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Biochemical Pharmacology May 2021Geoffrey Burnstock is a purinergic signalling legend who's discoveries and conceptualisation created and shaped the field. His scientific achievements were extraordinary... (Review)
Review
Geoffrey Burnstock is a purinergic signalling legend who's discoveries and conceptualisation created and shaped the field. His scientific achievements were extraordinary and sustained. They included his demonstration that ATP can act as a neurotransmitter and hence extracellular signalling molecule, which he championed despite considerable initial opposition to his proposal that ATP acts outside of its role as an energy source inside cells. He led on purine receptor classification: initially of the P1 and P2 receptor families, then the P2X and P2Y receptor families, and then subtypes of P2X and P2Y receptors. This was achieved across several decades as he conceptualised and made sense of the emerging and growing evidence that there were multiple receptor subtypes for ATP and other nucleotides. He made discoveries about short term and long term/trophic purinergic signalling. He was a leader in the field for over 50 years. He inspired many and was a great colleague and mentor. I had the privilege of spending over 10 years (from 1985) with Geoff at the Department of Anatomy and Developmental Biology, University College London. This review is a personal perspective of some of Geoff's research on P2 receptors carried out during that time. It is a tribute to Geoff who I regarded with enormous respect and admiration.
Topics: Adenosine Triphosphate; Animals; Biomedical Research; History, 20th Century; History, 21st Century; Humans; Male; Receptors, Purinergic P2; Signal Transduction
PubMed: 33279495
DOI: 10.1016/j.bcp.2020.114358 -
International Journal of Molecular... Jan 2023The purine signaling system is represented by purine and pyrimidine nucleotides and nucleosides that exert their effects through the adenosine, P2X and P2Y receptor... (Review)
Review
The purine signaling system is represented by purine and pyrimidine nucleotides and nucleosides that exert their effects through the adenosine, P2X and P2Y receptor families. It is known that, under physiological conditions, P2 receptors play only a minor role in modulating the functions of cells and systems; however, their role significantly increases under some pathophysiological conditions, such as stress, ischemia or hypothermia, when they can play a dominant role as a signaling molecule. The diversity of P2 receptors and their wide distribution in the body make them very attractive as a target for the pharmacological action of drugs with a new mechanism of action. The review is devoted to the involvement of P2 signaling in the development of pathologies associated with a loss of muscle mass. The contribution of adenosine triphosphate (ATP) as a signal molecule in the pathogenesis of a number of muscular dystrophies (Duchenne, Becker and limb girdle muscular dystrophy 2B) is considered. To understand the processes involving the purinergic system, the role of the ATP and P2 receptors in several models associated with skeletal muscle degradation is also discussed.
Topics: Humans; Receptors, Purinergic P2; Adenosine Triphosphate; Muscular Dystrophies; Adenosine; Signal Transduction
PubMed: 36675094
DOI: 10.3390/ijms24021587 -
Plant Signaling & Behavior Jan 2021Structural components of second messenger signaling (nucleotides and associated enzyme systems) within plant and animal cells have more in common than the hormones that...
Structural components of second messenger signaling (nucleotides and associated enzyme systems) within plant and animal cells have more in common than the hormones that initiate metabolic and functional changes. Neurotransmitters and hormones of mammalian pharmacologic classes relate to purine nucleotides in respect of chemical structure and the molecular changes they initiate. This study compares the molecular structures of purine nucleotides with compounds from the abscisic acid, auxin, brassinosteroid, cytokinin, gibberellin, and jasmonate classes by means of a computational program. The results illustrate how phytohomones relate to each other through the structures of nucleotides and cyclic nucleotides. Molecular similarity within the phytohormone structures relates to synergism, antagonism and the modulation of nucleotide function that regulates germination and plant development. As with the molecular evolution of mammalian hormones, cell signaling and cross-talk within the phytohormone classes is purine nucleotide centered.
Topics: Abscisic Acid; Cyclopentanes; Cytokinins; Gibberellins; Indoleacetic Acids; Oxylipins; Plant Growth Regulators; Purine Nucleotides; Signal Transduction
PubMed: 33100143
DOI: 10.1080/15592324.2020.1837544 -
Life Sciences Oct 2023Tumor cells are required to undergo metabolic reprogramming for rapid development and progression, and one of the metabolic characteristics of cancer cells is the... (Review)
Review
Tumor cells are required to undergo metabolic reprogramming for rapid development and progression, and one of the metabolic characteristics of cancer cells is the excessive synthesis and utilization of nucleotides. Abnormally increased nucleotides and their metabolites not only directly accelerate tumor cell progression but also indirectly act on stromal cells in the tumor microenvironment (TME) via a paracrine manner to regulate tumor progression. Purine nucleotides are mainly produced via de novo nucleotide synthesis in tumor cells; therefore, intervening in their synthesis has emerged as a promising strategy in anti-tumor therapy. De novo purine synthesis is a 10-step reaction catalyzed by six enzymes to synthesize inosine 5-monophosphate (IMP) and subsequently synthesize AMP and GMP. Phosphoribosylaminoimidazole carboxylase/phosphori-bosylaminoimidazole succinocarboxamide synthetase (PAICS) is a bifunctional enzyme that catalyzes de novo purine synthesis. Aberrantly elevated PAICS expression in various tumors is associated with poor prognosis. Evidence suggests that PAICS and its catalytic product, N-succinylcarboxamide-5-aminoimidazole ribonucleotide (SAICAR), could inhibit tumor cell apoptosis and promote the growth, epithelial-mesenchymal transition (EMT), invasion, and metastasis by regulating signaling pathways such as pyruvate kinase M2 (PKM2), extracellular signal-related kinases 1 and 2 (ERK1/2), focal adhesion kinase (FAK) and so on. This review summarizes the structure, biological functions and the molecular mechanisms of PAICS in cancer development and discusses its potential to be a target for tumor therapy.
Topics: Humans; Neoplasms; Purines; Nucleotides; Apoptosis; Catalysis; Tumor Microenvironment
PubMed: 37673296
DOI: 10.1016/j.lfs.2023.122070 -
Protein Science : a Publication of the... Sep 2022Inosine 5'-monophosphate dehydrogenase (IMPDH) is an evolutionarily conserved enzyme that mediates the first committed step in de novo guanine nucleotide biosynthetic... (Review)
Review
Inosine 5'-monophosphate dehydrogenase (IMPDH) is an evolutionarily conserved enzyme that mediates the first committed step in de novo guanine nucleotide biosynthetic pathway. It is an essential enzyme in purine nucleotide biosynthesis that modulates the metabolic flux at the branch point between adenine and guanine nucleotides. IMPDH plays key roles in cell homeostasis, proliferation, and the immune response, and is the cellular target of several drugs that are widely used for antiviral and immunosuppressive chemotherapy. IMPDH enzyme is tightly regulated at multiple levels, from transcriptional control to allosteric modulation, enzyme filamentation, and posttranslational modifications. Herein, we review recent developments in our understanding of the mechanisms of IMPDH regulation, including all layers of allosteric control that fine-tune the enzyme activity.
Topics: Allosteric Regulation; Enzyme Inhibitors; Guanine Nucleotides; IMP Dehydrogenase; Inosine Monophosphate
PubMed: 36040265
DOI: 10.1002/pro.4399 -
Science Signaling Mar 2021NAADP is a potent Ca-mobilizing messenger linked to numerous Ca-dependent effects across the natural world. On 18 February 2021, delegates attended a virtual symposium... (Review)
Review
NAADP is a potent Ca-mobilizing messenger linked to numerous Ca-dependent effects across the natural world. On 18 February 2021, delegates attended a virtual symposium to discuss studies of the mechanisms of action of NAADP, including the work of Gunaratne and Roggenkamp in this issue of .
Topics: Calcium Signaling; NADP
PubMed: 33758059
DOI: 10.1126/scisignal.abh2798 -
MBio Feb 2023The purine-derived signaling molecules c-di-AMP and (p)ppGpp control /PBP2a-mediated β-lactam resistance in methicillin-resistant Staphylococcus aureus (MRSA) raise the...
The purine-derived signaling molecules c-di-AMP and (p)ppGpp control /PBP2a-mediated β-lactam resistance in methicillin-resistant Staphylococcus aureus (MRSA) raise the possibility that purine availability can control antibiotic susceptibility. Consistent with this, exogenous guanosine and xanthosine, which are fluxed through the GTP branch of purine biosynthesis, were shown to significantly reduce MRSA β-lactam resistance. In contrast, adenosine (fluxed to ATP) significantly increased oxacillin resistance, whereas inosine (which can be fluxed to ATP and GTP via hypoxanthine) only marginally increased oxacillin susceptibility. Furthermore, mutations that interfere with purine synthesis ( operon), transport (NupG, PbuG, PbuX) and the salvage pathway (DeoD2, Hpt) increased β-lactam resistance in MRSA strain JE2. Increased resistance of a mutant was not significantly reversed by guanosine, indicating that NupG is required for guanosine transport, which is required to reduce β-lactam resistance. Suppressor mutants resistant to oxacillin/guanosine combinations contained several purine salvage pathway mutations, including and . Guanosine significantly increased cell size and reduced levels of c-di-AMP, while inactivation of GdpP, the c-di-AMP phosphodiesterase negated the impact of guanosine on β-lactam susceptibility. PBP2a expression was unaffected in or mutants, suggesting that guanosine-induced β-lactam susceptibility may result from dysfunctional c-di-AMP-dependent osmoregulation. These data reveal the therapeutic potential of purine nucleosides, as β-lactam adjuvants that interfere with the normal activation of c-di-AMP are required for high-level β-lactam resistance in MRSA. The clinical burden of infections caused by antimicrobial resistant (AMR) pathogens is a leading threat to public health. Maintaining the effectiveness of existing antimicrobial drugs or finding ways to reintroduce drugs to which resistance is widespread is an important part of efforts to address the AMR crisis. Predominantly, the safest and most effective class of antibiotics are the β-lactams, which are no longer effective against methicillin-resistant Staphylococcus aureus (MRSA). Here, we report that the purine nucleosides guanosine and xanthosine have potent activity as adjuvants that can resensitize MRSA to oxacillin and other β-lactam antibiotics. Mechanistically, exposure of MRSA to these nucleosides significantly reduced the levels of the cyclic dinucleotide c-di-AMP, which is required for β-lactam resistance. Drugs derived from nucleotides are widely used in the treatment of cancer and viral infections highlighting the clinical potential of using purine nucleosides to restore or enhance the therapeutic effectiveness of β-lactams against MRSA and potentially other AMR pathogens.
Topics: Methicillin-Resistant Staphylococcus aureus; Purine Nucleosides; Bacterial Proteins; Anti-Bacterial Agents; Oxacillin; beta-Lactams; Monobactams; Guanosine; Adenosine Triphosphate; Guanosine Triphosphate; Microbial Sensitivity Tests; Penicillin-Binding Proteins; beta-Lactam Resistance
PubMed: 36507833
DOI: 10.1128/mbio.02478-22 -
Trends in Plant Science Oct 2021The pyridine nucleotides nicotinamide adenine dinucleotide [NAD(H)] and nicotinamide adenine dinucleotide phosphate [NADP(H)] simultaneously act as energy transducers,... (Review)
Review
The pyridine nucleotides nicotinamide adenine dinucleotide [NAD(H)] and nicotinamide adenine dinucleotide phosphate [NADP(H)] simultaneously act as energy transducers, signalling molecules, and redox couples. Recent research into photosynthetic optimisation, photorespiration, immunity, hypoxia/oxygen signalling, development, and post-harvest metabolism have all identified pyridine nucleotides as key metabolites. Further understanding will require accurate description of NAD(P)(H) metabolism, and genetically encoded fluorescent biosensors have recently become available for this purpose. Although these biosensors have begun to provide novel biological insights, their limitations must be considered and the information they provide appropriately interpreted. We provide a framework for understanding NAD(P)(H) metabolism and explore what fluorescent biosensors can, and cannot, tell us about plant biology, looking ahead to the pressing questions that could be answered with further development of these tools.
Topics: Energy Metabolism; NAD; NADP; Oxidation-Reduction; Plants; Signal Transduction
PubMed: 34281784
DOI: 10.1016/j.tplants.2021.06.010 -
Brain Research Bulletin Sep 2019Retinal injuries and diseases are major causes of human disability involving vision impairment by the progressive and permanent loss of retinal neurons. During... (Review)
Review
Retinal injuries and diseases are major causes of human disability involving vision impairment by the progressive and permanent loss of retinal neurons. During development, assembly of this tissue entails a successive and overlapping, signal-regulated engagement of complex events that include proliferation of progenitors, neurogenesis, cell death, neurochemical differentiation and synaptogenesis. During retinal damage, several of these events are re-activated with both protective and detrimental consequences. Purines and pyrimidines, along with their metabolites are emerging as important molecules regulating both retinal development and the tissue's responses to damage. The present review provides an overview of the purinergic signaling in the developing and injured retina. Recent findings on the presence of vesicular and channel-mediated ATP release by retinal and retinal pigment epithelial cells, adenosine synthesis and release, expression of receptors and intracellular signaling pathways activated by purinergic signaling in retinal cells are reported. The pathways by which purinergic receptors modulate retinal cell proliferation, migration and death of retinal cells during development and injury are summarized. The contribution of nucleotides to the self-repair of the injured zebrafish retina is also discussed.
Topics: Adenosine; Adenosine Triphosphate; Animals; Cell Death; Cell Differentiation; Humans; Purines; Receptors, Purinergic; Receptors, Purinergic P2X; Receptors, Purinergic P2Y; Retina; Signal Transduction
PubMed: 30458250
DOI: 10.1016/j.brainresbull.2018.10.016 -
The Biochemical Journal Jun 2022Infection with schistosomes (blood flukes) can result in the debilitating disease schistosomiasis. These parasites survive in their host for many years, and we...
Infection with schistosomes (blood flukes) can result in the debilitating disease schistosomiasis. These parasites survive in their host for many years, and we hypothesize that proteins on their tegumental surface, interacting with the host microenvironment, facilitate longevity. One such ectoenzyme - the nucleotide pyrophosphatase/phosphodiesterase SmNPP5 can cleave ADP (to prevent platelet aggregation) and NAD (likely preventing Treg apoptosis). A second tegumental ectoenzyme, the glycohydrolase SmNACE, also catabolizes NAD. Here, we undertake a comparative biochemical characterization of these parasite ectoenzymes. Both are GPI-linked and exhibit different optimal pH ranges. While SmNPP5 requires divalent cations, SmNACE does not. The KM values of the two enzymes for NAD at physiological pH differ: SmNPP5, KM = 340 µM ± 44; SmNACE, KM = 49 µM ± 4. NAD cleavage by each enzyme yields different products. SmNPP5 cleaves NAD to form nicotinamide mononucleotide (NMN) and AMP, whereas SmNACE cleaves NAD to generate nicotinamide (NAM) and adenosine diphosphate ribose (ADPR). Each enzyme can process the other's reaction product. Thus, SmNACE cleaves NMN (to yield NAM and ribose phosphate) and SmNPP5 cleaves ADPR (yielding AMP and ribose phosphate). Metabolomic analysis of plasma containing adult worms supports the idea that these cleavage pathways are active in vivo. We hypothesize that a primary function of SmNPP5 is to cleave NAD to control host immune cell function and a primary function of SmNACE is to cleave NMN to generate the vital nutrient nicotinamide (vitamin B3) for convenient uptake by the worms. Chemical inhibition of one or both ectoenzymes could upset worm metabolism and control schistosome infection.
Topics: Adenosine Diphosphate Ribose; Adenosine Monophosphate; Animals; NAD; Niacinamide; Schistosoma mansoni
PubMed: 35593185
DOI: 10.1042/BCJ20210784