Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.4.2.30 (PARP)
13,611 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously reported the presence of an endogenous inhibitory activity in bovine brain for the ADP-ribosylation of GTP-binding proteins catalyzed by pertussis toxin (PT) (Hara-Yokoyama, M., and Furuyama, S. (1989) Biochem. Biophys. Res. Commun. 160, 67-71). In the present study, we identified the inhibitor as a ganglioside. The screening of various gangliosides revealed that GQ1b alpha most effectively inhibited the ADP-ribosyltransferase activities of both the holoenzyme and the catalytic subunit of PT. GQ1b alpha is a ganglioside newly identified as one of the antigens recognized by the cholinergic neuron-specific antibody, anti-Chol-1 alpha (Hirabayashi, Y., Nakao, T., Irie, F., Whittaker, V.P., Kon, K., and Ando, S. (1992) J. Biol. Chem. 267, 12973-12978). GQ1b alpha also inhibited the PT-catalyzed NAD+ glycohydrolysis. Unlike PT activity, the ADP-ribosylation and the NAD+ glycohydrolysis catalyzed by the C3 exoenzyme from Clostridium botulinum type C were inhibited by GT1b and GQ1b. The ADP-ribosylation catalyzed by either PT or the C3 exoenzyme was not inhibited by ceramide, galactocerebroside, or sialic acid. In addition to the inhibitory action of gangliosides on ADP-ribosylation, the importance of gangliosides as regulators of NAD+ metabolism is discussed.
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PMID:Identification of gangliosides as inhibitors of ADP-ribosyltransferases of pertussis toxin and exoenzyme C3 from Clostridium botulinum. 771 15

ADP-ribosylation factors (ARFs), initially described as activators of cholera toxin ADP-ribosyltransferase activity, regulate intracellular vesicular membrane trafficking and stimulate a phospholipase D (PLD) isoform. ARF-like (ARL) proteins are structurally related to ARFs but do not activate cholera toxin and have relatively little effect on PLD. A new human ARL gene termed hARL1, which shares 57% amino acid identity with hARF1, was identified using a polymerase chain reaction-based cloning method. To determine whether different structural elements are responsible for the activation structural elements are responsible for the activation of the A subunit of cholera toxin and PLD, chimeric proteins were constructed by switching the amino-terminal 73 amino acids of ARF1 and ARL1. The recombinant rL73/F protein, in which the amino-terminal 73 amino acids of ARL1 replaced those of ARF1, activated the A subunit of cholera toxin, whereas the rF73/L protein, in which the NH2-terminal 73 amino acids of ARF1 replaced those of ARL1, was inactive. The two chimeric proteins had quite opposite effects on PLD activity. rF73/L activated PLD as effectively as rARF1, whereas rL73/F protein activated PLD only slightly. It appears that the amino-terminal region of ARF1 is not critical for its action as a GTP-dependent activator of cholera toxin, whereas it is necessary for activation of the putative effector enzyme, PLD.
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PMID:Different ARF domains are required for the activation of cholera toxin and phospholipase D. 781 76

The ADP-ribosyltransferase produced by a pathogenic strain of Bacillus cereus was purified to near homogeneity. The transferase is a 28,000 Da molecular mass enzyme with a pI of 10.3. The specific enzyme activity is 7.0 nmol of ADP-ribose min-1 mg-1 with a Km for NAD of 0.3 microM. Partial amino acid sequence analysis of the exoenzyme reveals no significant homology to Clostridium botulinum C3 nor to Clostridium limosum exoenzyme. The novel exoenzyme selectively modifies the small GTP-binding proteins of the Rho family presumably at the same acceptor amino acid (Asn-41) as determined for C3. Besides cellular Rho, recombinant RhoA and -B are substrates for the exoenzyme. However, recombinant Rac1 and CDC42, although belonging to the Rho family, are not modified. B. cereus exoenzyme was photolabeled with [carbonyl-14C]NAD resulting in inhibition of ADP-ribosyltransferase and NAD-glycohydrolase activity. A glutamic acid residue was identified as part of the NAD-binding site which corresponds to Glu-174 of C3. This glutamic acid is located in a domain which shows high homology with the C-terminal part of C3 exoenzyme, C. limosum exoenzyme, and Staphylococcus aureus EDIN and which probably represents the catalytic site of the transferases. The data indicate that B. cereus exoenzyme is a novel member of the family of C3-like ADP-ribosyltransferases which share the same substrate protein Rho and which have an identical highly conserved catalytic domain.
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PMID:Rho-ADP-ribosylating exoenzyme from Bacillus cereus. Purification, characterization, and identification of the NAD-binding site. 781 16

Enterotoxin A is one of the major virulence factors of Clostridium difficile, and the causative agent of antibiotic-associated pseudomembranous colitis. In cell culture (NIH-3T3, rat basophilic leukemia cells) toxin A inhibits Clostridium botulinum ADP-ribosyltransferase C3 (C3)-catalyzed ADP-ribosylation of the low molecular mass GTP-binding Rho proteins. Rho participates in the regulation of the microfilament cytoskeleton. Decrease in ADP-ribosylation of Rho occurs in a time- and concentration-dependent manner and precedes the toxin A-induced destruction of the actin cytoskeleton. Action of toxin A is not due to proteolytical degradation of Rho or to an inherent ADP-ribosyltransferase activity of toxin A. Toxin A-induced decrease in ADP-ribosylation is observed also in cell lysates and with recombinant RhoA protein. A heat stable low molecular mass cytosolic factor is essential for the toxin effect on Rho. Thus, the enterotoxin (toxin A) resembles the effects of the C. difficile cytotoxin (toxin B) on Rho proteins (Just, I., G. Fritz, K. Aktories, M. Giry, M. R. Popoff, P. Boquet, S. Hegenbath, and C. Von Eichel-Streiber. 1994. J. Biol. Chem. 269:10706-10712). The data indicate that despite different in vivo effects, toxin A and toxin B act on the same cellular target protein Rho to elicit their toxic effects.
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PMID:The low molecular mass GTP-binding protein Rho is affected by toxin A from Clostridium difficile. 788 50

The mechanism by which NAD stimulates cardiac adenylate cyclase was investigated. In highly purified canine cardiac sarcolemma, NAD stimulated adenylate cyclase activity in the presence of agents which activate Gs (i.e. 5 mM AlF4-, 10 microM GTP gamma S, 10 microM GppNHp or isoproterenol plus 2 nM GTP gamma S). Furthermore, the EC50 of isoproterenol to stimulate adenylate cyclase was reduced in the presence of NAD. In membranes incubated with [32P]-NAD, AlF4-, 10 microM GTP gamma S or isoproterenol plus 2 nM GTP gamma S produced a selective increase in the radiolabeling of a single 45-kDa protein which was identified as Gs alpha by immunoprecipitation. Cholera toxin catalysed radiolabeling of the same protein. Neutral hydroxylamine released [32P]-ADP-ribose from Gs alpha prelabeled in the presence of AlF4- and [32P]-NAD indicating that an arginine residue on Gs alpha was modified by an endogenous ADP-ribosyltransferase. ADP-ribosyltransferase inhibitors, novobiocin, vitamin K1 or 3-aminobenzamide, inhibited AlF4- stimulated ADP-ribosylation of Gs alpha and NAD potentiation of adenylate cyclase with similar efficacies. The activity responsible for NAD potentiation of adenylate cyclase and ADP-ribosylation of Gs alpha was not removed under hypotonic or hypertonic conditions and therefore appears to be tightly membrane bound. Collectively, these observations indicate that canine cardiac sarcolemma possess an ADP-ribosyltransferase which may constitutively catalyse transfer of an ADP-ribose to activated Gs alpha.
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PMID:Modification of cardiac membrane adenylate cyclase activity and Gs alpha by NAD and endogenous ADP-ribosyltransferase. 800 86

ADP-ribosylation factors (ARFs) are highly conserved approximately 20-kDa guanine nucleotide-binding proteins that enhance the ADP-ribosyltransferase activity of cholera toxin, and are believed to participate in vesicular transport in both exocytic and endocytic pathways. Based on size, phylogenetic analysis, amino acid sequence, and gene structure, mammalian ARFs fall into three classes (class I, ARFs 1, 2, 3; class II, ARFs 4, 5; class III, ARF6). Two ARF genes (yARF1, yARF2) are known in Saccharomyces cerevisiae and believed to participate in vesicular trafficking in the Golgi system; the double deletion mutant is not viable. A third yeast ARF (yARF3) cDNA has been cloned by polymerase chain reaction-based procedures. It contains an open reading frame of 549 bases encoding a protein of 183 amino acids, with a deduced amino acid sequence more identical (60%) to that of the class III mammalian ARF than to those of the other two classes (52-56%). The yARF3 protein, however, reacted poorly with antibodies against any of the three classes of mammalian ARFs. In the presence of GTP, recombinant yARF3 protein stimulated cholera toxin-catalyzed auto-ADP-ribosylation. yARF3 gene transcription, similar to that of yARF2, was repressed by glucose. As yARF3 was not essential for cell viability and was not required for endoplasmic reticulum to Golgi protein transport, it may provide an opportunity to define an ARF function in another kind of vesicular trafficking.
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PMID:Characterization of a glucose-repressible ADP-ribosylation factor 3 (ARF3) from Saccharomyces cerevisiae. 806 10

It has been proposed that the amino-terminal domain of ADP-ribosylation factor (ARF) is critical for its stimulation of cholera toxin ADP-ribosyltransferase activity. In this study, recombinant ARF1 (rARF1), r delta 13ARF1 (recombinant ARF1 lacking the first 13 amino acids) and rPKA14ARF1 (recombinant ARF1 in which the first 14 amino acids were replaced by the first 7 amino acids of the cAMP-dependent protein kinase catalytic subunit) were used to assess the effect of the amino terminus on the ability of ARF to enhance ADP-ribosylation of agmatine by the cholera toxin A subunit. The GTP-dependent ARF activities of r delta 13ARF1 and rPKA14ARF1 were similar to that of rARF1, whereas the GTP requirement for half-maximal activation of cholera toxin A, was somewhat higher for rARF1 than it was for r delta 13ARF1 and rPKA14ARF1. These results are consistent with the view that the amino terminus of ARF1 is not critical for its action as a GTP-dependent activator of cholera toxin.
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PMID:Effect of ADP-ribosylation factor amino-terminal deletions on its GTP-dependent stimulation of cholera toxin activity. 814 66

ADP-ribosylation factors (ARFs) are approximately 20-kDa guanine nucleotide-binding proteins that participate in vesicular transport in the Golgi and other intracellular compartments and stimulate cholera toxin ADP-ribosyltransferase activity. ARFs are active in the GTP-bound form; hydrolysis of bound GTP to GDP, possibly with the assistance of a GTP hydrolysis (GTPase)-activating protein results in inactivation. Exchange of GDP for GTP and reactivation were shown by other workers to be enhanced by Golgi membranes in a brefeldin A-sensitive reaction, leading to the proposal that the guanine nucleotide-exchange protein (GEP) was a target of brefeldin A. In the studies reported here, a soluble GEP was partially purified from bovine brain. Exchange of nucleotide on ARFs 1 and 3, based on increased ARF activity in a toxin assay and stimulation of binding of guanosine 5'-[gamma-[35S]thio]triphosphate, was dependent on phospholipids, with phosphatidylserine being more effective than cardiolipin. GEP appeared to increase the rate of nucleotide exchange but did not affect the affinity of ARF for GTP. Whereas the crude GEP had a size of approximately 700 kDa, the partially purified GEP behaved on Ultrogel AcA 54 as a protein of 60 kDa. With purification, the GEP activity became insensitive to brefeldin A, consistent with the conclusion that, in contrast to earlier inferences, the exchange protein is not itself the target of brefeldin A.
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PMID:Identification of a brefeldin A-insensitive guanine nucleotide-exchange protein for ADP-ribosylation factor in bovine brain. 815 7

Cytotoxic necrotizing factor type 2 (CNF2) produced by Escherichia coli strains isolated from intestinal and extraintestinal infections is a dermonecrotic toxin of 110 kDa. We cloned the CNF2 gene from a large plasmid carried by an Escherichia coli strain isolated from a lamb with septicemia. Hydropathy analysis of the deduced amino acid sequence revealed a largely hydrophilic protein with two potential hydrophobic transmembrane domains. The N-terminal half of CNF2 showed striking homology (27% identity and 80% conserved residues) to the N-terminal portion of Pasteurella multocida toxin. Methylamine protection experiments and immunofluorescence studies suggested that CNF2 enters the cytosol of the target cell through an acidic compartment and induces the reorganization of actin into stress fibers. Since the formation of stress fibers in eukaryotic cells involves Rho proteins, we radiolabeled these small GTP-binding proteins from CNF2-treated and control cells with a Rho-specific ADP-ribosyltransferase. The [32P]ADP-ribosylated Rho proteins from CNF2-treated cells migrated slightly more slowly in SDS/PAGE than did the labeled proteins from the control cells. This shift in mobility of Rho proteins in SDS/PAGE was also observed when CNF2 and the RhoA protein were coexpressed in E. coli. We propose that Rho proteins are the targets of CNF2 in mammalian cells.
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PMID:Cytotoxic necrotizing factor type 2 produced by virulent Escherichia coli modifies the small GTP-binding proteins Rho involved in assembly of actin stress fibers. 817 Sep 93

The highly homologous Rho proteins RhoA, RhoB and RhoC are low-molecular-mass GTP-binding proteins. They are selectively ADP-ribosylated by Clostridium botulinum ADP-ribosyltransferase C3 (C3 exoenzyme). The biological function of the Rho proteins is still unclear; there is evidence that they are involved in the regulation of the filamental network of cells. Here we report that C3 exoenzyme-like toxins ADP-ribosylate small GTP-binding proteins in bovine spermatozoa and inhibit sperm motility. These findings indicate that Rho proteins which reportedly regulate the microfilament system are basically involved in sperm motility.
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PMID:ADP-ribosylation of Rho proteins inhibits sperm motility. 822 22


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