ADP-ribosylation of nuclear proteins

Purnell, Michael R.; Stone, Peter; Whish, William J. D.

doi:10.1042/bst0080215

Cited by 208 publications

(31 citation statements)

References 42 publications

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“…It has been suggested that the nuclear location of NAD pyrophosphorylase is related to the involvement of NAD+ in the regulation of cellular activity [6] and a correlation between NAD pyrophosphorylase activity and mitosis has been observed [7, 81; there are also numerous examples of a correlation between NAD pyrophosphorylase activity and DNA synthesis [4,. This suggestion was supported by the discovery of a chromosomal protein, poly(ADP-ribose) synthetase [13 -151, which uses NAD' as a substrate for the post-translational modification of nuclear proteins [16,17], including histones [I 8, 191. Although the precise physiological role of this enzyme remains unclear, there is evidence that poly(ADP-ribosy1)ation is involved in DNA replication, mitosis, transcription and the repair of damaged DNA [17, 20- only a small amount of exchange occurs and the reasonable conclusion was made that there is no support for an adenylylenzyme intermediate [24].…”

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confidence: 89%

The Stereochemical Course of Nucleotidyl Transfer Catalysed by NAD Pyrophosphorylase

Lowe

Tansley

1983

European Journal of Biochemistry

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NAD pyrophosphorylase catalyses nucleotidyl transfer from adenosine (R)-~'- [E-' 70]triphosphate to nicotinamide mononucleotide with inversion of configuration at the a-P giving (S)- ['70]NAD'. The simplest interpretation of this observation is that the adenylyl group is transferred directly from ATP to the co-substrate by an 'in line' mechanism. It is also shown that snake venom phosphodiesterase hydrolyses NAD ' regio-specifically at the adenylyl terminus of the pyrophosphate bond.NAD pyrophosphorylase catalyses nucleotidyl transfer from MgATP to nicotinamide mononucleotide (NMN) to form NAD' [I].This reaction is the final step in the main biosynthetic pathway to NAD' in eukaryotic cells [2] and it is particularly noteworthy that NAD pyrophosphorylase is the only enzyme in the pathway that is located in the cell nucleus [3 -51. It has been suggested that the nuclear location of NAD pyrophosphorylase is related to the involvement of NAD+ in the regulation of cellular activity [6] and a correlation between NAD pyrophosphorylase activity and mitosis has been observed [7, 81; there are also numerous examples of a correlation between NAD pyrophosphorylase activity and DNA synthesis [4,. This suggestion was supported by the discovery of a chromosomal protein, poly(ADP-ribose) synthetase [13 -151, which uses NAD' as a substrate for the post-translational modification of nuclear proteins [16,17], including histones [I 8, 191. Although the precise physiological role of this enzyme remains unclear, there is evidence that poly(ADP-ribosy1)ation is involved in DNA replication, mitosis, transcription and the repair of damaged DNA [17, 20-231.NAD pyrophosphorylase activity is very low in tumour cells when compared with normal adult cells and is probably close to the critical level for cell survival [4, 81. Consequently NAD pyrophosphorylase has been regarded as a potential target site for cancer chemotherapy [S], since the minimum inhibitory concentration lethal to tumour cells is not likely to cause serious damage to normal cells. Since a knowledge of the mechanism of action of this enzyme and the juxtaposition of the substrates when bound to the enzyme would undoubtedly assist in the design of a specific inhibitor, we have investigated the stereochemical course of nucleotidyl transfer catalysed by .NAD pyrophosphorylase.N AD pyrophosphorylase catalyses exchange between ATP and [32P]PPi in the presence of NMN; in the absence of NMN Enzyme. NAD pyrophosphorylase or NMN adenylyltransferase (EC 2.7.7.1).only a small amount of exchange occurs and the reasonable conclusion was made that there is no support for an adenylylenzyme intermediate [24]. However the possibility of an induced conformational change of the enzyme on binding NMN leading to a more facile adenylyl transfer to the putative adenylyl-enzyme intermediate is difficult to rule out [25]. We have undertaken therefore to determine the stereochemical course of the nucleotidyl transfer catalysed by NAD pyrophosphorylase using adenosine (R)-5'-[a-170]triphosphate [26,...

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confidence: 89%

The Stereochemical Course of Nucleotidyl Transfer Catalysed by NAD Pyrophosphorylase

Lowe

Tansley

1983

European Journal of Biochemistry

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“…[1][2][3][4]. Eukaryotic cells also contain endogenous proteins that are modified by single ADP-Rib residues (cf.…”

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confidence: 99%

Nonenzymic ADP-ribosylation of specific mitochondrial polypeptides.

Hilz¹,

Koch²,

Fanick³

et al. 1984

Proc. Natl. Acad. Sci. U.S.A.

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The apparent NAD:protein ADP-ribosyl transferase activity of mitochondria and submitochondrial particles from beef heart and rat liver is simulated by a reaction sequence that consists of an enzymic hydrolysis of NAD to ADP-ribose (ADP-Rib) by NAD glycohydrolase(s) and a nonenzymic ADP-ribosylation of acceptor proteins by the free ADP-Rib formed. The nonenzymic ADP-ribosylation of mitochondrial proteins showed two pH optima and exhibited the same remarkable selectivity as the reaction with NAD. The predominant acceptor in beef heart mitochondria was a 30-kDa protein, whereas in mitochondrial extracts of rat liver a 50-55 kDa polypeptide served as an acceptor. No authentic ADP-Rib transferase activity could be detected even when free ADP-Rib was trapped by NH2OH. Once formed, the mitochondrial ADP-Rib conjugates were resistant to hydroxylamine. NH2OH-resistant mono(ADP-Rib)-protein conjugates as found in most cells may also be products of nonenzymic ADP-ribosylation. In mouse tissues, their amounts relate to protein and NAD contents, and they increase specifically and reversibly in the hypothyroid status. Furthermore, intact rat liver mitochondria contain a mono(ADP-Rib)-polypeptide (50-55 kDa) that appeared to be identical with the polypeptide reacting with ADP-Rib in vitro.Various phage enzymes and bacterial toxins catalyze the transfer of single ADP-ribose (ADP-Rib) residues from NAD to one or several protein acceptors (for reviews, see refs. 1-4). Eukaryotic cells also contain endogenous proteins that are modified by single ADP-Rib residues (cf. ref. 5). In rat liver, most of these mono(ADP-Rib)-protein conjugates are located in the cytoplasm, whereas poly(ADP-Rib)-protein conjugates appear to be confined to the nucleus (6). Two types of endogenous mono(ADP-Rib)-conjugates can be distinguished by their sensitivity towards neutral hydroxylamine. They show independent changes and they are distributed unevenly in various organs of the mouse (5, 7).Interest in cytoplasmic ADP-ribosylation was greatly stimulated when diphtheria toxin-and cholera toxin-catalyzed ADP-ribosylation was detected (7-12) and when membrane-bound (12, 13), cytosolic (14), and mitochondrial (15, 16) ADP-ribosyl transferase activities were described. It was also reported that free ADP-Rib can form Schiff bases with amino groups of proteins, especially of the histones, when incubated at slightly alkaline conditions (17), while true ADP-Rib transferase activity in mitochondria was said to be operating at pH values <7 (18). However, the use of various inhibitors in mitochondrial preparations indicated to us that nonenzymic ADP-ribosylation was occurring at lower pH values as well.This paper describes a reaction sequence found in mitochondria (and plasma membranes) that involves the hydrolysis of NAD by NAD glycohydrolases and the nonezymic ADP-ribosylation of specific acceptors to form acid-stable conjugates. This reaction sequence simulated ADP-Rib transferase activity, and the similarity of acceptors in vivo and in vitro provides sugg...

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“…ADP-ribosyl transferase is a nuclear enzyme that transfers ADP-ribosyl residues from NAD ÷ to chromatin proteins, to form mono-, oligo-and poly(ADPribose) (reviews [1][2][3][4]). The enzyme is totally dependent on DNA [5] and is markedly stimulated by fragmentation of the DNA [6][7][8][9].…”

Section: Introductionmentioning

confidence: 99%

Inhibitors of nuclear ADP‐ribosyl transferase retard DNA repair after N‐methyl‐N‐nitroso‐urea

Gray¹,

Durkacz²,

Shall³

1981

FEBS Letters

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ADP-ribosylation of nuclear proteins

Abstract: ADP-ribosylation can be defined as the postsynthetic modification of protein by the covalent attachment of the ADP-ribose moiety of NAD+. ADP-ribosylation of elongation-factor Tu is

Cited by 208 publications

References 42 publications

The Stereochemical Course of Nucleotidyl Transfer Catalysed by NAD Pyrophosphorylase

The Stereochemical Course of Nucleotidyl Transfer Catalysed by NAD Pyrophosphorylase

Nonenzymic ADP-ribosylation of specific mitochondrial polypeptides.

Inhibitors of nuclear ADP‐ribosyl transferase retard DNA repair after N‐methyl‐N‐nitroso‐urea

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