02 May 2003
Med Sci Monit 2003; 9(1): 53- :: ID: 15116
Poly(ADP-ribose) glycohydrolase (PARG) is an O-glycosidase, other members of this family of enzymes contain catalytic acidic residues surrounding the labile glycosidic bond. Previously an inhibitor-binding residue in bovine PARG (Y796) has been mapped to a region of highly conserved PARG sequences. We have targeted all conserved glutamic and aspartic acid residues in this region of PARG for site directed mutagenesis based on the hypothesis that PARG, like other O-glycosidases, will utilize a similar mechanism. The mutants were purified and catalytic activity as well as binding to a PARG inhibitor, ADP-HPD, was performed to show that the mutations did not interfere with the ability to detect a substrate like moiety. Our screen has revealed three essential residues, two vicinal glutamic acid residues found in the conserved sequence 755QEE757 and a third residue found in the conserved sequence 737VDFAN741. Identification of catalytic acidic residues along with recent identification of a polymer binding residue Y796 and a glycine rich region 745GGG747 allowed us to define a PARG ‘signature sequence’ [DFA-X4-GGg-X6–7-vQEEIRf-X3-YTGY] which we have used in conjunction with PHI-BLAST to identify distantly related PARG sequences. We found that the catalytic domain of PARG is predicted to contain a mostly beta sheet structure and a secondary structure pattern similar to that observed in the ADP-ribosyltransferase fold found in PARP-1 and bacterial toxin ADP-ribosyltransferases.
Keywords: Poly(ADP-ribose) glycohydrolase, PARG, ADP-ribosyltransferase fold
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