title: Understanding ribonucleotide reductase inactivation by gemcitabine.
abstract: This paper focuses on the inhibition of ribonucleotide reductase (RNR) by gemcitabine, 2',2'-difluoro-2'-deoxycytidine (dFdC), a deoxycytidine analogue that is a very active drug against solid tumors and is currently commercialized as gemzar. RNR inactivation is reductant-dependent and occurs in a very different way from that of other known substrate analogues. In the presence of reductants monomer R1 of RNR is inhibited, whereas in the absence of reductants the radical is lost and monomer R2 is inhibited. As inside the cell reductants are available, it is likely that R1 inactivation is the most favorable mechanism responsible for drug cytotoxicity. This inhibition pathway has been unknown to date, but we have conducted a theoretical study that has led us to the first proposal of a mechanism for RNR inhibition by dFdC in the presence of reductants.
authors.affiliation: REQUIMTE, Faculdade de Ciências, Universidade do Porto, Rua Campo Alegre, 687, 4169-007 Portugal.
authors.forename: Nuno M F S A
authors.initials: NM
authors.lastname: Cerqueira
authors.forename: Pedro A
authors.initials: PA
authors.lastname: Fernandes
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Ramos
mesh_terms: D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008958:Models, Molecular; D011487:Protein Conformation; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000093542:Gemcitabine
chemical_list: D004791:Enzyme Inhibitors; D003841:Deoxycytidine; D012264:Ribonucleotide Reductases; D000093542:Gemcitabine