Synthesis of oligonucleotides containing 2'-fluorinated thymidine glycol as mechanism-based inhibitors of endonuclease III.
Endonuclease III is a base excision repair enzyme that recognizes oxidized pyrimidine bases including thymine glycol. This enzyme is a glycosylase/AP-lyase and forms a Schiff base-type intermediate with the substrate after the damaged base is removed. To investigate its substrate recognition mechanism by X-ray crystallography, we synthesized oligonucleotides containing 2'-fluorothymidine glycol (1-(2-deoxy-2-fluoro-beta-D-ribofuranosyl)-5,6-dihydro-5,6-dihydroxythymine), expecting that the electron-withdrawing fluorine atom at the 2' position would stabilize the covalent intermediate. Complex formation of the substrate analogs containing each thymine glycol isomer with endonuclease III was analyzed.
Doi
Yusuke
Y
Division of Chemistry, Graduate School of Engineering Science, Osaka University, 1-3 Machikaneyama, Toyonaka, Osaka 560-8531, Japan.
Hitomi
Kenichi
K
Tainer
John A
JA
Iwai
Shigenori
S
D018360:Crystallography, X-Ray; D004706:Endodeoxyribonucleases / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D009841:Oligonucleotides / Q000138:chemical synthesis / Q000737:chemistry*; D009943:Organophosphorus Compounds / Q000737:chemistry; D013936:Thymidine / Q000031:analogs & derivatives* / Q000737:chemistry
C509335:1-(2-deoxy-2-fluororibofuranosyl)-5,6-dihydro-5,6-dihydroxythymine; D004791:Enzyme Inhibitors; D009841:Oligonucleotides; D009943:Organophosphorus Compounds; C434331:phosphoramidite; D004706:Endodeoxyribonucleases; D013936:Thymidine