O

the repair of deaminated or alkylated bases. The hydrolysis is carried out by a hydroxide anion generated by deprotonation of a molecule of water by a Asn or Asp residue (Fig. 12.14).70

Bifunctional glycosylases normally remove bases that have suffered oxidative damage. The catalytic cycle of these enzymes involves an initial SN1-like attack at the C-1' position by Lys or Pro residues that removes the aberrant base. In the second step, and because of their purinic/apyrimidinic (AP) lyase activity, they catalyze a subsequent p-elimination reaction of the 3'-phosphodiester bond on the protonated Schiff base intermediate and subsequent hydrolysis. As shown in Fig. 12.15, this mechanism results in strand scission.

Three classes of DNA glycosylase inhibitors are known,71,72 all of which are oligonucleotides obtained using solid phase DNA synthetic methodology73:

1. Abasic site analogues that are reduced and chemically more stable (e.g., compound 12.1). These compounds bind to glycosylases because these enzymes are end product-inhibited.

2. Oligonucleotides that contain pyrrolidine moieties that mimic the positive charge at the transition state (e.g., 12.2).

3. Nucleotides with stabilized glycosidic bonds, which cannot be processed by the DNA glycosylases (e.g., 12.3)

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