Theoretical studies on the mechanism of inhibition of Ribonucleotide Reductase by (E)-2'-Fluoromethylene-2'-deoxycitidine-5'-diphosphate

Journal of the American Chemical Society
Pedro Alexandrino Fernandes, Maria João Ramos

Abstract

(E)-2'-Fluoromethylene-2'-deoxycitidine-5'-diphosphate (FMCDP) is a potent time-dependent inactivator of the enzyme Ribonucleotide Reductase, which operates by destructing an essential tyrosil radical and performing a covalent addition to an active site residue. Considerable effort to elucidate the inhibition mechanism has been undertaken in recent years, and some insights have been obtained. Although a mechanistic proposal has been put forward, based on a general paradigm of inhibition of RNR by 2' substituted substrate analogues, details about the mechanism have remained elusive. Namely, the exact residue that adds to the inhibitor is still not identified, although mutagenesis experiments suggest that it should correspond to the E441 residue. In this work, we performed an extensive theoretical exploration of the potential energy surface of a model system representing the active site of RNR with FMCDP, using Density Functional Theory. This study establishes the detailed mechanism of inhibition, which is considerably different from the one proposed earlier. The proposed mechanism is fully consistent with available experimental data. Energetic results reveal unambiguously that the residue adding to the inhibitor is a cysteine, m...Continue Reading

References

Apr 1, 1989·Proceedings of the National Academy of Sciences of the United States of America·M FontecaveP Reichard
Jan 4, 1988·European Journal of Biochemistry·A WillingG Auling
Sep 15, 1988·Biochemical and Biophysical Research Communications·T Barlow
Jul 1, 1965·Proceedings of the National Academy of Sciences of the United States of America·W S Beck, J Hardy
Jul 27, 1964·Biochemical and Biophysical Research Communications·R L Blakley, H A Barker
Oct 30, 1981·Biochemical and Biophysical Research Communications·G Schimpff-WeilandG Auling
Mar 1, 1996·Critical Reviews in Oncology/hematology·G Nocentini
Dec 1, 1995·Chemistry & Biology·J Stubbe, W A van der Donk
Dec 26, 2001·The Journal of Biological Chemistry·Alex KasrayanBritt-Marie Sjoberg
Feb 19, 2002·Chemical Reviews·JoAnne Stubbe, Wilfred A. van Der Donk

❮ Previous
Next ❯

Citations

Sep 12, 2012·Journal of Computer-aided Molecular Design·Giovanni GraziosoCarlo De Micheli
Jul 12, 2007·Proteins·Bruno TamamesMaria João Ramos
Oct 28, 2006·Proteins·Sérgio Filipe SousaMaria João Ramos
Dec 20, 2005·Biophysical Journal·Nuno M F S A CerqueiraMaria João Ramos
May 13, 2004·Journal of Computational Chemistry·Susana PereiraMaria João Ramos
Oct 14, 2004·Journal of Computational Chemistry·Nuno M F S A CerqueiraMaria João Ramos
Mar 8, 2007·Journal of Computational Chemistry·Sérgio Filipe SousaMaria João Ramos
Mar 2, 2005·Journal of Computational Chemistry·T K ManojkumarKwang S Kim
Jul 20, 2007·Chemistry : a European Journal·Nuno M F S A CerqueiraMaria J Ramos
Feb 24, 2006·Organic & Biomolecular Chemistry·Rita KakkarN P Radhika
Feb 23, 2011·Chemphyschem : a European Journal of Chemical Physics and Physical Chemistry·Luís Pinto da Silva, Joaquim C G Esteves da Silva
Jun 22, 2007·The Journal of Physical Chemistry. a·Noriko TsuchidaShinichi Yamabe
Jul 21, 2006·The Journal of Physical Chemistry. B·Pedro J Silva, Maria João Ramos
Jun 18, 2010·The Journal of Physical Chemistry. B·Pedro J SilvaMaria João Ramos
May 10, 2008·Accounts of Chemical Research·Maria J Ramos, Pedro A Fernandes
Jul 3, 2010·The Journal of Physical Chemistry. B·Feng-Chao CuiJing-Yao Liu
Apr 12, 2011·Journal of Chemical Theory and Computation·Luís Pinto da Silva, Joaquim C G Esteves da Silva
Oct 20, 2006·The Journal of Physical Chemistry. B·Nuno M F S A CerqueiraMaria J Ramos
Feb 1, 2007·Journal of the American Chemical Society·Sérgio F SousaMaria João Ramos
Sep 14, 2006·Chemical Reviews·Andrea CavalliMaurizio Recanatini

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.