Inhibitors and activators of ADP-ribosylation reactions

Abstract

ADP-ribosylation reaction, that is the transfer of the ADP-ribose moiety of NAD+ to acceptor protein, is catalyzed by two classes of ADP-ribosyltransferases, i.e., poly(ADP-ribose) synthetase and mono(ADP-ribosyl)transferases. These two types differ not only in the number of transferring ADP-ribose units but also in the acceptor amino acid(s) and protein. Their inhibitors, particularly those of poly(ADP-ribose) synthetase, have been successfully employed in studies on biological functions of the enzymes and other related fields of research. Recently, we found many potent and specific inhibitors of poly(ADP-ribose) synthetase, and broadened their chemical as well as biochemical variety. More recently, we found several potent inhibitors of arginine-specific mono(ADP-ribosyl)transferases and activators of poly(ADP-ribose) synthetase.

The Dynamic Role of GRP78/BiP in the Coordination of mRNA Translation with Protein Processing

“…Both the modified and unmodified forms of GRP78 were fully accessible and susceptible to proteolysis by trypsin. ADP-ribosylation of various proteins has been reported to be inhibited by novobiocin and nicotinamide (29). The small amount of GRP78 that was modified in control cells was found to be abolished by either agent (Fig.…”

UV‐B‐ and oxidative stress‐induced increase in nicotinamide and trigonelline and inhibition of defensive metabolism induction by poly(ADP‐ribose)polymerase inhibitor in plant tissue

“…3-AB is frequently used as an inhibitor of the DNA strand break-induced enzyme poly(ADP-ribose)polymerase (PADPRP), especially in animal cell systems [42]. There are indications that PADPRP may influence secondary metabolism in plant tissues; when pigment-producing callus culture of red beet (Beta vulgaris) was treated with 3-AB (1 mM), there was a block in the pigment production [43].…”

Ecto-ADP-Ribosyltransferases (ARTs): Emerging Actors in Cell Communication and Signaling

“…Most of these inhibitors, however, have IC 50 above 1µM, often in the range of 1mM. Moreover, nicotinamide derivatives can also affect other enzymes such as microsomal NADase, CD38, adenosine-3'-5'-cyclic monophosphate phosphodiesterase , nicotinamide N-methyl transferase, deaminase, phosphoribosyl transferase or PARPs [150]. Present day ART inhibitors have thus a rather weak selectivity.…”

“…6). In addition, several molecules structurally unrelated to nicotinamide can inhibit mono-ADP-ribosylation such as the antibiotic novobiocin, coumermycin A 1 , vitamins K 1 and K 3 or unsaturated fatty acids [150][151][152]. The mechanisms by which unsaturated fatty acids can block ART-activity are still unknown, but ectoARTs being GPI-anchored proteins, fatty acids might disturb the environment of arts in the cell membrane.…”

“…Since the discovery of mono(ADPribosyl)transferases in turkey erythrocytes [149], attempts have been made to improve or inhibit ART activity [150]. Numerous compounds have been tested which can be split in two main categories: (1) analogs of nicotinamide, which principally act as competitive antagonists of NAD through binding at the ART catalytic site [151,152], and (2) ADPribose acceptors, which deviate ART activity from its natural protein targets [111,153].…”