Molecular dynamics simulations of arachidonic acid complexes with COX-1 and COX-2: insights into equilibrium behavior

Biochemistry
Kristina E FurseTerry P Lybrand

Abstract

The cyclooxygenase (COX) enzymes are responsible for the committed step in prostaglandin biosynthesis, the generation of prostaglandin H(2). As a result, these enzymes are pharmacologically important targets for nonsteroidal antiinflammatory drugs, such as aspirin and newer COX-2 selective inhibitors. The cyclooxygenases are functional homodimers, and each subunit contains both a cyclooxygenase and a peroxidase active site. These enzymes are quite interesting mechanistically, as the conversion of arachidonic acid to prostaglandin H(2) requires two oxygenation and two cyclization reactions, resulting in the formation of five new chiral centers with nearly absolute regio- and stereochemical fidelity. We have used molecular dynamics (MD) simulations to investigate the equilibrium behavior of both COX-1 and COX-2 enzyme isoforms with bound arachidonate. These simulations were compared with reference simulations of arachidonate in solution to explore the effect of enzyme on substrate conformation and positioning in the active site. The simulations suggest that the substrate has greater conformational freedom in the COX-2 active site, consistent with the larger COX-2 active site volume observed in X-ray crystal structures. The simula...Continue Reading

References

Apr 12, 1994·Proceedings of the National Academy of Sciences of the United States of America·J L MasferrerK Seibert
Feb 1, 1996·Journal of Molecular Graphics·T J CallahanT P Lybrand
Nov 1, 1996·Nature Structural Biology·C LuongM F Browner
Mar 1, 1996·Biopolymers·M F SannerJ C Spehner
Jun 8, 2001·Annual Review of Biochemistry·X HuangF M Raushel
Jun 13, 2001·The Journal of Biological Chemistry·K R KozakL J Marnett
May 22, 2002·Archives of Internal Medicine·Daniel H SolomonJerry Avorn
Jul 23, 2002·Nature Structural Biology·David E HyrePatrick S Stayton
Aug 15, 2002·Biochemical and Biophysical Research Communications·Jeffery J PrusakiewiczLawrence J Marnett
Sep 5, 2002·Journal of the American Chemical Society·Sheng PengWilfred A van der Donk
Jun 12, 2003·Chemical Reviews·Carol A Rouzer, Lawrence J Marnett
Oct 8, 2004·The New England Journal of Medicine·Garret A Fitzgerald

❮ Previous
Next ❯

Citations

May 14, 2010·The Journal of Biological Chemistry·Alex J VecchioMichael G Malkowski
May 15, 2012·Antioxidants & Redox Signaling·Stefan SchildknechtMarkus Michael Bachschmid
Sep 10, 2013·PloS One·Daniel H LopezXavier Busquets
Aug 26, 2011·European Journal of Medicinal Chemistry·Liana Guimarães Sachett, Hugo Verli
Aug 2, 2011·Journal of Molecular Graphics & Modelling·Wilson Maldonado-Rojas, Jesus Olivero-Verbel
Sep 5, 2009·Archives of Biochemistry and Biophysics·Ah-Lim Tsai, Richard J Kulmacz
Nov 6, 2008·Archives of Biochemistry and Biophysics·Stefan Schildknecht, Volker Ullrich
Oct 24, 2008·Journal of Computational Chemistry·Shunzhou Wan, Peter V Coveney
Apr 22, 2015·Analytical and Bioanalytical Chemistry·Giuseppe PagliaGiuseppe Astarita
May 26, 2007·Chemistry & Biology·Claus SchneiderAlan R Brash
Apr 24, 2015·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·André Luiz LourençoLucio Mendes Cabral
Jun 6, 2018·Journal of Molecular Modeling·Menyhárt-Botond Sárosi
Jul 8, 2020·Physical Chemistry Chemical Physics : PCCP·Vipin Kumar Mishra, Sabyashachi Mishra
Sep 30, 2020·Journal of Biomolecular Structure & Dynamics·Loubna TaidiMohammed Reda Britel
Dec 20, 2019·Angewandte Chemie·Anuj K YadavJefferson Chan
May 1, 2021·International Journal of Molecular Sciences·Seung-Hwa BaekDaeui Park
Nov 30, 2019·The Journal of Physical Chemistry. B·Vipin Kumar Mishra, Sabyashachi Mishra
Aug 2, 2018·Journal of Chemical Information and Modeling·Menyhárt-Botond Sárosi, Terry P Lybrand

❮ 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.