Structural evidence that peroxiredoxin catalytic power is based on transition-state stabilization.

Journal of Molecular Biology
Andrea HallP Andrew Karplus

Abstract

Peroxiredoxins (Prxs) are important peroxidases associated with both antioxidant protection and redox signaling. They use a conserved Cys residue to reduce peroxide substrates. The Prxs have a remarkably high catalytic efficiency that makes them a dominant player in cell-wide peroxide reduction, but the origins of their high activity have been mysterious. We present here a novel structure of human PrxV at 1.45 A resolution that has a dithiothreitol bound in the active site with its diol moiety mimicking the two oxygens of a peroxide substrate. This suggests diols and similar di-oxygen compounds as a novel class of competitive inhibitors for the Prxs. Common features of this and other structures containing peroxide, peroxide-mimicking ligands, or peroxide-mimicking water molecules reveal hydrogen bonding and steric factors that promote its high reactivity by creating an oxygen track along which the peroxide oxygens move as the reaction proceeds. Key insights include how the active-site microenvironment activates both the peroxidatic cysteine side chain and the peroxide substrate and how it is exquisitely well suited to stabilize the transition state of the in-line S(N)2 substitution reaction that is peroxidation.

References

Apr 1, 1997·Nature Structural Biology·K Diederichs, P A Karplus
Sep 1, 1999·Free Radical Biology & Medicine·C C Winterbourn, D Metodiewa
Jan 9, 2003·Trends in Biochemical Sciences·Zachary A WoodLeslie B Poole
Dec 10, 2003·Comparative Biochemistry and Physiology. Part B, Biochemistry & Molecular Biology·Gregory LeyensBernard Knoops
Jan 13, 2004·Science·Mireia Garcia-VilocaDonald G Truhlar
Feb 6, 2004·BioFactors·Leopold FlohéBirgit Hofmann
Mar 30, 2004·Journal of Molecular Biology·Christine EvrardJean-Paul Declercq
May 1, 1997·Acta Crystallographica. Section D, Biological Crystallography·G N MurshudovE J Dodson
Oct 28, 2004·The Journal of Biological Chemistry·Susan E Akerman, Sylke Müller
Dec 2, 2004·Acta Crystallographica. Section D, Biological Crystallography·Paul Emsley, Kevin Cowtan
Feb 11, 2005·Journal of Molecular Biology·Simon LiEdward N Baker
Apr 22, 2006·Acta Crystallographica. Section D, Biological Crystallography·Matthias StehrMahavir Singh
Dec 14, 2006·Acta Crystallographica. Section D, Biological Crystallography·Gerard J Kleywegt
Mar 3, 2007·The Journal of Biological Chemistry·Alexander V PeskinChristine C Winterbourn
Apr 25, 2007·Nucleic Acids Research·Ian W DavisDavid C Richardson
Jan 1, 2008·Proceedings of the National Academy of Sciences of the United States of America·Derek ParsonageLeslie B Poole
Apr 19, 2008·Nature Chemical Biology·Christine C Winterbourn
Nov 7, 2008·Biochemistry·Kimberly J NelsonLeslie B Poole
May 30, 2009·The FEBS Journal·Andrea HallLeslie B Poole
Dec 23, 2009·The Biochemical Journal·Andrew G CoxMark B Hampton

❮ Previous
Next ❯

Citations

Aug 30, 2012·Biochemistry·Arden PerkinsP Andrew Karplus
Sep 15, 2011·Journal of the American Chemical Society·Haiying ZhouKent S Gates
Mar 10, 2012·The Journal of Physical Chemistry. B·Freddie R SalsburyJacquelyn S Fetrow
Mar 12, 2011·Chemical Research in Toxicology·Gerardo Ferrer-SuetaAna Denicola
Mar 10, 2011·The Journal of Biological Chemistry·Péter NagyChristine C Winterbourn
Oct 26, 2010·Antioxidants & Redox Signaling·Andrea HallP Andrew Karplus
Nov 22, 2011·Antioxidants & Redox Signaling·Michael C GretesP Andrew Karplus
Dec 19, 2012·Antioxidants & Redox Signaling·Alberto Bindoli, Maria Pia Rigobello
Mar 25, 2014·Biochimica Et Biophysica Acta·Bastian Groitl, Ursula Jakob
Jan 10, 2016·Redox Biology·Alex J WadleySteven J Coles
Sep 4, 2015·Free Radical Research·Madia TrujilloRafael Radi
Jan 28, 2016·Molecules and Cells·Michel B Toledano, Bo Huang
Jan 28, 2016·Molecules and Cells·Christine C Winterbourn, Alexander V Peskin
Jan 27, 2016·Molecules and Cells·Leslie B Poole, Kimberly J Nelson
Jan 28, 2016·Molecules and Cells·Bernard KnoopsOksana Kuznetsova
May 2, 2015·Proceedings of the National Academy of Sciences of the United States of America·Inseong JoNam-Chul Ha
Jun 12, 2013·Biochimica Et Biophysica Acta·Vinayak Gupta, Kate S Carroll
Aug 14, 2013·Biochimica Et Biophysica Acta·Rebecca A Poynton, Mark B Hampton
Jan 24, 2014·Biochemical Society Transactions·Rachel E MartinNeil J Bulleid
Aug 1, 2013·Free Radical Biology & Medicine·Jun Lu, Arne Holmgren
Mar 14, 2014·Redox Biology·Brian CunniffNicholas H Heintz
Jun 13, 2015·Trends in Biochemical Sciences·Arden PerkinsP Andrew Karplus
May 25, 2011·Free Radical Biology & Medicine·Goedele Roos, Joris Messens
Jan 24, 2014·Redox Biology·Ryan J MaillouxWilliam G Willmore
Nov 12, 2014·Antioxidants & Redox Signaling·Samia BoukhenounaSophie Rahuel-Clermont
Nov 30, 2014·Free Radical Biology & Medicine·Leslie B Poole
Dec 3, 2014·Free Radical Biology & Medicine·P Andrew Karplus
Jan 13, 2015·Biological Chemistry·Marcel Deponte, Christopher Horst Lillig
Jul 30, 2016·Scientific Reports·Laura A H van BergenJoris Messens
Sep 7, 2016·Structure·Arden PerkinsP Andrew Karplus

❮ 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.