Theoretical study on the inhibition of ribonucleotide reductase by 2 '-mercapto-2 '-deoxyribonucleoside-5 '-diphosphates

• Type: Article in International Scientific Journal
• Date: 2005

Authors

Pereira, S (Author) Other; Fernandes, PA (Author) FCUP; Ramos, MJ (Author) FCUP

Journal

Title: Journal of the American Chemical Society

Vol. 127 No. 41

Pages: 5174-5179

ISSN: 0002-7863

Publisher: American Chemical Society

Indexing

ISI Web of Knowledge - 18 Citations

Scopus - 18 Citations

Scientific classification

FOS: Natural sciences > Chemical sciences

Other information

Authenticus ID: P-000-3VJ

DOI: 10.1021/ja046662w

Abstract (EN): Ribonucleotide reductase (RNR) is responsible for the reduction of ribonucleotides into the correspondent 2'-deoxyribonucleotides in the only physiological process that yields the monomers of DNA. The enzyme has thus become an attractive target for chemotherapies that fight proliferation-based diseases, specifically cancer and infections by some viruses and parasites. 2'-Mercapto-2'-deoxyribonucleoside-5'-diphosphates (SHdNDP) are mechanism-based inhibitors of RNR and therefore potential chemotherapeutic agents for those indications. Previous experimental studies established the in vitro and in vivo activity of SHdNDP. In the in vitro studies, it was observed that the activity was dependent on the oxidative status of the medium, with the inactivation of RNR only occurring when molecular oxygen was available. To better understand the mechanism involved in RNR inactivation by SHdNDP, we performed theoretical calculations on the possible reactions between the inhibitors and the RNR active site. As a result, we propose the possible mechanistic pathways for the chemical events that occur in the absence and in the presence of O-2. They correspond to a refinement and a complement of those proposed in the literature.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 6