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Antony Galione - One of the best experts on this subject based on the ideXlab platform.
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aplysia californica mediated cyclisation of novel 3 modified nad analogues a role for hydrogen bonding in the recognition of cyclic adenosine 5 diphosphate Ribose
Bioorganic & Medicinal Chemistry, 2004Co-Authors: Christopher J W Mort, Antony Galione, Marie E Migaud, Barry V L PotterAbstract:Abstract Cyclic ADP-Ribose mobilizes intracellular Ca 2+ in a variety of cells. To elucidate the nature of the interaction between the C3′ substituent of cADP-Ribose and the cADPR receptor, three analogues of NAD + modified in the adenosine ribase (xyloNAD + 3′F-xyloNAD + and 3′F-NAD + were chemically synthesised from d -xylose and adenine starting materials. 3′F-NAD + was readily converted to cyclic 3′F-ADP Ribose by the action of the cyclase enzyme derived from the mollusc Aplysia californica . XyloNAD + and 3′F-xyloNAD + were cyclised only reluctantly and in poor yield to afford unstable cyclic products. Biological evaluation of cyclic 3′F-ADP Ribose for calcium release in sea urchin egg homogenate gave an EC 50 of 1.5±0.5 μM. This high value suggests that the ability of the C3′ substituent to donate a hydrogen bond is crucial for agonism.
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cyclic aristeromycin diphosphate Ribose a potent and poorly hydrolysable ca2 mobilising mimic of cyclic adenosine diphosphate Ribose
FEBS Letters, 1996Co-Authors: Victoria C Bailey, Antony Galione, Simon M Fortt, Robin J Summerhill, Barry V L PotterAbstract:Abstract Cyclic aristeromycin diphosphate Ribose, a carbocyclic analogue of cyclic adenosine diphosphate Ribose, was synthesised using a chemo-enzymatic route involving activation of aristeromycin 5′-phosphate by diphenyl phosphochloridate. The calcium-releasing properties of this novel analogue were investigated in sea urchin egg homogenates. While cyclic aristeromycin diphosphate Ribose has a calcium release profile similar to that of cyclic adenosine diphosphate Ribose (EC50 values are 80 nM and 30 nM, respectively), it is degraded significantly more slowly ( t 1 2 values are 170 min and 15 min, respectively) and may, therefore, be a useful tool to investigate the activities of cyclic adenosine diphosphate Ribose.
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Cyclic ADP-Ribose, the ADP-ribosyl cyclase pathway and calcium signalling
Molecular and Cellular Endocrinology, 1994Co-Authors: Antony GalioneAbstract:Cyclic adenosine diphosphate-Ribose, an endogenous metabolite of nicotinamide adenine dinucleotide was first characterized as a potent Ca2+ mobilizing agent in sea urchin eggs. Mounting evidence points to it being an endogenous activator of Ca(2+)-induced Ca2+ release by non-skeletal muscle ryanodine receptors in several invertebrate and mammalian cell types. Cyclic adenosine diphosphate-Ribose is synthesized by adenosine diphosphate-ribosyl cyclases, which have been found to be widespread enzymes. Recent data suggests that cyclic adenosine diphosphate-Ribose may function as a second messenger in sea urchin eggs at fertilization and in stimulus secretion coupling in pancreatic beta-cells. A second messenger role for cyclic adenosine diphosphate-Ribose requires that its intracellular levels be under the control of extracellular stimuli. Another second messenger, cGMP, stimulates the synthesis of cyclic adenosine diphosphate-Ribose from nicotinamide adenine dinucleotide by activating the adenosine diphosphate-ribosyl cyclase pathway in sera urchin eggs and egg homogenates, suggesting that cyclic adenosine diphosphate-Ribose may be an intracellular messenger for cell surface receptors or nitric oxide, which activate cGMP-producing guanylate cyclases. Cyclic adenosine diphosphate-Ribose may have a similar role to inositol trisphosphate in controlling intracellular calcium signalling with these two calcium-mobilizing second messengers activating ryanodine receptors and inositol trisphosphate receptors respectively.
Ivan Ahel - One of the best experts on this subject based on the ideXlab platform.
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ENPP1 processes protein ADP-ribosylation in vitro.
The FEBS journal, 2016Co-Authors: Luca Palazzo, Anthony K L Leung, Casey M. Daniels, Joanne E. Nettleship, Nahid Rahman, Robert Lyle Mcpherson, Shao En Ong, Kazuki Kato, Osamu Nureki, Ivan AhelAbstract:ADP‐ribosylation is a conserved post‐translational protein modification that plays a role in all major cellular processes, particularly DNA repair, transcription, translation, stress response and cell death. Hence, dysregulation of ADP‐ribosylation is linked to the physiopathology of several human diseases including cancers, diabetes and neurodegenerative disorders. Protein ADP‐ribosylation can be reversed by the macrodomain‐containing proteins PARG, TARG1, MacroD1 and MacroD2, which hydrolyse the ester bond known to link proteins to ADP‐Ribose as well as consecutive ADP‐Ribose subunits; targeting this bond can thus result in the complete removal of the protein modification or the conversion of poly(ADP‐Ribose) to mono(ADP‐Ribose). Recently, proteins containing the NUDIX domain – namely human NUDT16 and bacterial RppH – have been shown to process in vitro protein ADP‐ribosylation through an alternative mechanism, converting it into protein‐conjugated Ribose‐5′‐phosphate (R5P, also known as pR). Though this protein modification was recently identified in mammalian tissues, its physiological relevance and the mechanism of generating protein phosphoribosylation are currently unknown. Here, we identified ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) as the first known mammalian enzyme lacking a NUDIX domain to generate pR from ADP‐Ribose on modified proteins in vitro. Thus, our data show that at least two enzyme families – Nudix and ENPP/NPP – are able to metabolize protein‐conjugated ADP‐Ribose to pR in vitro, suggesting that pR exists and may be conserved from bacteria to mammals. We also demonstrate the utility of ENPP1 for converting protein‐conjugated mono(ADP‐Ribose) and poly(ADP‐Ribose) into mass spectrometry‐friendly pR tags, thus facilitating the identification of ADP‐ribosylation sites.
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the structure and catalytic mechanism of a poly adp Ribose glycohydrolase
Nature, 2011Co-Authors: Dea Slade, Mark S Dunstan, Eva Barkauskaite, Ria Weston, Marijan Ahel, Pierre Lafite, David Leys, Neil Dixon, Ivan AhelAbstract:Post-translational modification of proteins by poly(ADP-ribosyl)ation regulates many cellular pathways that are critical for genome stability, including DNA repair, chromatin structure, mitosis and apoptosis1. Poly(ADP-Ribose) (PAR) is composed of repeating ADP-Ribose units linked via a unique glycosidic Ribose–Ribose bond, and is synthesized from NAD by PAR polymerases1, 2. PAR glycohydrolase (PARG) is the only protein capable of specific hydrolysis of the Ribose–Ribose bonds present in PAR chains; its deficiency leads to cell death3, 4. Here we show that filamentous fungi and a number of bacteria possess a divergent form of PARG that has all the main characteristics of the human PARG enzyme. We present the first PARG crystal structure (derived from the bacterium Thermomonospora curvata), which reveals that the PARG catalytic domain is a distant member of the ubiquitous ADP-Ribose-binding macrodomain family5, 6. High-resolution structures of T. curvata PARG in complexes with ADP-Ribose and the PARG inhibitor ADP-HPD, complemented by biochemical studies, allow us to propose a model for PAR binding and catalysis by PARG. The insights into the PARG structure and catalytic mechanism should greatly improve our understanding of how PARG activity controls reversible protein poly(ADP-ribosyl)ation and potentially of how the defects in this regulation are linked to human disease.
Joel Moss - One of the best experts on this subject based on the ideXlab platform.
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structure of human adp ribosyl acceptor hydrolase 3 bound to adp Ribose reveals a conformational switch that enables specific substrate recognition
Journal of Biological Chemistry, 2018Co-Authors: Yasin Pourfarjam, Joel Moss, Jessica Ventura, Igor Kurinov, Ahra Cho, Inkwon KimAbstract:ADP-ribosyl-acceptor hydrolase 3 (ARH3) plays important roles in regulation of poly(ADP-ribosyl)ation, a reversible post-translational modification, and in maintenance of genomic integrity. ARH3 degrades poly(ADP-Ribose) to protect cells from poly(ADP-Ribose)–dependent cell death, reverses serine mono(ADP-ribosyl)ation, and hydrolyzes O-acetyl-ADP-Ribose, a product of Sirtuin-catalyzed histone deacetylation. ARH3 preferentially hydrolyzes O-linkages attached to the anomeric C1″ of ADP-Ribose; however, how ARH3 specifically recognizes and cleaves structurally diverse substrates remains unknown. Here, structures of full-length human ARH3 bound to ADP-Ribose and Mg2+, coupled with computational modeling, reveal a dramatic conformational switch from closed to open states that enables specific substrate recognition. The glutamate flap, which blocks substrate entrance to Mg2+ in the unliganded closed state, is ejected from the active site when substrate is bound. This closed-to-open transition significantly widens the substrate-binding channel and precisely positions the scissile 1″-O-linkage for cleavage while securing tightly 2″- and 3″-hydroxyls of ADP-Ribose. Our collective data uncover an unprecedented structural plasticity of ARH3 that supports its specificity for the 1″-O-linkage in substrates and Mg2+-dependent catalysis.
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the 39 kda poly adp Ribose glycohydrolase arh3 hydrolyzes o acetyl adp Ribose a product of the sir2 family of acetyl histone deacetylases
Proceedings of the National Academy of Sciences of the United States of America, 2006Co-Authors: Tohru Ono, Atsushi Kasamatsu, Shunya Oka, Joel MossAbstract:The silent information regulator 2 (Sir2) family of NAD-dependent N-acetyl-protein deacetylases participates in the regulation of gene silencing, chromatin structure, and longevity. In the Sir2-catalyzed reaction, the acetyl moiety of N-acetyl-histone is transferred to the ADP-Ribose of NAD, yielding O-acetyl-ADP-Ribose and nicotinamide. We hypothesized that, if O-acetyl-ADP-Ribose were an important signaling molecule, a specific hydrolase would cleave the (O-acetyl)–(ADP-Ribose) linkage. We report here that the poly(ADP-Ribose) glycohydrolase ARH3 hydrolyzed O-acetyl-ADP-Ribose to produce ADP-Ribose in a time- and Mg2+-dependent reaction and thus could participate in two signaling pathways. This O-acetyl-ADP-Ribose hydrolase belongs to a family of three structurally related 39-kDa ADP-Ribose-binding proteins (ARH1–ARH3). ARH1 was reported to hydrolyze ADP-ribosylarginine, whereas ARH3 degraded poly(ADP-Ribose). ARH3-catalyzed generation of ADP-Ribose from O-acetyl-ADP-Ribose was significantly faster than from poly(ADP-Ribose). Like the degradation of poly(ADP-Ribose) by ARH3, hydrolysis of O-acetyl-ADP-Ribose was abolished by replacement of the vicinal aspartates at positions 77 and 78 of ARH3 with asparagine. The rate of O-acetyl-ADP-Ribose hydrolysis by recombinant ARH3 was 250-fold that observed with ARH1; ARH2 and poly(ADP-Ribose) glycohydrolase were inactive. All data support the conclusion that the Sir2 reaction product O-acetyl-ADP-Ribose is degraded by ARH3.
Barry V L Potter - One of the best experts on this subject based on the ideXlab platform.
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aplysia californica mediated cyclisation of novel 3 modified nad analogues a role for hydrogen bonding in the recognition of cyclic adenosine 5 diphosphate Ribose
Bioorganic & Medicinal Chemistry, 2004Co-Authors: Christopher J W Mort, Antony Galione, Marie E Migaud, Barry V L PotterAbstract:Abstract Cyclic ADP-Ribose mobilizes intracellular Ca 2+ in a variety of cells. To elucidate the nature of the interaction between the C3′ substituent of cADP-Ribose and the cADPR receptor, three analogues of NAD + modified in the adenosine ribase (xyloNAD + 3′F-xyloNAD + and 3′F-NAD + were chemically synthesised from d -xylose and adenine starting materials. 3′F-NAD + was readily converted to cyclic 3′F-ADP Ribose by the action of the cyclase enzyme derived from the mollusc Aplysia californica . XyloNAD + and 3′F-xyloNAD + were cyclised only reluctantly and in poor yield to afford unstable cyclic products. Biological evaluation of cyclic 3′F-ADP Ribose for calcium release in sea urchin egg homogenate gave an EC 50 of 1.5±0.5 μM. This high value suggests that the ability of the C3′ substituent to donate a hydrogen bond is crucial for agonism.
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cyclic aristeromycin diphosphate Ribose a potent and poorly hydrolysable ca2 mobilising mimic of cyclic adenosine diphosphate Ribose
FEBS Letters, 1996Co-Authors: Victoria C Bailey, Antony Galione, Simon M Fortt, Robin J Summerhill, Barry V L PotterAbstract:Abstract Cyclic aristeromycin diphosphate Ribose, a carbocyclic analogue of cyclic adenosine diphosphate Ribose, was synthesised using a chemo-enzymatic route involving activation of aristeromycin 5′-phosphate by diphenyl phosphochloridate. The calcium-releasing properties of this novel analogue were investigated in sea urchin egg homogenates. While cyclic aristeromycin diphosphate Ribose has a calcium release profile similar to that of cyclic adenosine diphosphate Ribose (EC50 values are 80 nM and 30 nM, respectively), it is degraded significantly more slowly ( t 1 2 values are 170 min and 15 min, respectively) and may, therefore, be a useful tool to investigate the activities of cyclic adenosine diphosphate Ribose.
Felix R. Althaus - One of the best experts on this subject based on the ideXlab platform.
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poly adp Ribose binds to the splicing factor asf sf2 and regulates its phosphorylation by dna topoisomerase i
Journal of Biological Chemistry, 2008Co-Authors: Maria Malanga, Alicja Czubaty, Agnieszka Girstun, Krzysztof Staron, Felix R. AlthausAbstract:Human DNA topoisomerase I plays a dual role in transcription, by controlling DNA supercoiling and by acting as a specific kinase for the SR-protein family of splicing factors. The two activities are mutually exclusive, but the identity of the molecular switch is unknown. Here we identify poly(ADP-Ribose) as a physiological regulator of the two topoisomerase I functions. We found that, in the presence of both DNA and the alternative splicing factor/splicing factor 2 (ASF/SF2, a prototypical SR-protein), poly(ADP-Ribose) affected topoisomerase I substrate selection and gradually shifted enzyme activity from protein phosphorylation to DNA cleavage. A likely mechanistic explanation was offered by the discovery that poly(ADP-Ribose) forms a high affinity complex with ASF/SF2 thereby leaving topoisomerase I available for directing its action onto DNA. We identified two functionally important domains, RRM1 and RS, as specific poly(ADP-Ribose) binding targets. Two independent lines of evidence emphasize the potential biological relevance of our findings: (i) in HeLa nuclear extracts, ASF/SF2, but not histone, phosphorylation was inhibited by poly(ADP-Ribose); (ii) an in silico study based on gene expression profiling data revealed an increased incidence of alternative splicing within a subset of inflammatory response genes that are dysregulated in cells lacking a functional poly(ADP-Ribose) polymerase-1. We propose that poly(ADP-Ribose) targeting of topoisomerase I and ASF/SF2 functions may participate in the regulation of gene expression.
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Poly(ADP-Ribose) binds to specific domains in DNA damage checkpoint proteins.
Journal of Biological Chemistry, 2000Co-Authors: Jutta M. Pleschke, Hanna E. Kleczkowska, Mark Strohm, Felix R. AlthausAbstract:Abstract Poly(ADP-Ribose) is formed in possibly all multicellular organisms by a familiy of poly(ADP-Ribose) polymerases (PARPs). PARP-1, the best understood and until recently the only known member of this family, is a DNA damage signal protein catalyzing its automodification with multiple, variably sized ADP-Ribose polymers that may contain up to 200 residues and several branching points. Through these polymers, PARP-1 can interact noncovalently with other proteins and alter their functions. Here we report the discovery of a poly(ADP-Ribose)-binding sequence motif in several important DNA damage checkpoint proteins. The 20-amino acid motif contains two conserved regions: (i) a cluster rich in basic amino acids and (ii) a pattern of hydrophobic amino acids interspersed with basic residues. Using a combination of alanine scanning, polymer blot analysis, and photoaffinity labeling, we have identified poly(ADP-Ribose)-binding sites in the following proteins: p53, p21CIP1/WAF1, xeroderma pigmentosum group A complementing protein, MSH6, DNA ligase III, XRCC1, DNA polymerase e, DNA-PKCS, Ku70, NF-κB, inducible nitric-oxide synthase, caspase-activated DNase, and telomerase. The poly(ADP-Ribose)-binding motif was found to overlap with five important functional domains responsible for (i) protein-protein interactions, (ii) DNA binding, (iii) nuclear localization, (iv) nuclear export, and (v) protein degradation. Thus, PARPs may target specific signal network proteins via poly(ADP-Ribose) and regulate their domain functions.
