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Redox Biology Nov 2021Purinergic signaling is a cell communication pathway mediated by extracellular nucleotides and nucleosides. Tri- and diphosphonucleotides are released in physiological... (Review)
Review
Purinergic signaling is a cell communication pathway mediated by extracellular nucleotides and nucleosides. Tri- and diphosphonucleotides are released in physiological and pathological circumstances activating purinergic type 2 receptors (P2 receptors): P2X ion channels and P2Y G protein-coupled receptors. The activation of these receptors triggers the production of reactive oxygen and nitrogen species and alters antioxidant defenses, modulating the redox biology of cells. The activation of P2 receptors is controlled by ecto-enzymes named ectonucleotidases, E-NTPDase1/CD39 and ecto-5'-nucleotidase/CD73) being the most relevant. The first enzyme hydrolyzes adenosine triphosphate (ATP) and adenosine diphosphate (ADP) into adenosine monophosphate (AMP), and the second catalyzes the hydrolysis of AMP to adenosine. The activity of these enzymes is diminished by oxidative stress. Adenosine actives P1 G-coupled receptors that, in general, promote the maintenance of redox hemostasis by decreasing reactive oxygen species (ROS) production and increase antioxidant enzymes. Intracellular purine metabolism can also contribute to ROS generation via xanthine oxidase activity, which converts hypoxanthine into xanthine, and finally, uric acid. In this review, we describe the mechanisms of redox biology modulated by purinergic signaling and how this signaling may be affected by disturbances in the redox homeostasis of cells.
Topics: Adenosine; Adenosine Diphosphate; Adenosine Triphosphate; Biology; Oxidation-Reduction
PubMed: 34563872
DOI: 10.1016/j.redox.2021.102137 -
Journal of the American Chemical Society Oct 2023Under enzyme catalysis, adenosine triphosphate (ATP) transfers a phosphoryl group to canonical ribonucleotide diphosphates (NDPs) to form ribonucleotide triphosphates...
Under enzyme catalysis, adenosine triphosphate (ATP) transfers a phosphoryl group to canonical ribonucleotide diphosphates (NDPs) to form ribonucleotide triphosphates (NTPs), the direct biosynthetic precursors to RNA. However, it remains unclear whether the phosphorylation of NDPs could have occurred in water before enzymes existed and why an adenosine derivative, rather than another canonical NTP, typically performs this function. Here, we show that adenosine diphosphate (ADP) in the presence of Fe or Al promotes phosphoryl transfer from acetyl phosphate to all canonical NDPs to produce their corresponding NTP in water at room temperature and in the absence of enzymes. No other NDPs were found to promote phosphorylation, giving insight into why adenosine derivatives specifically became used for this purpose in biology. The metal-ADP complexes also promote phosphoryl transfer to ribonucleoside monophosphates (NMPs) to form a mixture of the corresponding NDPs and NTPs, albeit less efficiently. This work represents a rare example in which a single nucleotide carries out a function critical to biology without enzymes. ADP-metal complexes may have played an important role in nucleotide phosphorylation in prebiotic chemistry.
Topics: Ribonucleotides; Phosphorylation; Coordination Complexes; Adenosine Triphosphate; Adenosine Diphosphate; Adenosine; Water
PubMed: 37750669
DOI: 10.1021/jacs.3c08047 -
Organic & Biomolecular Chemistry Jun 2019ADP-ribosylation is an important post-translational modification that plays a pivotal role in many cellular processes, including cell signaling, DNA repair, gene... (Review)
Review
ADP-ribosylation is an important post-translational modification that plays a pivotal role in many cellular processes, including cell signaling, DNA repair, gene regulation and apoptosis. Although chemical synthesis of mono- or poly-ADP-ribosylated biomolecules is extremely difficult due to the challenges in regio- and stereoselective glycosylation, suitable protective group manipulations and pyrophosphate construction, synthetic procedures towards these bio-related targets have been reported in recent years. Chemically synthesized well-defined ADP-ribose derivatives serve as useful tools in biological experiments aimed to further elucidate native ADP-ribosylation. In this review, we will discuss the synthetic studies on mono-ADP-ribosylated proteins and oligo-ADP-ribose chains. Future possible synthetic targets and upcoming new methods for the synthesis of these molecules are also included.
Topics: ADP-Ribosylation; Adenosine Diphosphate Ribose; Humans; Molecular Conformation; Peptides; Protein Processing, Post-Translational
PubMed: 31112180
DOI: 10.1039/c9ob00501c -
Chemical Communications (Cambridge,... Oct 2021AzuFluor® 435-DPA-Zn, an azulene fluorophore bearing two zinc(II)-dipicolylamine receptor motifs, exhibits fluorescence enhancement in the presence of adenosine...
AzuFluor® 435-DPA-Zn, an azulene fluorophore bearing two zinc(II)-dipicolylamine receptor motifs, exhibits fluorescence enhancement in the presence of adenosine diphosphate. Selectivity for ADP over ATP, AMP and PPi results from appropriate positioning of the receptor motifs, since an isomeric sensor cannot discriminate between ADP and ATP.
Topics: Adenosine Diphosphate; Azulenes; Fluorescent Dyes; Humans; Molecular Structure; Spectrometry, Fluorescence
PubMed: 34570136
DOI: 10.1039/d1cc04122c -
FEBS Letters Jul 2019Hypertrophic cardiomyopathy (HCM) is the most common form of hereditary cardiomyopathy and is mainly caused by mutations of genes encoding cardiac sarcomeric proteins.... (Review)
Review
Hypertrophic cardiomyopathy (HCM) is the most common form of hereditary cardiomyopathy and is mainly caused by mutations of genes encoding cardiac sarcomeric proteins. HCM is characterized by hypertrophy of the left ventricle, frequently involving the septum, that is not explained solely by loading conditions. HCM has a heterogeneous clinical profile, but diastolic dysfunction and ventricular arrhythmias represent two dominant features of the disease. Preclinical evidence indicates that the enhanced Calcium (Ca ) sensitivity of the myofilaments plays a key role in the pathophysiology of HCM. Notably, this is not always a direct consequence of sarcomeric mutations, but can also result from secondary mutation-driven alterations. Here, we review experimental and clinical evidence indicating that increased myofilament Ca sensitivity lies upstream of numerous cellular derangements which potentially contribute to the progression of HCM toward heart failure and sudden cardiac death.
Topics: Adenosine Diphosphate; Animals; Cardiomyopathy, Hypertrophic; Energy Metabolism; Humans; Reactive Oxygen Species
PubMed: 31209876
DOI: 10.1002/1873-3468.13496 -
Developmental Cell Apr 2020Understanding of NAD metabolism provides many critical insights into health and diseases, yet highly sensitive and specific detection of NAD metabolism in live cells and...
Understanding of NAD metabolism provides many critical insights into health and diseases, yet highly sensitive and specific detection of NAD metabolism in live cells and in vivo remains difficult. Here, we present ratiometric, highly responsive genetically encoded fluorescent indicators, FiNad, for monitoring NAD dynamics in living cells and animals. FiNad sensors cover physiologically relevant NAD concentrations and sensitively respond to increases and decreases in NAD. Utilizing FiNad, we performed a head-to-head comparison study of common NAD precursors in various organisms and mapped their biochemical roles in enhancing NAD levels. Moreover, we showed that increased NAD synthesis controls morphofunctional changes of activated macrophages, and directly imaged NAD declines during aging in situ. The broad utility of the FiNad sensors will expand our mechanistic understanding of numerous NAD-associated physiological and pathological processes and facilitate screening for drug or gene candidates that affect uptake, efflux, and metabolism of this important cofactor.
Topics: Adenosine Diphosphate; Adenosine Triphosphate; Adult; Aging; Animals; Biosensing Techniques; Fluorescence; HEK293 Cells; Humans; Luminescent Proteins; Macrophages; Male; Mice; Middle Aged; NAD; Young Adult; Zebrafish
PubMed: 32197067
DOI: 10.1016/j.devcel.2020.02.017 -
Purinergic Signalling Sep 2020Extracellular purine nucleotides and nucleosides including ADP and ATP regulate a wide array of physiological processes including platelet aggregation, vasomotor... (Review)
Review
Extracellular purine nucleotides and nucleosides including ADP and ATP regulate a wide array of physiological processes including platelet aggregation, vasomotor responses and inflammation through specific purinergic receptors. In the recent years, a strong association has been reported between circulating cytoplasmic-type creatine kinase and adverse clinical outcomes such as major bleeding, hypertension and obesity. Therefore, it is proposed that extracellular CK may modulate purinergic signalling through its ADP binding and/or ATP-generating effect.
Topics: Adenosine Diphosphate; Adenosine Triphosphate; Animals; Creatine Kinase; Humans; Receptors, Purinergic; Signal Transduction
PubMed: 32572751
DOI: 10.1007/s11302-020-09707-0 -
Biological Chemistry Jan 2019Mitochondria and oxidative phosphorylation (OXPHOS) are emerging as intriguing targets for the efficient elimination of cancer cells. The specificity of this approach is... (Review)
Review
Mitochondria and oxidative phosphorylation (OXPHOS) are emerging as intriguing targets for the efficient elimination of cancer cells. The specificity of this approach is aided by the capacity of non-proliferating non-cancerous cells to withstand oxidative insult induced by OXPHOS inhibition. Recently we discovered that mitochondrial targeting can also be employed to eliminate senescent cells, where it breaks the interplay between OXPHOS and ATP transporters that appear important for the maintenance of mitochondrial morphology and viability in the senescent setting. Hence, mitochondria/OXPHOS directed pharmacological interventions show promise in several clinically-relevant scenarios that call for selective removal of cancer and senescent cells.
Topics: Adenosine Diphosphate; Adenosine Triphosphate; Biological Transport; Cell Death; Cell Proliferation; Cellular Senescence; Humans; Mitochondria; Neoplasms; Oxidative Phosphorylation; Reactive Oxygen Species
PubMed: 30281511
DOI: 10.1515/hsz-2018-0256 -
Chembiochem : a European Journal of... May 2022ATP is generally defined as the "energy currency" of the cell. Its phosphoanhydride P-O bonds are often considered to be "high energy" linkages that release free energy... (Review)
Review
ATP is generally defined as the "energy currency" of the cell. Its phosphoanhydride P-O bonds are often considered to be "high energy" linkages that release free energy when broken, and its hydrolysis is described as "strongly exergonic". However, breaking bonds cannot release energy and ATP hydrolysis in motor and active transport proteins is not "strongly exergonic". So, the relevance of ATP resides elsewhere. As important as the nucleotide are the proteins that undergo functionally relevant conformational changes upon both ATP binding and release of ADP and inorganic phosphate. ATP phosphorylates proteins for signaling, active transport, and substrates in condensation reactions. The ensuing dephosphorylation has different consequences in each case. In signaling and active transport the phosphate group is hydrolyzed whereas in condensation reactions the phosphoryl fragment acts as a dehydrating agent. As it will be discussed in this article, ATP does much more than simply contribute free energy to biological processes.
Topics: Adenosine Diphosphate; Adenosine Triphosphate; Energy Metabolism; Hydrolysis; Phosphates
PubMed: 35353443
DOI: 10.1002/cbic.202200064 -
Current Protein & Peptide Science 2016ADP-ribosylation describes an ancient and highly conserved posttranslational modification (PTM) of proteins. Many cellular processes have been identified that are... (Review)
Review
ADP-ribosylation describes an ancient and highly conserved posttranslational modification (PTM) of proteins. Many cellular processes have been identified that are regulated by ADP-ribosylation, including DNA repair, gene transcription and signaling processes. Enzymes catalyzing ADP-ribosylation use NAD+ as a cofactor to transfer ADP-ribose to a substrate under release of nicotinamide. In mammals extracellular and intracellular enzymes have been described. ADP-ribosylation is catalyzed by ADP-ribosyltransferases (ARTs) and some Sirtuins. Extracellular and intracellular ARTs belong to the cholera toxin-like (ARTC) and the diphtheria toxin-like (ARTD) subclass, respectively. ARTDs can be further subdivided depending on their ability to either generate poly-ADP-ribose chains, or to mono-ADP-ribosylate substrates. Similar to the latter, ARTCs and Sirtuins are restricted to mono-ADP-ribosylation. Recent findings have provided information about the functional consequences of ADP-ribosylation. Analogous to other PTMs, ADP-ribosylation can exert allosteric effects on enzymes, thereby controlling their catalytic activity. Moreover, this PTM can be read by multiple protein motifs and domains mediating protein-protein interactions. Typically these readers can distinguish between mono- and poly-ADP-ribosylation. Furthermore, with the description of proteins that can erase ADP-ribosylation, this posttranslational modification is fully reversible and thus provides an additional mechanism to transiently control protein functions and networks. In this review we will describe the most recent findings on motifs and domains that are related to ADP-ribosylation processes with a particular focus on readers and erasers. These new findings provide evidence for broad functional roles of ADP-ribosylation and a high diversity of mechanisms that contribute to the downstream consequences of this modification.
Topics: ADP Ribose Transferases; Adenosine Diphosphate; Adenosine Diphosphate Ribose; Animals; Glycosylation; Humans; Multigene Family; Phosphoric Monoester Hydrolases; Poly(ADP-ribose) Polymerases; Protein Binding; Protein Interaction Domains and Motifs; Protein Processing, Post-Translational; Sirtuins
PubMed: 27090904
DOI: 10.2174/1389203717666160419144846