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[ADP-ribose and cADP-ribose--endogenous regulators of cellular ionic balance. Cardiotropic effects of ADP-ribose].

Functions and possible mechanisms of action of adenosine diphosphate ribose (ADP-ribose) and its cyclic analogue--cycle-ADP-ribose (cADP-ribose)-- substances pretend to role of novel second messengers are reviewed. Possible mechanisms of ADP-ribose and cADP-ribose synthesis regulation and metabolism are analyzed. Prospective mechanisms of ADP-ribose and cADP-ribose transportation into the cell are described. ADP-ribose and cADP-ribose are considered as endogenous regulators of ionic balance (in particular regulators of calcium balance) in different tissues. Effects of ADP-ribose on isolated heart of frog and warm-blooded animal (rat), as well as on rat heart in vivo are discussed. The role of ionic channels and receptors, gated by ADP- and cADP-ribose in regulation of cardiomyocyte ionic balance in normal and pathological condition are analyzed. The possible role of purine receptors in ADP-ribose and cADP-ribose effects on heart are discussed.

Adenosine Diphosphate Ribose↗
PubMed1981

The branching and linear portions of poly(adenosine diphosphate ribose) have the same alpha(1 leads to 2) ribose-ribose linkage.

The structure of the branching site of poly(ADP-ribose) was determined as O-alpha-D-ribofuranosyl-(1"' leads to 2")-O-alpha-D-ribofuranosyl-(1" leads to 2')-adenosine-5',5",5"'-tris(phosphate) by gas chromatography, mass spectrometry, and 1H-NMR measurements. Thus the structures of all the ribose-ribose linkages known in poly(ADP-ribose) are uniformly alpha(1 leads to 2)glycosidic bond. This indicates that branching ADP-ribosylation and elongating ADP-ribosylation of poly(ADP-ribose) synthesis are catalyzed by similar alpha(1 leads to 2)-specific ADP-ribosyl transferases or the same enzyme. Poly(ADP-ribose) glycohydrolase, which specifically hydrolyzes the ribose-ribose bonds of poly(ADP-ribose), also cleaves the ribose-ribose-ribose bonds at the site of branching.

Chromatography, Gas↗
PubMed1994

Non-covalent interaction between poly(ADP-ribose) and cellular proteins: an application of a poly(ADP-ribose)-western blotting method to detect poly(ADP-ribose) binding on protein-blotted filter.

We describe a sensitive method for the detection of interactions between poly(ADP-ribose) and proteins. Proteins were blotted onto nitrocellulose filters and incubated with 32P-labeled poly(ADP-ribose). Purified core histones and poly(ADP-ribose) polymerase were found to bind poly(ADP-ribose) polymer. Blots of HeLa cell protein extracts revealed a 48 kDa protein and several others of smaller than 35 kDa likewise bound the polymers even at high salt concentrations. Those proteins, along with a 69 kDa protein, also showed resistance to competitor DNA. Polymer binding of aforesaid HeLa extract proteins was restricted to polymers above 20 residues in length. Thus poly(ADP-ribose)-protein affinities were polymer-length dependent.

Base Sequence↗
PubMed2001

Human placenta hydrolases active on free ADP-ribose: an ADP-sugar pyrophosphatase and a specific ADP-ribose pyrophosphatase.

Free ADP-ribose has a reducing ribose moiety and it is hazardous due to its nonenzymic reactivity toward protein side chains. ADP-ribose hydrolases are putative protective agents to avoid the intracellular accumulation of ADP-ribose. In mammalian sources, two types of enzymes with ADP-ribose hydrolase activity are known: (i) highly specific ADP-ribose pyrophosphatases, which in a Mg(2+)-dependent fashion hydrolyse only ADP-ribose and the nonphysiological analogue IDP-ribose, and (ii) less specific nucleoside diphosphosugar or diphosphoalcohol (NDP-X) pyrophosphatases, which besides A(I)DP-ribose hydrolyse also some nonreducing NDP-X substrates. So far, of these two enzyme types only the less specific one has been reported in human sources: an ADP-sugar pyrophosphatase purified from erythrocytes or expressed from cDNA clones. Here we report that human placenta extracts contain two ADP-ribose hydrolases, which were characterised after a near 1000-fold purification. One is an ADP-sugar pyrophosphatase: it hydrolysed ADP-ribose, ADP-glucose and ADP-mannose, but not e.g. UDP-glucose, at similar rates. It resembles the erythrocyte and recombinant enzyme(s), but showed a 5-20-fold lower K(m) for ADP-ribose (7 microM). The other enzyme is a highly specific ADP-ribose pyrophosphatase (the first of this kind to be reported in humans): it hydrolysed only ADP-ribose and IDP-ribose at similar rates, with a very low, 0.4 microM K(m) for the former. This is a major candidate to control the accumulation of free ADP-ribose in humans. It remains to be seen whether it belongs to the 'nudix' protein family, which includes several ADP-ribose hydrolases and other 'housecleaning' enzymes (M.J. Bessman, D.N. Frick, S.F. O'Handley, J. Biol. Chem. 271 (1996) 25059-25062).

Adenosine Diphosphate Ribose↗
PubMed1992

Synthesis of poly(ADP-ribose)-agarose beads: an affinity resin for studying (ADP-ribose)n-protein interactions.

Polymers of ADP-ribose bind chromatosomal histones in solution and may play a role in chromatin accessibility in vivo. We have enzymatically synthesized a poly(ADP-ribose) affinity resin to further characterize binding of nuclear proteins to ADP-ribose polymers. NAD+- and (ADP-ribose)-derivatized agarose beads were recognized as polymer acceptors by the nuclear enzyme poly(ADP-ribose) polymerase. This polymerase elongated the existing ligands by successive addition of exogenously available ADP-ribose residues to form polymers covalently linked to the agarose beads. Poly(ADP-ribose) formation on the beads was dependent on incubation time and the mode of ligand attachment to the agarose. The resulting poly(ADP-ribose)-derivatized agarose beads possessed polymers which closely resembled those modifying the ADP-ribose polymerase by the automodification reaction. Fractionation of rat liver nuclear lysate over the poly(ADP-ribose) resin revealed a strong affinity of H1 for ADP-ribose polymers, thereby supporting a role for poly(ADP-ribose) in chromatin functions. Poly(ADP-ribose)-agarose beads are extremely stable and will be useful not only for affinity studies, but also for mechanistic studies involving polymer elongation and catabolism.

Animals↗
PubMed1984

Presence of poly (ADP-ribose) polymerase and poly (ADP-ribose) glycohydrolase in the dinoflagellate Crypthecodinium cohnii.

Poly(ADP-ribose) polymerase and poly(ADP-ribose) glycohydrolase have been detected in chromatin extracts from the dinoflagellate Crypthecodinium cohnii. Poly(ADP-ribose) glycohydrolase was detected by the liberation of ADP-ribose from poly(ADP-ribose). Poly(ADP-ribose) polymerase was proved by (a) demonstration of phosphoribosyl-AMP in the phosphodiesterase digest of the reaction product, (b) demonstration of ADP-ribose oligomers by fractionation of the reaction product on DEAE-Sephadex. The (ADP-ribose)-protein transfer is dependent on DNA; it is inhibited by nicotinamide, thymidine, theophylline and benzamide. The protein-(ADP-ribose bond is susceptible to 0.1 M NaOH (70%) and 0.4 M NH2OH (33%). Dinoflagellates, nucleated protists, are unique in that their chromatin lacks histones and shows a conformation like bacterial chromatin [Loeblich, A. R., III (1976) J. Protozool. 23, 13--28]; poly(ADP-ribose) polymerase, however, has been found only in eucaryotes. Thus our results suggest that histones were not relevant to the establishment of poly(ADP-ribose) during evolution.

Chemical Phenomena↗
PubMed1985

Amino acid-specific ADP-ribosylation. Sensitivity to hydroxylamine of [cysteine(ADP-ribose)]protein and [arginine(ADP-ribose)]protein linkages.

Hydroxylamine stability has been used to classify (ADP-ribose)protein bonds into sensitive and resistant linkages, with the former representing (ADP-ribose)glutamate, and the latter, (ADP-ribose)arginine. Recently, it was shown that cysteine also serves as an ADP-ribose acceptor. The hydroxylamine stability of [cysteine([32P]ADP-ribose)]protein and [arginine([32P] ADP-ribose)]protein bonds was compared. In transducin, pertussis toxin catalyzes the ADP-ribosylation of a cysteine residue, whereas choleragen (cholera toxin) modifies an arginine moiety. The (ADP-ribose)cysteine bond formed by pertussis toxin was more stable to hydroxylamine than was the (ADP-ribose)arginine bond formed by choleragen. The (ADP-ribose)cysteine bond apparently represents a third class of ADP-ribose bonds. Pertussis toxin ADP-ribosylates the inhibitory guanyl nucleotide-binding regulatory protein (Gi) of adenylate cyclase, whereas choleragen modifies the stimulatory guanyl nucleotide-binding regulatory protein (Gs). These (ADP-ribose)protein linkages are identical in stability to those formed in transducin by the two toxins, consistent with the probability that cysteine and arginine are modified in Gi and Gs, respectively. Bonds exhibiting differences in hydroxylamine-stability were found in membranes from various non-intoxicated mammalian cells following incubation with [32P]NAD, which may reflect the presence of endogenous NAD:protein-ADP-ribosyl-transferases.

Adenosine Diphosphate Ribose↗
PubMed1998

Poly(ADP-ribose) polymerase null mouse cells synthesize ADP-ribose polymers.

Poly(ADP-ribose) polymerase (PARP) (EC 2.4.2.30), the only enzyme known to synthesize ADP-ribose polymers from NAD+, is activated in response to DNA strand breaks and functions in the maintenance of genomic integrity. Mice homozygous for a disrupted gene encoding PARP are viable but have severe sensitivity to gamma-radiation and alkylating agents. We demonstrate here that both 3T3 and primary embryo cells derived from PARP-/- mice synthesized ADP-ribose polymers following treatment with the DNA-damaging agent, N-methyl-N'-nitro-N-nitrosoguanidine, despite the fact that no PARP protein was detected in these cells. ADP-ribose polymers isolated from PARP-/- cells were indistinguishable from that of PARP+/+ cells by several criteria. First, they bound to a boronate resin selective for ADP-ribose polymers. Second, treatment of polymers with snake venom phosphodiesterase and alkaline phosphatase yielded ribosyladenosine, a nucleoside diagnostic for the unique ribosyl-ribosyl linkages of ADP-ribose polymers. Third, they were digested by treatment with recombinant poly(ADP-ribose) glycohydrolase, an enzyme highly specific for ADP-ribose polymers. Collectively, these data demonstrate that ADP-ribose polymers are formed in PARP-/- cells in a DNA damage-dependent manner. Because the PARP gene has been disrupted, these results suggest the presence of a previously unreported activity capable of synthesizing ADP-ribose polymers in PARP-/- cells.

3T3 Cells↗
PubMed1989

Evidence for a novel metabolic pathway of (ADP-ribose)n: pyrophosphorolysis of ADP-ribose in HeLa S3 cell nuclei.

ADP-ribose liberated from (ADP-ribose)n by the action of (ADP-ribose)n glycohydrolase was converted to ATP and ribose 5-phosphate (ribose 5-P) in the presence of pyrophosphate (PPi) in HeLa S3 cell nuclei. This reaction was reversible and dependent on the simultaneous presence of ADP-ribose, PPi, Mg2+, and nuclei. These results suggest the presence of a novel enzyme in the nuclei, designated as ADP-ribose pyrophosphorylase, which catalyzes the reaction shown in Equation 1. ADP-ribose + PPi in equilibrium ATP + Ribose 5-P (1) This reaction could represent a pathway for the biosynthesis of ATP from (ADP-ribose)n in eukaryotic cell nuclei.

Adenosine Diphosphate Ribose↗
PubMed1991

Ribose infusion accelerates thallium redistribution with early imaging compared with late 24-hour imaging without ribose.

To determine if early (4-h) thallium-201 imaging with ribose infusion would enhance detection of thallium redistribution better than late (24-h) imaging without ribose infusion, 15 patients with coronary artery disease underwent thallium stress tests by both methods within 2 weeks. All 15 patients had quantitative coronary angiography. After immediate postexercise planar imaging during the first of two exercise tests, patients were randomized to receive either intravenous ribose (3.3 mg/kg per min) or a control infusion of saline solution for 30 min. Images performed at 4 h for the ribose study were compared with those at 24 h for the saline control study. During the second test, exercise was carried to the same rate-pressure product and each patient received the opposite infusion. Four-hour postexercise images after ribose infusion identified 21 reversible defects not seen in the 24-h saline study. Three reversible defects were seen only in saline studies, but not with ribose at 4 h (p less than 0.01); 15 reversible defects were seen with both tests. When analyzed with respect to the 31 vascular territories supplied by a coronary artery with a greater than 50% stenosis, 8 territories had reversible defects present in the ribose but not the saline study and the saline study did not demonstrate reversible defects in territories that were seen in the ribose study (p less than 0.01). In 14 of these territories, reversible defects were seen with both tests. In 6 of 15 patients, additional vascular territories with reversible defects were identified after ribose infusion. It is concluded that ribose enhances the detection of thallium redistribution at 4 h compared with 24-h control images in patients with coronary artery disease and, therefore, substantially improves the identification of viable ischemic myocardium.

Aged↗
PubMed2002

Analysis of O-acetyl-ADP-ribose as a target for Nudix ADP-ribose hydrolases.

The Sir2 family of NAD(+)-dependent histone/protein deacetylases has been implicated in a wide range of biological activities, including gene silencing, life span extension, and chromosomal stability. Recent evidence has indicated that these proteins produce a novel metabolite O-acetyl-ADP-ribose (OAADPr) during deacetylation. Cellular studies have demonstrated that this metabolite exhibits biological effects when microinjected in living cells. However, the molecular targets of OAADPr remain to be identified. Here we have analyzed the ADP-ribose-specific Nudix family of hydrolases as potential in vivo metabolizing enzymes of OAADPr. In vitro, we found that the ADP-ribose hydrolases (yeast YSA1, mouse NudT5, and human NUDT9) cleaved OAADPr to the products AMP and acetylated ribose 5'-phosphate. Steady-state kinetic analyses revealed that YSA1 and NudT5 hydrolyzed OAADPr with similar kinetic constants to those obtained with ADP-ribose as substrate. In dramatic contrast, human NUDT9 was 500-fold less efficient (k(cat)/K(m) values) at hydrolyzing OAADPr compared with ADP-ribose. The inability of OAADPr to inhibit the reaction of NUDT9 with ADP-ribose suggests that NUDT9 binds OAADPr with low affinity, likely due to steric considerations of the additional acetylated-ribose moiety. We next explored whether Nudix hydrolytic activities against OAADPr could be observed in cell extracts from yeast and human. Using a detailed analysis of the products generated during the consumption of OAADPr in extracts, we identified two robust enzymatic activities that were not consistent with the known Nudix hydrolases. Instead, we identified cytoplasmic esterase activities that hydrolyze OAADPr to acetate and ADP-ribose, whereas a distinct activity residing in the nucleus is consistent with an OAADPr-specific acetyltransferase. These findings establish for the first time that select members of the ADP-ribose hydrolases are potential targets of OAADPr metabolism. However, the predominate endogenous activities observed from diverse cell extracts represent novel enzymes.

Animals↗
PubMed1986

Purification and characterization of poly(ADP-ribose) glycohydrolase. Different modes of action on large and small poly(ADP-ribose).

Poly(ADP-ribose) glycohydrolase was purified approximately 74,000-fold to apparent homogeneity from calf thymus with a yield of 3.2%. The enzyme was a monomeric protein of Mr = 59,000, as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The action of glycohydrolase on poly(ADP-ribose) was exoglycosidic in the direction of adenosine terminus----ribose terminus; radioactive ADP-ribose monomers were immediately produced from evenly labeled poly(ADP-ribose), but not from the polymer labeled selectively at the ribose terminus. The enzymatic degradation of large poly(ADP-ribose) (greater than 20 ADP-ribose residues) proceeded in a biphasic as well as bimodal manner. In the early and rapid phase, the enzyme degraded part of large polymers successively, leaving the remainder completely intact, and accumulated ADP-ribose monomers and small polymers of the size less than half of original polymers, indicating that the enzyme action was processive up to a certain extent. In the late and 20-fold slower phase, by contrast, the enzyme degraded the accumulated small polymers gradually and evenly, i.e. in a nonprocessive manner. The Km for large polymers was approximately 100-fold lower than that for small polymers. Similar rates and processivities were observed with large and small polymers bound to various proteins. These results suggested that the glycohydrolase may regulate differentially the levels of large and small poly(ADP-ribose) in the cell.

Animals↗
PubMed1978

Determination of ADP-ribose and poly(ADP-ribose) by a new radioimmunoassay.

A specific and sensitive radioimmunoassay for ADP-ribose has been developed on the basis of the selective conversion of ADP-ribose to 5'-AMP by alkaline treatment. Antibodies highly specific against 5'-AMP allowed quantification of ADP-ribose converted to 5'-AMP in the range of 1-40 pmol, and in the presence of large quantities of nucleic acids or 3'-AMP. Poly(ADP-ribose) could also be determined when degraded to ADP-ribose by poly(ADP-ribose) glycohydrolase. Determination of the chain length of purified polymer was possible by a parallel determination of ADP-ribose residues after glycohydrolase treatment and of 5'-AMP from the non-reducing end obtained by phosphodiesterase catalyzed hydrolysis. The high specificities of the alkaline conversion of ADP-ribose to 5'-AMP and of the radioimmunoassay for 5'-AMP allowed quantification of protein-bound ADP-ribose residues in crude tissue extracts as verified by comparison with chromatographically purified samples.

Adenosine Diphosphate Sugars↗
PubMed1981

Protein-bound polymeric and monomeric ADP-ribose residues in hepatic tissues. Comparative analyses using a new procedure for the quantification of poly(ADP-ribose).

Determination of poly(ADP-ribose) levels was performed by a new procedure involving covalent chromatography of released polymer, degradation to phosphoribosyl AMP and quantification of this specific derivative by a radioimmunoassay. In adult rat liver, about 85 pmol polymeric ADP-ribose residues/g tissue was found. Similar values were obtained when the determination was carried out by an independent procedure not involving boronate chromatography or sedimentation of DNA. In adult rat liver, polymeric ADP-ribose residues amounted to about 1/200 of total monomeric ADP-ribose residues. Most of the polymeric ADP-ribose residues were linked to proteins by NH2OH-sensitive bonds, while mono(ADP-ribose)-protein conjugates consisted of about equal amounts of NH2OH-sensitive and NH2OH-resistant subfractions. Poly(ADP-ribose) levels immediately after birth were similar to the adult status. They decreased, however, by a factor of three at the time of most rapid post-natal liver growth (day 17). A comparison with the protein-bound monomeric ADP-ribose residues indicated independent changes, and therefore presumably independent functions of these monomeric ADP-ribose residues.

Adenosine Diphosphate Ribose↗
PubMed1996

Ribose catabolism of Escherichia coli: characterization of the rpiB gene encoding ribose phosphate isomerase B and of the rpiR gene, which is involved in regulation of rpiB expression.

Escherichia coli strains defective in the rpiA gene, encoding ribose phosphate isomerase A, are ribose auxotrophs, despite the presence of the wild-type rpiB gene, which encodes ribose phosphate isomerase B. Ribose prototrophs of an rpiA genetic background were isolated by two different approaches. Firstly, spontaneous ribose-independent mutants were isolated. The locus for this lesion, rpiR, was mapped to 93 min on the linkage map, and the gene order zje::Tn10-rpiR-mel-zjd::Tn10-psd-purA was established. Secondly, ribose prototrophs resulted from the cloning of the rpiB gene on a multicopy plasmid. The rpiB gene resided on a 4.6-kbp HindIII-EcoRV DNA fragment from phage lambda 10H5 (642) of the Kohara gene library and mapped at 92.85 min. Consistent with this map position, the cloned DNA fragment contained two divergent open reading frames of 149 and 296 codons, encoding ribose phosphate isomerase B (molecular mass, 16,063 Da) and a negative regulator of rpiB gene expression, RpiR (molecular mass, 32,341 Da), respectively. The 5' ends of rpiB- and rpiR-specified transcripts were located by primer extension analysis. No significant amino acid sequence similarity was found between ribose phosphate isomerases A and B, but ribose phosphate isomerase B exhibited high-level similarity to both LacA and LacB subunits of the galactose 6-phosphate isomerases of several gram-positive bacteria. Analyses of strains containing rpiA, rpiB, or rpiA rpiB mutations revealed that both enzymes were equally efficient in catalyzing the isomerization step in either direction and that the construction of rpiA rpiB double mutants was a necessity to fully prevent this reaction.

Aldose-Ketose Isomerases↗
PubMed1993

Preferential degradation of protein-bound (ADP-ribose)n by nuclear poly(ADP-ribose) glycohydrolase from human placenta.

Poly(ADP-ribose) glycohydrolase, extensively purified to homogeneity from nuclei of human placenta, is composed of a single polypeptide with a molecular mass of 71,000 daltons on sodium dodecyl sulfate-polyacrylamide gel. Judging from its physico-chemical and catalytic properties, the enzyme is similar to the nuclear glycohydrolase (glycohydrolase I), but not to the cytoplasmic glycohydrolase (glycohydrolase II) that has been purified from guinea pig liver (Tanuma, S., Kawashima, K., and Endo, H. (1986) J. Biol. Chem. 261, 965-969; Maruta, H., Inageda, K., Aoki, T., Nishina, H., and Tanuma, S. (1991) Biochemistry 30, 5907-5912). The rates of hydrolysis of (ADP-ribose)n bound to various proteins by the purified nuclear glycohydrolase were higher than those of the corresponding free polymers. Kinetic analyses revealed that the enzyme had more activity toward poly(ADP-ribose) bound to histone H1 or to poly(ADP-ribose) polymerase than toward oligo(ADP-ribose) bound to cytoplasmic proteins from mitochondria or mRNA ribonucleoprotein although the Km and Vmax values were dependent on the chain length (n). In contrast, cytoplasmic glycohydrolase purified from human erythrocytes was more active toward oligo(ADP-ribose) (n = 2.6 or 4.2) bound to the cytoplasmic proteins than to poly(ADP-ribose) (n = 14.6) bound to histone H1, and their kinetic parameters of glycohydrolase II were rather dependent on the acceptor molecules for (ADP-ribose)n. These results suggest that poly(ADP-ribose) glycohydrolase I may play an important role in regulation of poly(ADP-ribosyl)ation levels on chromosomal proteins in nuclei.

Amino Acids↗
PubMed1994

The use of biotinylated poly(ADP-ribose) for studies on poly(ADP-ribose)-protein interaction.

Poly(ADP-ribose) is routinely detected by the use of radioactive polymers formed from labeled substrates. In this report a simple and time-saving method for the biotinylation and the detection of poly(ADP-ribose) on blots is described. The polymer modified by light-induced reaction with photobiotin was colorimetrically detected and quantified, using streptavidine-alkaline phosphatase conjugates. The separation of poly(ADP-ribose) chains on polyacrylamide gels was not affected by the biotinylation of the polymers. When biotinylated poly(ADP-ribose) was used to detect the poly(ADP-ribose) binding capability of proteins in ligand blots, the results were comparable to those obtained with poly([32P]ADP-ribose). Experiments with histones and rat liver nuclear proteins demonstrate that in studies on poly(ADP-ribose)-protein interaction, this method is applicable to the detection of poly(ADP-ribose) binding proteins.

Affinity Labels↗