O-Acetyl-ADP-ribose

BRCT BRCAl C-terminus-like DBD DNA-binding domain dPARP Drosophila PARP MPTP l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine NAD+ Nicotinamide adenine dinucleotide NAm Nicotinamide NLS Nuclear locahzation signal OAADPR O-acetyl-ADP-ribose PAR Poly(ADP-ribose) PARG Poly(ADP-ribose) glycohydrolase PARP Poly(ADP-ribose) polymerase PARylation poly(ADP-ribosyl)ation... 

Tanner, K.G., Landry, J., Sternglanz, R. and Denu, J.M. (2000) Silent information regulator 2 family of NAD- dependent histone/protein deacetylases generates a unique product, 1-O-acetyl-ADP-ribose. Proceedings of the National Academy of Sciences of the United States of America, 97, 14178-14182. 

Sir2 protein deacetylases (sirtuins) use an acetyl lysine residue as an oxygen nucleophile to displace nicotinamide from NAD" in a second step the imidate intermediate is hydrolysed to 1-O-acetyl ADP ribose and a lysine residue. A study of the effect of acyl substitution in the acyl lysine yielded a p value of — 1.9 for the first step, equivalent to a of >1, an extraordinarily... 

Figure 1. Derivatives of NAD and NADP with messenger functions. While cyclic ADP-ribose (cADPR) and nicotinic add adenine dinudeotide phosphate (NAADP) have been established as intracellular calcium mobilising molecules, the potentid role of O-acetyl ADP-ribose as a signalling molecule has yet to be identified.

The proposed mechanism for the NAD -utilising HDACs (Sirtuins) is more complex, involving in the first step the formation of an O-glycosyl iminoyl ether and release of nicotinamide (Figure 5.10b). The iminoyl ether is then hydrolysed by a molecule of water, assisted anchimerically by the 2 -OH group of the ribosyl moiety, to give 2-O-acetyl ADP-ribose and the deacetylated lysine. 

One of the main classes of nucleoside diphosphate derivatives are the p-glycosyl conjugates. A one-step synthesis of O-acetyl-ADP-ribose and its derivatives has been deseribed starting from NAD. Uridine diphosphate V-acetylglucosamine (20) (UDP-GlcNAc) is ubiquitously found in eukaryotes involved in post-translational modification of proteins. Using... 

Besides the deacetylation of the target protein, the by-product generated by the reaction of sirtuins is of considerable interest. The acetyl group becomes eventually attached to the 2 or 3 -hydroxyl of the terminal ribose of ADP-ribose forming O-acetyl-ADP-tibose, (Fig. 1C). It is suspected that this molecule may have messenger functions, too. ... 

Fig. 5. Phosphorylation of poly(ADP-ribose) synthetase by purified rat brain protein kinase C. Enzyme reaction was performed principally as described by Kikkawa et al. (20) with l-oleoyl-2-acetyl-rac-glycerol (OAG) and phosphatidyl serine as activator. A The reaction was carried out with (O ) or without ( ) C-kinase activator (Ca /OAG/phosphatidyl-serine) the indicated concentration of poly(ADP-ribose) s mthetase was added to the reaction nuxture in place of phosphate-accepting protein. B Time course of the reaction.

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