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Fluorine at the C5 Position of 2′‐Deoxyuridine Enhances Repair of a O 4 ‐Methyl Adduct by O 6 ‐Alkylguanine DNA Alkyltransferases
Author(s) -
Sacre Lauralicia,
Wilds Christopher J.
Publication year - 2017
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.201700466
Subject(s) - chemistry , nucleobase , deoxyuridine , thymine , steric effects , dna , thymidine , adduct , stereochemistry , guanine , methyl group , alkylation , deoxyguanosine , oligonucleotide , biochemistry , nucleotide , gene , organic chemistry , group (periodic table) , catalysis
Alkylation damage at the O 6 ‐ and O 4 ‐atoms of 2′‐deoxyguanosine (dG) and thymidine (T), respectively, can be removed by O 6 ‐alkylguanine‐DNA alkyltransferases (AGTs). Previous studies have shown that human AGT (hAGT) repairs small adducts poorly at the O 4 ‐atom of T, in comparison to the E. coli variants (OGT and Ada‐C). The C5 methyl group of the thymine nucleobase is suspected to contribute to hAGT repair proficiency possibly due to steric effects in the protein active site. In the present study, repair of oligonucleotides containing a 5‐fluoro‐ O 4 ‐methyl‐2′‐deoxyuridine ( dFU‐Me ) insert by hAGT, E. coli AGT variants (OGT and Ada‐C) and a chimeric hAGT/OGT protein was evaluated. All AGT variants, particularly hAGT and the hAGT/OGT chimera, demonstrated improved proficiency at removing the O 4 ‐methyl group from substrates containing dFU‐Me , relative to the thymidine and 2′‐deoxyuridine counterparts.