Understanding ribonucleotide reductase inactivation by gemcitabine.

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Cerqueira NM, Fernandes PA, Ramos MJ

Understanding ribonucleotide reductase inactivation by gemcitabine.

Chemistry. 2007;13(30):8507-15.

PubMed ID

17636467 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Gemcitabine	Ribonucleoside-diphosphate reductase large subunit	Protein	Humans	Yes	Inhibitor	Details