25] Preparation of low molecular weight model conjugates for ADP-ribose linkages to protein

Abstract

Most of the physiological acceptors for ADP-ribose are nucleophiles found in proteins. This posttranslational protein modification is versatile, as six different classes of protein nucleophiles have been shown to function as ADP-ribose acceptors. Several different bacterial toxins function as protein-mono-ADP-ribosyltransferases, irreversibly altering cellular metabolism by catalyzing the modification of specific cellular target proteins. Different toxins modify guanidino (arginine), thiol (cysteine), amide (asparagine), and imidazolyl (diphthamide) groups on their target proteins. Endogenous protein-mono-ADP-ribosyltransferases have been characterized from eukaryotic sources with specificities for transfer to the same amino acids modified by the bacterial toxins, and additional evidence suggests that protein hydroxyl groups (serine, threonine, tyrosine, or hydroxyproline) and histidine residues also may be modified by the action of transferases not yet characterized. Poly(ADP-ribose) polymerase catalyzes the modification of nuclear proteins at carboxylate groups, primarily glutamate residues. Another class of enzymes catalyzes intramolecular ADP-ribose transfer resulting in the synthesis of cyclic ADP-ribose and phosphocyclic ADP-ribose. All classes of ADP-ribose transfer enzymes also catalyze transfer of ADP-ribose to water with varying degrees of efficiency.