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Acta Biochimica Polonica Nov 2022Nucleotides are the most common compounds produced constantly by living organisms. They are involved in most cellular processes like the synthesis of other nucleotides... (Review)
Review
Nucleotides are the most common compounds produced constantly by living organisms. They are involved in most cellular processes like the synthesis of other nucleotides and nucleic acids, generation of energy needed for the maintenance of cells, and molecular signaling. In the 70s sir. Geoffrey Burstock discovered a new class of transmembrane proteins - nucleotide receptors responding to nucleotides and their derivatives. For historical reasons, we distinguish two main classes of nucleotide receptors: P1 - which are G protein-coupled adenosine receptors, and P2 - nucleotide receptors that respond to ATP and its derivatives. Additionally, the P2 receptors family can be divided into two subgroups: P2Y - G protein-coupled receptors and P2X cation channel receptors. This paper focuses mainly on the most researched receptor in the nucleotide receptors family - the P2X7 receptor - presenting it in the background of the nucleotide signaling landscape. Almost thirty years of extensive studies on the receptor contributed to understanding protein structure, splicing variants, and mechanism of action in somatic cells. Despite such a wide spectrum of research, the role of the receptor in cancer progression is still undetermined. In many reports, we can find information about the anti-tumorigenic role of this receptor caused by activation of the cell death mechanism after membrane pore formation. These results, however, contradict other studies in which the same receptor is known to promote cancer development through stimulation of proliferation and activation of pro-survival pathways. Ultimately, all this gathered knowledge points to two faces of the receptor in tumor progression. Therefore, we do provide a comprehensive overview of the topic. Finally, we also try to systemize previous and recent literature about the role of this receptor in somatic and cancer cells and provide access to it in the form of a convenient table.
Topics: Nucleotides; Receptors, Purinergic P2X7; Adenosine; Signal Transduction; Receptors, G-Protein-Coupled; Adenosine Triphosphate; Neoplasms
PubMed: 36367953
DOI: 10.18388/abp.2020_6310 -
Molecular Oncology Nov 2022The exploitation of the DNA damage response and DNA repair proficiency of cancer cells is an important anticancer strategy. The replication and repair of DNA are... (Review)
Review
The exploitation of the DNA damage response and DNA repair proficiency of cancer cells is an important anticancer strategy. The replication and repair of DNA are dependent upon the supply of deoxynucleoside triphosphate (dNTP) building blocks, which are produced and maintained by nucleotide metabolic pathways. Enzymes within these pathways can be promising targets to selectively induce toxic DNA lesions in cancer cells. These same pathways also activate antimetabolites, an important group of chemotherapies that disrupt both nucleotide and DNA metabolism to induce DNA damage in cancer cells. Thus, dNTP metabolic enzymes can also be targeted to refine the use of these chemotherapeutics, many of which remain standard of care in common cancers. In this review article, we will discuss both these approaches exemplified by the enzymes MTH1, MTHFD2 and SAMHD1. © 2022 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.
Topics: Humans; Neoplasms; Nucleotides; DNA Damage; DNA Repair
PubMed: 35583750
DOI: 10.1002/1878-0261.13227 -
ChemMedChem Jun 2016The masking of nucleoside phosphate and phosphonate groups by an aryl motif and an amino acid ester, nowadays known as the 'ProTide' technology, has proven to be...
The masking of nucleoside phosphate and phosphonate groups by an aryl motif and an amino acid ester, nowadays known as the 'ProTide' technology, has proven to be effective in the discovery of nucleotide therapeutics. Indeed, this technology, which was invented by Chris McGuigan in the early 1990s, has inspired the discovery of two FDA-approved antiviral nucleotide drugs, and many more are currently undergoing (pre)clinical development. The usefulness of this technology in the discovery of nucleotide therapeutics is showcased in this Highlight by discussing the ProTides development and the various ProTides that have reached clinical trials.
Topics: Anti-HIV Agents; Antiviral Agents; HIV Infections; HIV-1; Hepacivirus; Hepatitis C; Humans; Nucleotides; Prodrugs
PubMed: 27159529
DOI: 10.1002/cmdc.201600156 -
Current Opinion in Microbiology Jun 2020Since the initial discovery of bacterial nucleotide second messengers (NSMs), we have made huge progress towards understanding these complex signalling networks. Many... (Review)
Review
Since the initial discovery of bacterial nucleotide second messengers (NSMs), we have made huge progress towards understanding these complex signalling networks. Many NSM networks contain dozens of metabolic enzymes and binding targets, whose activity is tightly controlled at every regulatory level. They function as global regulators and in specific signalling circuits, controlling multiple aspects of bacterial behaviour and development. Despite these advances there is much still to discover, with current research focussing on the molecular mechanisms of signalling circuits, the role of the environment in controlling NSM pathways and attempts to understand signalling at the whole cell/community level. Here we examine recent developments in the NSM signalling field and discuss their implications for understanding this important driver of microbial behaviour.
Topics: Bacteria; Bacterial Physiological Phenomena; Bacterial Proteins; Biofilms; Gene Expression Regulation, Bacterial; Nucleotides; Nucleotides, Cyclic; Second Messenger Systems; Signal Transduction
PubMed: 32172083
DOI: 10.1016/j.mib.2020.02.006 -
Nucleic Acids Research Jan 2021The International Nucleotide Sequence Database Collaboration (INSDC; http://www.insdc.org/) has been the core infrastructure for collecting and providing nucleotide...
The International Nucleotide Sequence Database Collaboration (INSDC; http://www.insdc.org/) has been the core infrastructure for collecting and providing nucleotide sequence data and metadata for >30 years. Three partner organizations, the DNA Data Bank of Japan (DDBJ) at the National Institute of Genetics in Mishima, Japan; the European Nucleotide Archive (ENA) at the European Molecular Biology Laboratory's European Bioinformatics Institute (EMBL-EBI) in Hinxton, UK; and GenBank at National Center for Biotechnology Information (NCBI), National Library of Medicine, National Institutes of Health in Bethesda, Maryland, USA have been collaboratively maintaining the INSDC for the benefit of not only science but all types of community worldwide.
Topics: Academies and Institutes; Base Sequence; Databases, Nucleic Acid; Europe; High-Throughput Nucleotide Sequencing; Humans; International Cooperation; Japan; Metadata; Nucleotides; Sequence Analysis, DNA; Sequence Analysis, RNA; United States
PubMed: 33166387
DOI: 10.1093/nar/gkaa967 -
Nucleic Acids Research Jan 2022The European Nucleotide Archive (ENA, https://www.ebi.ac.uk/ena), maintained at the European Molecular Biology Laboratory's European Bioinformatics Institute (EMBL-EBI)...
The European Nucleotide Archive (ENA, https://www.ebi.ac.uk/ena), maintained at the European Molecular Biology Laboratory's European Bioinformatics Institute (EMBL-EBI) provides freely accessible services, both for deposition of, and access to, open nucleotide sequencing data. Open scientific data are of paramount importance to the scientific community and contribute daily to the acceleration of scientific advance. Here, we outline the major updates to ENA's services and infrastructure that have been delivered over the past year.
Topics: Computational Biology; Databases, Nucleic Acid; High-Throughput Nucleotide Sequencing; Humans; Internet; Molecular Sequence Annotation; Nucleotides; Software
PubMed: 34850158
DOI: 10.1093/nar/gkab1051 -
Scientific Reports Feb 2017Kinesin-1 is an ATP-dependent motor protein that moves towards microtubules (+)-ends. Whereas structures of isolated ADP-kinesin and of complexes with tubulin of...
Kinesin-1 is an ATP-dependent motor protein that moves towards microtubules (+)-ends. Whereas structures of isolated ADP-kinesin and of complexes with tubulin of apo-kinesin and of ATP-like-kinesin are available, structural data on apo-kinesin-1 in the absence of tubulin are still missing, leaving the role of nucleotide release in the structural cycle unsettled. Here, we identified mutations in the kinesin nucleotide-binding P-loop motif that interfere with ADP binding. These mutations destabilize the P-loop (T87A mutant) or magnesium binding (T92V), highlighting a dual mechanism for nucleotide release. The structures of these mutants in their apo form are either isomorphous to ADP-kinesin-1 or to tubulin-bound apo-kinesin-1. Remarkably, both structures are also obtained from the nucleotide-depleted wild-type protein. Our results lead to a model in which, when detached from microtubules, apo-kinesin possibly occupies the two conformations we characterized, whereas, upon microtubule binding, ADP-kinesin converts to the tubulin-bound apo-kinesin conformation and releases ADP. This conformation is primed to bind ATP and, therefore, to run through the natural nucleotide cycle of kinesin-1.
Topics: Adenosine Diphosphate; Humans; Kinesins; Microtubules; Models, Biological; Models, Molecular; Molecular Conformation; Mutation; Nucleotides; Protein Binding; Tubulin
PubMed: 28195215
DOI: 10.1038/srep42558 -
International Journal of Molecular... Mar 2023Adenylate kinase (AK) regulates adenine nucleotide metabolism and catalyzes the ATP + AMP ⇌ 2ADP reaction in a wide range of organisms and bacteria. AKs regulate... (Review)
Review
Adenylate kinase (AK) regulates adenine nucleotide metabolism and catalyzes the ATP + AMP ⇌ 2ADP reaction in a wide range of organisms and bacteria. AKs regulate adenine nucleotide ratios in different intracellular compartments and maintain the homeostasis of the intracellular nucleotide metabolism necessary for growth, differentiation, and motility. To date, nine isozymes have been identified and their functions have been analyzed. Moreover, the dynamics of the intracellular energy metabolism, diseases caused by AK mutations, the relationship with carcinogenesis, and circadian rhythms have recently been reported. This article summarizes the current knowledge regarding the physiological roles of AK isozymes in different diseases. In particular, this review focused on the symptoms caused by mutated AK isozymes in humans and phenotypic changes arising from altered gene expression in animal models. The future analysis of intracellular, extracellular, and intercellular energy metabolism with a focus on AK will aid in a wide range of new therapeutic approaches for various diseases, including cancer, lifestyle-related diseases, and aging.
Topics: Animals; Humans; Adenine Nucleotides; Adenylate Kinase; Nucleotides; Adenine; Isoenzymes; Adenosine Monophosphate; Adenosine Triphosphate
PubMed: 36982634
DOI: 10.3390/ijms24065561 -
Current Protocols in Nucleic Acid... Mar 2014Incorporation of modified nucleotides into in vitro RNA or DNA selections offers many potential advantages, such as the increased stability of selected nucleic acids... (Review)
Review
Incorporation of modified nucleotides into in vitro RNA or DNA selections offers many potential advantages, such as the increased stability of selected nucleic acids against nuclease degradation, improved affinities, expanded chemical functionality, and increased library diversity. This unit provides useful information and protocols for in vitro selection using modified nucleotides. It includes a discussion of when to use modified nucleotides; protocols for evaluating and optimizing transcription reactions, as well as confirming the incorporation of the modified nucleotides; protocols for evaluating modified nucleotide transcripts as template in reverse transcription reactions; protocols for the evaluation of the fidelity of modified nucleotides in the replication and the regeneration of the pool; and a protocol to compare modified nucleotide pools and selection conditions.
Topics: DNA; Nucleotides; RNA
PubMed: 25606981
DOI: 10.1002/0471142700.nc0906s56 -
Comprehensive Physiology Dec 2023Purine nucleotides play central roles in energy metabolism in the heart. Most fundamentally, the free energy of hydrolysis of the adenine nucleotide adenosine...
Purine nucleotides play central roles in energy metabolism in the heart. Most fundamentally, the free energy of hydrolysis of the adenine nucleotide adenosine triphosphate (ATP) provides the thermodynamic driving force for numerous cellular processes including the actin-myosin crossbridge cycle. Perturbations to ATP supply and/or demand in the myocardium lead to changes in the homeostatic balance between purine nucleotide synthesis, degradation, and salvage, potentially affecting myocardial energetics and, consequently, myocardial mechanics. Indeed, both acute myocardial ischemia and decompensatory remodeling of the myocardium in heart failure are associated with depletion of myocardial adenine nucleotides and with impaired myocardial mechanical function. Yet there remain gaps in the understanding of mechanistic links between adenine nucleotide degradation and contractile dysfunction in heart disease. The scope of this article is to: (i) review current knowledge of the pathways of purine nucleotide depletion and salvage in acute ischemia and in chronic heart disease; (ii) review hypothesized mechanisms linking myocardial mechanics and energetics with myocardial adenine nucleotide regulation; and (iii) highlight potential targets for treating myocardial metabolic and mechanical dysfunction associated with these pathways. It is hypothesized that an imbalance in the degradation, salvage, and synthesis of adenine nucleotides leads to a net loss of adenine nucleotides in both acute ischemia and under chronic high-demand conditions associated with the development of heart failure. This reduction in adenine nucleotide levels results in reduced myocardial ATP and increased myocardial inorganic phosphate. Both of these changes have the potential to directly impact tension development and mechanical work at the cellular level. © 2024 American Physiological Society. Compr Physiol 14:5345-5369, 2024.
Topics: Humans; Adenosine Triphosphate; Myocardium; Purine Nucleotides; Nucleotides; Heart Diseases; Heart Failure; Energy Metabolism; Ischemia
PubMed: 38158366
DOI: 10.1002/cphy.c230011