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Updated: Jul 13, 2026
10:26
Profiling Ubiquitin and Ubiquitin-like Dependent Post-translational Modifications and Identification of Significant Alterations
Published on: November 7, 2019
Understanding ribonucleotide reductase inactivation by gemcitabine
Nuno M F S A Cerqueira1, Pedro A Fernandes, Maria J Ramos
1REQUIMTE, Faculdade de Ciências, Universidade do Porto, Rua Campo Alegre, 687, 4169-007 Portugal.
Chemistry (Weinheim an Der Bergstrasse, Germany)
|July 20, 2007
Summary
Gemcitabine (dFdC) inhibits ribonucleotide reductase (RNR) by targeting its R1 monomer in the presence of cellular reductants. This newly proposed mechanism explains the drug
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Therapeutics
Background:
- Gemcitabine (2',2'-difluoro-2'-deoxycytidine, dFdC) is a deoxycytidine analogue effective against solid tumors.
- Ribonucleotide reductase (RNR) is a key enzyme in DNA synthesis and a target for cancer chemotherapy.
- The precise mechanism of RNR inhibition by gemcitabine has been previously unknown.
Purpose of the Study:
- To elucidate the mechanism of ribonucleotide reductase (RNR) inhibition by gemcitabine (dFdC).
- To investigate the differential inhibition of RNR monomers (R1 and R2) under varying reductant conditions.
- To propose a theoretical model for RNR inhibition by dFdC in the presence of cellular reductants.
Main Methods:
- Theoretical study of RNR inhibition by gemcitabine (dFdC).
- Analysis of reductant-dependent RNR inactivation pathways.
- Comparison of inhibition mechanisms in the presence and absence of reductants.
Main Results:
- RNR inactivation by gemcitabine (dFdC) is reductant-dependent.
- In the presence of reductants, gemcitabine inhibits the R1 monomer of RNR.
- In the absence of reductants, the radical is lost, and the R2 monomer is inhibited.
Conclusions:
- The R1 monomer inactivation pathway is the most likely mechanism for gemcitabine's (dFdC) cytotoxicity due to cellular reductants.
- This study provides the first proposed mechanism for RNR inhibition by dFdC in the presence of reductants.
- Understanding this mechanism can inform the development of more effective cancer therapies targeting RNR.
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