ADP-ribosylation inhibitors

Effect of ADP-Ribosylation Inhibitors on Induction of Mutation and Malignant Transformation... 

Table 2. Effect of ADP-ribosylation inhibitors on malignant transformation...

The results presented here are in general agreement with previous studies that have shown that benzamide and its derivatives are very potent inhibitors of poly(ADP-ribose) polymerase in vitro (1,2). The results shown here have demonstrated that the benzamides are also effective inhibitors of poly(ADP-ribose) polymerase in vivo at concentrations in the medium which are much lower than those generally used in studies designed to assess the effects of ADP-ribosylation inhibitors on biological responses (1-11). The large quantitative differences between the in vitro inhibition curves of poly(ADP-ribose) polymerase and the mono(ADP-ribosyl) transferases examined suggests that it may be possible to inhibit poly(ADP-ribose) polymerase with minimal effects on mono(ADP-ribosyl) transferases. 

G, is the G-protein responsible for inhibiting adenylate cyclase. The inhibition is mediated by the a subunit. Unlike Gs, G, is not affected by CTx but instead is ADP-ribosylated (and inhibited) by PTx. Of the three isoforms of G, (Gn 3), an is the most potent inhibitor of cyclase. G, also activates inward-rectifier (Kir3.1/3.2 and Kir 3.1/3.4) K+ channels (GIRK channels), and this activation is mediated by released f v subunits (see below). 

Banasik M, Komura H, Shimoyama M, Ueda K (1992) Specific inhibitors of poly(ADP-ribose) synthetase and mono(ADP-ribosyl)transferase. J Biol Chem 267 1569-1575... 

Beneke S, Diefenbach J, Burkle A (2004) Poly(ADP-ribosyl)ation inhibitors promising drug candidates for a wide variety of pathophysiologic conditions. Int J Cancer 111 813-818... 

Curtin NJ (2006) PARP inhibitors and cancer therapy. In Biirlde A (ed) Poly(ADP-Ribosyl)ation. Landes Bioscience, Georgetown, pp218—233... 

NO is also a likely candidate for the NANC messenger of the myenteric plexus of neurons in the gastrointestinal tract, which mediate peristaltic movements. These neurons are rich in NO synthase and inhibitors of this enzyme prevent the nerve-evoked relaxation of the gut [12]. Nitric oxide released from nitroprusside also stimulates ADP ribosylation of glyceradehyde 3-phosphate dehydrogenase [56]. Consequently, there may be a number of enzymes, which are probably Fe-centered, that may be activated by NO. 

Several other inhibitors of protein synthesis are notable because of their toxicity to humans and other mammals. Diphtheria toxin (Mr 58,330) catalyzes the ADP-ribosylation of a diphthamide (a modified histidine) residue of eukaryotic elongation factor eEF2, thereby inactivating it. Ricin (Afr 29,895), an extremely toxic protein of the castor bean, inactivates the 60S subunit of eukaryotic ribosomes by depurinating a specific adenosine in 23S rRNA. 

Zhou G-C, Parikh SL, Tyler PC, Evans GB, Furneaux GB, Zubkova OV, Benjes PA, Schramm VL (2004) Inhibitors of ADP-ribosylating bacterial toxins based on oxacarbenium ion character at their transition states. J. Am. Chem. Soc. 126 5690-5698... 

Graf R, Codina J, Birnbaumer L (1992) Peptide inhibitors of ADP-ribosylation by pertussis toxin are substrates with affinities comparable to those of the trimeric GTP-binding proteins. In Mol. Pharmacol. 42 760-764. 

G proteins are located in different compartments within the cell (Nurnberg and Ahnert-Hilger, 1996). Although most G proteins are found attached to the plasma membrane and intracellular membranes, some are also located within the cytoplasm (Rudolph et al., 1989). Therefore, G proteins in preparations of disrupted cells, or in cell and tissue extracts are also subject to pertussis toxin-mediated ADP-ribosylation. In this case, precautions have to be taken to prevent proteolysis, and protease inhibitors should be included in the buffer (aprotonin, p-aminobenzamidine, leupeptin, phenylmethylsul-fonyl fluoride, or soybean or lima bean trypsin inhibitors) (Carty, 1994). 

Fig. 1. ADP-ribosylafion of Rho by C3 transferases. Rho proteins are regulated by a GTPase cycle. The GTP-binding proteins ore inactive with GDP bound, and active in the GTP-bound form. GDP/GTP exchange is facilitated by guanine nucleotide dissociation stimulator(s) (GDS) and inhibited by guanine nucleotide dissociation inhibitor(s) (GDI). In the active form, Rho protein interacts with its effector(s) and induces several cellular responses, one of which is polymerization of actin. Rho is ADP-ribosylated by C3 transferases at asparagine-41. Most likely, the modification inhibits the interaction of Rho with its effector(s) which results in inhibition of Rho dependent processes (e.g. F-actin depolymerization)...

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. 

Sugai M, Hashimoto K, Kikuchi A etal. (1992) Epidermal cell differentiation inhibitor ADP-ribosylates small GTP-binding proteins and induces hyperplasia of epidermis. In J. Biol. Chem. 267 2600-4... 

A carbocyclic NAD(+) analogue (91) incorporating a methylenebisphospho-nate linkage in place of the natural pyrophosphate has been prepared as an inhibitor of ADP-ribosyl cyclase which is resistant to non-specific phosphatase degradation.The analogue 91 was obtained in 25% yield following a Poulter coupling of the precursor 92 with adenosine 5 -methylenebisphosphonate. 

Yamashita and co-workers reported that nicotinamide exhibit attaching repellent activity against the blue mussel (Mytilus edulis) [119]. Nicotinamide (34) is a product of NAD+ cleavage by mono (ADP-ribosyl) transferase, and it serves as an effective inhibitor of the enzyme activity... 

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