N.R. Jena - O6-Methylguanine Repair by O6-Alkylguanine Alkyl Transferase.

Version 1

      Publication Details (including relevant citation   information):

      J. Phys. Chem. B 2009, 113, 16285.

      Abstract:

      O6-Alkylguanine-DNA alkyltransferase (AGT) repairs   O6-methylguanine (O6mG) in DNA that is known to cause mutation   and cancer. On the basis of calculations performed using density   functional theory involving the active site of AGT, a mechanism   for catalytic demethylation of O6mG to guanine has been proposed.   In this mechanism, roles of six amino acids, i.e., Cys145,   His146, Glu172, Tyr114, Lys165, and Ser159 in catalytic   demethylation of O6mG are involved. This mechanism has three   steps as follows. At the first step, Cys145 in the   Cys145-water-His146-Glu172 tetrad is converted to cysteine   thiolate anion while at the second step, abstraction of the   Tyr114 proton by the N3 site of O6mG occurs in a barrierless   manner. In the third step, abstraction of Lys165 proton by   deprotonated Tyr114 and transfer of the methyl group of O6mG
      to the thiolate group of Cys145 anion occur simultaneously. As   AGT is a major target in cancer therapy, identification of the   roles of the different amino acids in demethylation of O6mG is   expected to be useful in designing efficient AGT inhibitors.

      Address (URL): http://pubs.acs.org/doi/abs/10.1021/jp907836w