoproteins that are difficult to express in more established systems.
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Naegeli, Hanspeter. "Enzyinology of huinan nucleotide excision repair". W DNA Recombination and Repair, 99–137. Oxford University PressOxford, 1999. http://dx.doi.org/10.1093/oso/9780199637072.003.0005.
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Abstract Damaged bases are eliminated from human genomes by two completely different excision mechanisms: repair by base excision and repair by nucleotide excision. Base excision involves the hydrolysis of N-glycosidic bonds and is restricted to a rather narrow range of defective or inappropriate DNA constituents (1, 2). Nucleotide excision repair (NER), on the other hand, proceeds through dual endonucleolytic cleavage of damaged strands and is capable of removing a nearly infinite variety of base lesions with little regard for the modification itself. The extraordinary substrate versatility of NER is necessary to cope with bulky (helix distorting) injuries to DNA that arise mainly from exposure to UV radiation and chemical carcinogens (3-6). NER is, in fact, the sole mechanism for the error-free removal of bulky DNA adducts in human cells and, as a consequence, provides a key line of defence against such genotoxic adversities. In addition, NER displays a backup role for the repair of apurinic-apyrimidinic (AP) sites, thymine glycol, 8-hydroxyguanine, O6-methylguanine, and similar non-bulky base lesions that are normally processed by more specific repair enzymes, primarily AP endonucleases, DNA glycosylases, or O6- methylguanine-DNA methyltransferase (7, 8). To exert these multiple DNA repair functions, human NER lacks selectivity for a particular type of damage, i.e. a limited number of gene products accommodates and processes a large repertoire of unrelated base modifications while ignoring the normal conformational fluctuations of undamaged DNA. This flexibility is achieved by means of a repair strategy that avoids the direct processing of modified deoxyribonucleotide residues, but, instead, operates exclusively on unmodified segments of native DNA around each lesion site.
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Matabaro, Emmanuel, Haigang Song, Clara Chepkirui, Hannelore Kaspar, Luca Witte, James H. Naismith, Michael F. Freeman i Markus Künzler. "Enzyme-mediated backbone N-methylation in ribosomally encoded peptides". W Synthetic and Enzymatic Modifications of the Peptide Backbone, 429–58. Elsevier, 2021. http://dx.doi.org/10.1016/bs.mie.2021.04.014.
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Kirschke, Heidrun, Alan J. Barrett i Neil D. Rawlings. "Reaction with inhibitors". W Lysosmal Cysteine Proteases, 48–56. Oxford University PressOxford, 1998. http://dx.doi.org/10.1093/oso/9780198502494.003.0011.
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Abstract Cysteine proteinases contain a highly reactive cysteine residue in their active centre. They react readily with many thiol-blocking reagents, such as Hg2+ derivates, disulfides, heavy metal ions, iodoacetate and N-ethylmaleimide. To achieve a more selective reaction with the enzymes rather than with SH-containing compounds generally, several peptidyl derivatives can be used. Compounds of this type can show selectivity amongst the cysteine proteinases. As will be shown in this section, nearly all of the synthesized cysteine proteinase inhibitors react (in some cases very weakly) with serine proteinases, with the exception of the epoxysuccinyl peptides. Selectivity amongst the individual cysteine proteinases has been obtained by variation of the peptidyl portion of the inhibitors, and in some cases (peptidyl-O-acyl hydroxamates and peptidyl-(acyloxy)methanes) also by modification of the leaving group.
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Pennings, Sari, Timothy E. O’Neill, Geert Meersseman, i E. Morton Bradbury. "Nucleosomes: dynamic repressors of transcription". W Nuclear Organization, Chromatin Structure, and Gene Expression, 3–18. Oxford University PressOxford, 1997. http://dx.doi.org/10.1093/oso/9780198549239.003.0001.
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Abstract The structure of the nucleosome, which was elucidated from early work on enzyme digestion patterns, neutron scatter, X-ray diffraction data, and histone— DNA crosslinking (reviewed by Van Bolde 1988), is essentially a static picture of an average structure. This is because these experimental approaches average out the heterogeneities across the largely native bulk nucleosome and chromatin samples, as well as any fluctuations in the structure over time. Most notably, the model of the nucleosome rarely includes the long N-terminal and short C-terminal ‘tails’ of the histones, which are highly dynamic and contain the sites of reversible chemical modifications associated with chromatin functions (reviewed by Bradbury 1992; also see Chapter 3). Studies of higher order structures of chromatin also hold this caveat and here the paucity of data allows for several models of the 30 nm fibril model (reviewed by Van Bolde 1988). However useful these structural models arc in understanding the packaging of chromatin, they fail to convey how chromatin structure can be flexible enough not only to accommodate the wide range of DNA sequences in the genome, but also to allow dynamic processes such as transcription and replication to take place. An insight into the dynamic nature of chromatin is essential in order to understand how chromatin can be a functional component of the active eukaryotic nucleus.
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Fields, Gregg B., i Janelle L. Lauer-Fields. "Principles and Practice of Solid-Phase Peptide Synthesis". W Synthetic Peptides. Oxford University Press, 2002. http://dx.doi.org/10.1093/oso/9780195132618.003.0006.
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Peptides play key structural and functional roles in biochemistry, pharmacology, and neurobiology, and are important probes for research in enzymology, immunology, and molecular biology. The amino acid building blocks can be among the 20 genetically encoded L-residues, or else unusual ones, and the sequences can be linear, cyclic, or branched. It follows that rapid, efficient, and reliable methodology for the chemical synthesis of these molecules is of utmost interest. A number of synthetic peptides are significant commercial or pharmaceutical products, ranging from the sweet dipeptide L-Asp-L-Phe-OMe (aspartame) to clinically used hormones such as oxytocin, adrenocorticotropic hormone, calcitonin, and gonadotropin releasing hormone (GnRH) super-agonists. Synthesis can lead to potent and selective new drugs by judicious substitutions that change functional groups and/or conformations of the parent peptide. These include introduction of N- or C-alkyl substituents, unnatural or D-amino acids, side-chain modifications including sulfate or phosphate groups or carbohydrate moieties, and constraints such as disulfide bridges between half-cystines or side-chain lactams between Lys and Asp or Glu. Commercially important products that evolved from such studies include protease inhibitors, such as captopril and other angiotensin converting enzyme (ACE) inhibitors, peptidomimetic HIV protease inhibitors, and the somatostatin analog lanreotide. Most of the biologically or medicinally important peptides which are the targets for useful structure-function studies by chemical synthesis comprise under 50 amino acid residues, but occasionally a synthetic approach can lead to important conclusions about small proteins (full or domains) in the 100-200 residue size range. Methods for synthesizing peptides are divided conveniently into two categories: solution (classical) and solid-phase pep tide synthesis (SPPS). The classical methods have evolved since the beginning of the twentieth century, and they are described amply in several reviews and books (Wünsch, 1974; Finn and Hofmann, 1976; Bodanszky and Bodanszky, 1984; Goodman et al, 2001). The solid-phase alternative was conceived and elaborated by R. B. Merrifield beginning in 1959, and has also been covered comprehensively (Erickson and Merrifield, 1976; Birr, 1978; Barany and Merrifield, 1979; Stewart and Young, 1984; Merrifield, 1986; Barany et al., 1987, 1988; Kent, 1988; Atherton and Sheppard, 1989; Fields and Noble, 1990; Barany and Albericio, 1991; Fields et al., 1992; Gutte, 1995; Fields, 1997; Lloyd-Williams et al., 1997; Chan and White, 2000; Kates and Albericio, 2000).
Streszczenia konferencji na temat "Enzymes de modifications N-terminales"
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Hopmeier, P., M. Halbmayer, H. P. Schwarz, F. Heuss i M. Fischer. "PROTEIN C AND PROTEIN S IN MILD AND MODERATE PREECLAMPSIA". W XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644285.
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In normal pregnancy, total protein S antigen and activity have been reported to be markedly reduced, whereas protein C level was found unaltered. In contrast, in severe preeclampsia protein C antigen was found to be considerably reduced. The presentstudy was done to clarify whether similar changes in protein Cwould alsobe observed for the mildand moderatepreeclamptic state andwhether there would be any effects on the level ofprotein S, since nodata on this cofactor in preeclampsia have been reported to date. 4-0 women in the 3rd trimester of pregnancy - 20 with uncomplicated pregnancies and 20 who had developed a mild (n = 14-) or moderate (n = 6) preeclamptic condition - were included in the study. All groups were well matched in age and gestational age. In addition, 20 healthynon-pregnant women served as controls. All probands had normal liver (SGOT, SGPT) and kidney (BUN, creatinine) values and no other medication than oral vitamins was used. Classification of preeclampsia was done according to a modification of the gestosis index of Goecke using an 11 gradeindex system (0 - 11). ProteinC antigen was measured by an enzyme-linkedimmunosorbent assay and protein S by the Laurell rocket technique.For statistics, the Wilcoxon rank sum test was appliedWe conclude that in comparison tonormal pregnancies, protein S is found elevated at least in the moderate, and protein C in the moderateas well as in the mild preeclamptic state
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Schapira, M., B. Waeber, H. R. Brunner, R. Crystal i M. Courtney. "PROTECTION BY α1-ANTITRYPSIN ALA-357 ARG-358 AGAINST ARTERIAL HYPOTENSION INDUCED BY FACTOR XII FRAGMENT". W XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1642801.
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The specificity of serine protease inhibitors belonging to the serpin superfamily depends on the nature of the reactive center amino acid residues. For example, Met→Arg mutation at the reactive center P1 residue (position 358) alters the specificity of α1-antitrypsin (AT) from the Met-specific enzyme neutrophil elastase to the Arg-specific proteases thrombin, plasma kallikrein (K) and activated Factor XII fragment (XIIf). To obtain an inhibitor species which would inhibit K and XIIf but not thrombin, we now have produced by site-directed mutagenesis of cloned AT cDNA an AT variant having Arg at P1 and Ala at P2. This modification at P2 was made because C1-inhibitor, the major inhibitor of K and XIIf, also has Ala at P2. In purified systems, AT Ala-357 Arg-358 inactivated thrombin, K and XIIf with 2nd-order rate constants of 1.1, 21.8 and 0.6 μM-1 min-1 whereas values of 8.5, 4.2 and 2.1 μM-1 min-1 were found with AT Arg-358. Thus, when compared to AT Arg-358, AT Ala-357 Arg-358 was 5.2 times more efficient for inhibiting K but 7.7 times less efficient for inhibiting thrombin. In vivo, AT Ala-357 Arg-358 (0.7 mg i.v.) did not modify the thrombin time of male Wistar rats while a 2-fold prolongation was seen with 0.7 mg AT Arg-358. However, AT Ala-357 Arg-358 (0.7 mg i.v.) partially prevented the kinin-mediated circulatory collapse induced by XIIf (0.1 μg i.v.) since rats (n=4) treated with this double mutant had a blood pressure fall of 14 ±3 (meaniSD) mmHg while control animals (n = 8) receiving saline or AT Val-358 (0.7 mg i.v.) had a decrease of 27 ± 3 mmHg (p<0.01 by t test). AT Ala-357 Arg-358 has therapeutic potential for disease states with activation of the plasma kinin-forming system such as angioedema attacks or septic shock.