Methylating and ethylating agents are used in the chemical industry and produced 
during tobacco smoking. They generate DNA base damage whose role in cancer 
induction has been documented. Alkylated bases are repaired by the base excision 
repair pathway. We have established the repair efficiency of methylated and 
ethylated bases by various Escherichia coli repair proteins, namely 
3-methyladenine-DNA-glycosylase I (TagA protein), which excises 3-methyladenine 
and 3-methylguanine, 3-methyladenine-DNA-glycosylase II (AlkA protein), which 
has a broad substrate specificity including 3- and 7-alkylated purines and the 
formamidopyrimidine(Fapy)-DNA-glycosylase (Fpg protein) repairing imidazole 
ring-opened 7-methylguanine. The comparison of the Km values of these various 
enzymes showed that methylated bases were excised more efficiently than 
ethylated bases. Several 3-alkyladenine derivatives have been synthesized and 
examined for their ability to inhibit the activity of the various repair 
proteins. We have shown that 3-ethyl-, 3-propyl-, 3-butyl- and 3-benzyladenine 
were much more efficient inhibitors of TagA protein than 3-methyladenine. The 
inhibitory effect was increased with the increase of the size of alkyl-group and 
IC50 for 3-benzyladenine was 0.4 +/- 0.1 microM as compared to 1.5 +/- 0.3 mM 
for 3-methyladenine. These compounds inhibited neither the AlkA protein nor 
human 3-methyladenine-DNA-glycosylase (ANPG protein). Moreover, 
3-hydroxyethyladenine did not affect the activity of any of these enzymes. Taken 
together, these results suggest that hydrophobic interactions are involved in 
the mechanism of inhibition and/or recognition and excision of alkylated purines 
by TagA protein.