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)

RT6.2 is a 26-kDa alloantigen expressed only on post-thymic T cells and attached to the cell membrane through a glycosylphosphatidylinositol (GPI) anchor. It has been reported that expression of RT6.2 in animal models may correlate with lymphopenia and genetically-induced insulin-dependent diabetes mellitus. Its physiological function is unclear. Since RT6.2 has significant amino acid identity with a GPI-anchored rabbit muscle NAD:arginine ADP-ribosyltransferase, RT6.2 was expressed in rat mammary adenocarcinoma cells and the ability of the expressed protein to catalyze ADP-ribose transfer reactions was examined. Cells transformed with the RT6.2 gene expressed NAD glycohydrolase activity that was released from intact cells by phosphatidylinositol-specific phospholipase C, consistent with its presence on the cell surface. A similar activity was not detected with vector-transformed cells. RT6.2 did not ADP-ribosylate simple guanidino compounds. The molecular weight of the phosphatidylinositol-specific phospholipase C-released NAD glycohydrolase, determined by SDS-polyacrylamide gel electrophoresis, was 22,000-24,000, in good agreement with that of native RT6.2. These results strongly suggest that the rat T cell alloantigen RT6.2 is a GPI-anchored NAD glycohydrolase.
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PMID:Expression of NAD glycohydrolase activity by rat mammary adenocarcinoma cells transformed with rat T cell alloantigen RT6.2. 814 25

NAD:arginine ADP-ribosyltransferases catalyze the transfer of the ADP-ribose moiety from NAD to an arginine in an acceptor protein, whereas ADP-ribosylarginine hydrolases remove ADP-ribose, regenerating free arginine and completing an ADP-ribosylation cycle. A family of four mono-ADP-ribosyltransferases was isolated and characterized from turkey erythrocytes. Transferases from rabbit and human skeletal muscle were cloned. The muscle transferases are glycosylphosphatidylinositol-anchored proteins and highly conserved across mammalian species. The rat T cell alloantigen RT6.2 has significant amino acid sequence identity to the muscle ADP-ribosyltransferase. Mammalian cells transformed with the RT6.2 coding region cDNA expressed NAD glycohydrolase activity. Sequences of RT6.2, rabbit muscle transferase and several of the bacterial toxin ADP-ribosyltransferases contain regions of amino acid similarity which, in the bacterial toxin ADP-ribosyltransferases, form the NAD-binding and active-site domains. ADP-ribosylarginine hydrolase, initially purified from turkey erythrocytes, was cloned from rat, mouse, and human brain. Deduced amino acid sequences of the rat and mouse hydrolases were 94% identical with five conserved cysteines whereas the human hydrolase sequence was 83% identical to that of the rat, with four conserved cysteines. It is unclear how an intracellular hydrolase acts in concert with a surface ADP-ribosyltransferase.
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PMID:Characterization of mammalian ADP-ribosylation cycles. 852 84

A family of glycosylphosphatidylinositol-linked ADP-ribosyltransferases, of which cDNAs were cloned from various mammalian cells, possess a common Glu-rich motif (EEEVLIP) near their carboxyl termini. Although the first Glu in the common motif is replaced by Gln (Q207EEVLIP) in rat T lymphocyte alloantigens RT6.1 and RT6.2, the two RT6s appear to have both activities of NAD+ glycohydrolase and ADP-ribosyltransferase to a lesser extent. To investigate the significance of the Glu-rich motif in the two enzyme activities, we produced a mutant RT6.1 (Q207E), in which Gln207 was replaced by Glu, together with wild-type RT6s, in Escherichia coli. Kinetic analysis revealed that there were no marked differences in the Vmax and Km values of NAD+ glycohydrolases among the three recombinant proteins. The recombinant RT6.1 and RT6.2 displayed extremely low auto-ADP-ribosylation, although the latter modification was somewhat higher than the former. In contrast, much greater auto-modification was observed for the Q207E mutant. Moreover, the mutant could effectively ADP-ribosylate agmatine as a substrate. Thus, the single amino acid mutation of RT6.1 caused a marked increase in its ADP-ribosyltransferase activity, indicating that the Glu-rich motif near the carboxy terminus plays an important role in the enzyme activity.
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PMID:Increase in ADP-ribosyltransferase activity of rat T lymphocyte alloantigen RT6.1 by a single amino acid mutation. 869 84

ADP-ribosylation of proteins has been observed in numerous animal tissues including chicken heterophils, rat brain, human platelets, and mouse skeletal muscle. ADP-ribosylation in these tissues is thought to modulate critical cellular functions such as muscle cell development, actin polymerization, and cytotoxic T lymphocyte proliferation. Specific substrates of the ADP-ribosyltransferases have been identified; the skeletal muscle transferase ADP-ribosylates integrin alpha 7 whereas the chicken heterophil enzyme modifies the heterophil granule protein p33 and the CTL enzyme ADP-ribosylates the membrane-associated protein p40. Transferase sequence has been determined which should assist in elucidating the role of ADP-ribosylation in cells. There is sequence similarity among the vertebrate transferases and the rodent RT6 alloantigens. The RT6 family of proteins are NAD glycohydrolases that have been shown to possess auto-ADP-ribosyltransferase activity whereas the mouse Rt6-1 is also capable of ADP-ribosylating histone. Absence of RT6+ T cells has been associated with the development of an autoimmune-mediated diabetes in rodents. Humans have an RT6 pseudogene and do not express RT6 proteins. The reversal of ADP-ribosylation is catalyzed by ADP-ribosylarginine hydrolases, which have been purified and cloned from rodent and human tissues. In principle, the transferases and hydrolases could form an intracellular ADP-ribosylation regulatory cycle. In skeletal muscle and lymphocytes, however, the transferases and their substrates are extracellular membrane proteins whereas the hydrolases described thus far are cytoplasmic. In cultured mouse skeletal muscle cells, processing of the ADP-ribosylated integrin alpha 7 was carried out by phosphodiesterases and possibly phosphatases, leaving a residual ribose attached to the (arginine)protein. Several bacterial toxin and eukaryotic mono-ADP-ribosyltransferases, and perhaps other NAD-utilizing enzymes such as the RT6 alloantigens share regions of amino acid sequence similarity, which form, in part, the catalytic site. The catalytic cleft, found in the bacterial toxins that have been studied thus far, contains a critical glutamate and other amino acids that function to position NAD for nucleophilic attack at the N-glycosidic linkage, for either ADP-ribose transfer or NAD hydrolysis. Amino acid differences among the transferases at the active site may be required for accommodating the different ADP-ribose acceptor molecules.
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PMID:Structure and function of eukaryotic mono-ADP-ribosyltransferases. 889 63

A rat T-cell antigen RT6.1 catalyzes NAD glycohydrolysis but not ADP-ribose transfer, even though the antigen has significant amino acid identity with eucaryotic arginine-specific ADP-ribosyltransferases. Since a highly conserved Glu in the catalytic region of these transferases is substituted with Gln at position 207 in RT6.1, we replaced the Gln with Glu, Asp, or Ala, by site-directed mutagenesis. The Glu-207 mutant produced ADP-ribosylarginine during incubation with NAD and L-arginine. The Asp-207 mutant but not the Ala-207 mutant produced ADP-ribosylarginine, but at a lower rate. In contrast, these mutations affected NAD glycohydrolase activity of RT6.1 to a much lesser extent. Kinetic studies of transferase reaction revealed that kcat of the Glu-207 mutant increased compared to findings with the Asp-207 mutant. Moreover, the mouse homologue of rat RT6 lost arginine-specific ADP-ribosyltransferase activity when Glu-207 was replaced with Gln. Thus, Glu-207 in rodent T-cell RT6 antigens is essential for transfer reaction of ADP-ribose to arginine.
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PMID:Glutamic acid 207 in rodent T-cell RT6 antigens is essential for arginine-specific ADP-ribosylation. 893 82

Rat RT6 proteins, and perhaps mouse Rt6, identify a set of immunoregulatory T lymphocytes. Rat RT6.1 (RT6.1) and rat RT6.2 (RT6. 2) are NAD glycohydrolases, which catalyze auto-ADP-ribosylation, but not ADP-ribosylation of exogenous proteins. Mouse Rt6.1 (mRt6.1) also catalyzes auto-ADP-ribosylation. The activity of mouse cytotoxic T lymphocytes is reportedly inhibited by ADP-ribosylation of surface proteins, raising the possibility that mRt6 may participate in this process. The reactions catalyzed by mRt6, would, however, need to be more diverse than those of the rat homologues and include the ADP-ribosylation of acceptors other than itself. To test this hypothesis, mRt6.1 and rat RT6.2 were synthesized in Sf9 insect cells and rat mammary adenocarcinoma (NMU) cells. mRt6.1, but not rat RT6.2, catalyzed the ADP-ribosylation of guanidino-containing compounds (e.g. agmatine). Unlike RT6.2, mRt6.1 was a weak NAD glycohydrolase. In the presence of agmatine, however, the ratio of [adenine-14C]ADP-ribosylagmatine formation from [adenine-14C]NAD to [carbonyl-14C]nicotinamide formation from [carbonyl-14C]NAD was approximately 1.0, demonstrating that mRt6.1 is primarily a transferase. ADP-ribosylarginine hydrolase, which preferentially hydrolyzes the alpha-anomer of ADP-ribosylarginine, released [U-14C]arginine from ADP-ribosyl[U-14C]arginine synthesized by mRT6.1, consistent with the conclusion that mRt6.1 catalyzes a stereospecific Sn2-like reaction. Thus, mRt6.1 is an NAD:arginine ADP-ribosyltransferase capable of catalyzing a multiple turnover, stereospecific Sn2-like reaction.
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PMID:Characterization of mouse Rt6.1 NAD:arginine ADP-ribosyltransferase. 902 Jan 54

Mono-ADP-ribosylation, like phosphorylation, is an enzyme-catalyzed, reversible post-translational modification that modulates protein function. It was originally discovered as the pathogenic principle of diphtheria-, cholera-, and other potent bacterial toxins. By analogy, corresponding enyzmes were postulated to exist in animal tissues, and mounting biochemical evidence indicates that such enzymes, indeed, play important regulatory roles in cellular functions. The molecular cloning of the first mammalian mono(ADP-ribosyl)transferase from rabbit skeletal muscle, the finding of its homology to a well-studied T-cell marker, RT6, and the molecular cloning of additional gene family members from mammals and birds is providing fresh impetus to research in this field. Intriguingly, these vertebrate enzymes are predicted to be secretory or membrane proteins. They are expressed in lymphatic tissues, muscle, testis, bone marrow, and erythroblasts. Here we review the relationship between this novel family of eucaryotic mono(ADP-ribosyl)transferases (mADPRTs), ADP-ribosylating bacterial toxins, the poly(ADP-ribose)polymerase (PARP), the ADP-ribosyl cyclases, and the ADP-ribosylprotein hydrolase (ARH) in terms of their structure, enzymatic properties and possible biological functions.
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PMID:Mono(ADP-ribosyl)transferases and related enzymes in animal tissues. Emerging gene families. 919 31

Among a number of tissues and peripheral blood cells in chicken, leukocytes, bone marrow cells, liver and spleen showed high ADP-ribosyltransferase activity, with leukocytes having the highest. Density gradient centrifugation of the leukocytes revealed that the leukocyte ADP-ribosyltransferase originates in the polymorphonuclear cells, so called heterophils. Subcellular distribution of the cells showed the localization of the enzyme in the granule fraction. Based on the obtained amino acid sequences of arginine-specific ADP-ribosyltransferase purified from chicken peripheral heterophils, two arginine-specific ADP-ribosyltransferase cDNAs (designated AT1 and AT2) were obtained from chicken bone marrow cells. Each cDNA encodes a different peptide of 312 amino acid residues. Homology of the deduced amino acid sequences between AT1 and AT2 was 78.3%. Arginine-specific ADP-ribosyltransferase activity was detected in culture medium of COS 7 cells transiently transfected with AT1 cDNA, while activity from the cells transfected with AT2 cDNA was found in both culture medium and cell lysate. AT1 transferase required 2-mercaptoethanol (MSH) for the activity and in the presence of NaCl, the activity was inhibited while the AT2 enzyme was activated by either agent. Highly conserved regions were observed among the deduced amino acid sequences of AT1, AT2, chicken erythroblast and rabbit and human skeletal muscle ADP-ribosyltransferases, and rodent T-cell surface antigen RT6. Two forms of the transferase with much the same properties as AT1 and AT2 proteins, regarding the effect of NaCl and MSH, were detected in bone marrow cells. Based on these results it seems that AT1 and AT2 cDNAs encode the two forms of arginine-specific ADP-ribosyltransferase detected in chicken bone marrow cells.
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PMID:Molecular cloning and characterization of arginine-specific ADP-ribosyltransferases from chicken bone marrow cells. 919 46

We searched the database of expressed sequence tags (dbEST) for relatives of the known human and murine mono(ADP-ribosyl)transferases (mADPRT), poly(ADP-ribosyl)polymerases (PARP), ADP-ribosyl cyclases, and ADP-ribosylarginine hydrolases (ARH). By May 31, 1996, all of the known enzymes except for RT6 were represented in dbEST by exact sequence matches from mouse and/or human tissues. Several ESTs show significant sequence similarity but not identity to known mADPRTs. We isolated, cloned, and sequenced the corresponding genes. Our results show that seven human ESTs stem from a novel gene, provisionally designated LART, which is specifically expressed in lymphatic tissues. Five human ESTs stem from a novel gene, here designated TART1, which is specifically expressed in testis. This gene is also represented by a single mouse EST. One other mouse EST stems from a distinct gene, here designated TART2, which is also expressed in testis. These genes have similar exon/intron structures. The predicted LART and TART1 gene products contain hydrophobic N- and C-terminal signal peptides characteristic for GPI-anchored surface proteins, TART2 lacks the GPI-anchor signal peptide. The predicted native proteins show 28-42% sequence identity to one another. They each contain four cysteine residues that probably form conserved disulfide bonds. They each also contain a conserved glutamic acid residue within the proposed active site motif LART and TART1 show interesting deviations from the surrounding consensus sequence.
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PMID:Use of the EST database resource to identify and clone novel mono(ADP-ribosyl)transferase gene family members. 919 49

We report that rat RT6.2 and recombinant mouse Rt6 locus 1 proteins possess auto-ADP-ribosyltransferase activity and that Rt6, but not RT6, catalyzes the ADP-ribosylation of exogenous histones. Based on NH2OH sensitivity, it appeared that the ADP-ribose was attached to arginine residues on proteins. We also observed that the NAD+ concentration in culture medium correlates inversely with the proliferation of rat RT6+ T cells. The data suggest that lymphocyte surface ADP-ribosyltransferases could be involved in signaling and immunoregulatory processes.
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PMID:Mouse RT6 locus 1 and rat RT6.2 are NAD+. Arginine ADP-ribosyltransferases with auto-ADP-ribosylation activity. 919 50


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