Mono ADP-ribosyltransferase

ART Mono-ADP-ribosyltransferase family of proteins, large group of A-B toxins... 

Like other bacterial ADP-ribosylating toxins (e.g. diphtheria toxin. Pseudomonas aeruginosa exotoxin A, cholera toxin, pertussis toxin, and C. botulinum C2 toxin (Aktories and Just, 1993)), C3 is a mono-ADP-ribosyltransferase (Aktories et ai, 1988b). Treatment of ADP-ribosylated Rho with phosphodiesterase releases 5 -AMP and not phosphoribosyl-AIVtP, a cleavage product of poly(ADP-ribose) (Aktories et ai, 1988b Rubin ef a/., 1988). Accordingly, thymidine, an inhibitor of poly(ADP-ribose)polymerase, does not block C3-like ADP-ribosyltransferases, and can be included in C3 ADP-ribosylation assays to block poly-ADP-ribosylation reactions. 

Mono-ADP-ribosyltransferases are found in both eukaryotes and prokaryotes. The bacterial toxins are the best understood in terms of structure and function. These toxins include cholera, diphtheria, pertussis, botulinum D, and functionally related toxins. In all cases studied thus far, the covalent attachment of the ADP-ribose group to the target proceeds with inversion at the (nicotinamide)-ribose C-1 to generate a-linkages. In the absence of appropriate acceptors the mono-ADP-ribosyltransferases also catalyze a much slower hydrolysis of NAD. This latter reaction occurs without detectable methanolysis, which precludes stereochemical analysis of the hydrolytic reaction. The enzymes and acceptor preferences for these enzymes are summarized in Table V (108-120). 

Okazaki, I.J. and Moss, J., Characterization of glycosysphosphatidyl inositol-anchored, secreted and intraceUnlar vertebrate mono-ADP-ribosyltransferases, Ann. Rev. Nutrition, 19, 485, 1999. 

Okazaki IJ, Moss J. Glycosylphosphatidylinositol-anchored and secretory isoforms of mono-ADP-ribosyltransferases. J Biol Chem 1998 273 23617-23620. 

A mono ADP-ribosyltransferase that catalyzes the transfer of ADP-ribose moiety of NAD to arginine and a variety of proteins (139, 140, 143) has been identified in animal tissues. The physiological func-tion(s) of this enzyme have not been established. The mono ADP-ribosyltransferases are described in Table I. 

Soman G, Mickelson JR, Louis CF, Graves DJ (1984) NAD guanidino group specific mono ADP-ribosyltransferase activity in skeletal muscle. Biochem Biophys Res Commun 120 973-980... 

West REJr, Moss J (1984) NAD arginine mono-ADP-ribosyltransferases in turkey erythrocytes Characterization of a membrane-associated transferase different from the cytosolic enzymes. Fed Proc 43 1786... 

There is a class of mono-ADP-ribosyltransferases that are distinguished by their ability to utilize as ADP-ribose acceptors the free amino acid arginine, other simple guanidino compoimds, and proteins. Several transferases of this type were identified in and purified from turkey erythrocytes (1-3). The enzymes displayed different physical, kinetic and regulatory properties and were localized to the soluble, membrane and nuclear compartments (1-3). Similar NAD arginine ADP-ribosyltransferases have been observed in other tissues and organ systems from a variety of species (1-5). The enzymes are found in vimses, bacteria and animal cells (1-7). 

Three classes of enzymes cleave the p-A-glycosylic bond of NAD to free nicotinamide and catalyse the transfer of ADP-ribose in non-redox reactions (Lautier et al. 1993). The first class consists of ADP ribose transferases mono-ADP-ribosyltransferases and poly-ADP-ribose polymerase, which catalyse ADP-ribose transfer to proteins. The second class correspond to ADP-ribosyl cyclases—enzymes that promote the formation of cyclic ADP-ribose, a compound that mobilizes calcium from intracellular stores in many types of cells (Poliak et al. 2007). The third class of NAD consuming enzymes consists of sirtuins—proteins that possess either histone deacetylase or mono-ribosyl-transferase activity. 

Figure 7.5 Adenosine diphosphate (ADP)-ribosylation biochemical reactions. Mono-ADP-ribosyltransferases (ARTs) and poly-ADP-ribose pol5mierases Poly (PARPs) catalyse the ADP-ribose moiety of NAD transfer to amino acid residues. ADP-ribosyl cyclases generate cyclic ADP-ribose and 2-phospho-cyclic ADP-ribose from NAD and NADP, respectively. Both molecules trigger cyclic ADP-ribose cytosolic Ca " elevation, presumably by activating the ryanodine receptor in the endoplasmic/sarcoplasmic reticulum (RER). SIRTl catalyses a reaction that couples protein deacetylation to NAD hydrolysis.

Research has shown that NAD is the substrate for three important classes of enzymes mono-ADP-ribosyltransferases (Hassa et al. 2006), poly-ADP-ribose polymerases (PARP) (Virag and Szabo 2002) and sirtuin enzymes (Sauve et al. 2006). These enzymes are responsible for protein modifications, DNA repair, endocrine signalling and apoptosis, and act to transfer ADP-ribose to nucleophiles. 

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