Efficacy of aldose reductase inhibitors is affected by oxidative stress induced under X-ray irradiation

Scientific Reports
Albert CastellvíJudith Juanhuix

Abstract

Human aldose reductase (hAR, AKR1B1) has been explored as drug target since the 1980s for its implication in diabetic complications. An activated form of hAR was found in cells from diabetic patients, showing a reduced sensitivity to inhibitors in clinical trials, which may prevent its pharmacological use. Here we report the conversion of native hAR to its activated form by X-ray irradiation simulating oxidative stress conditions. Upon irradiation, the enzyme activity increases moderately and the potency of several hAR inhibitors decay before global protein radiation damage appears. The catalytic behavior of activated hAR is also reproduced as the KM increases dramatically while the kcat is not much affected. Consistently, the catalytic tetrad is not showing any modification. The only catalytically-relevant structural difference observed is the conversion of residue Cys298 to serine and alanine. A mechanism involving electron capture is suggested for the hAR activation. We propose that hAR inhibitors should not be designed against the native protein but against the activated form as obtained from X-ray irradiation. Furthermore, since the reactive species produced under irradiation conditions are the same as those produced under...Continue Reading

References

Apr 1, 1986·Metabolism: Clinical and Experimental·S K SrivastavaB Das
Nov 1, 1985·Diabetes·B Das, S K Srivastava
Nov 1, 1985·Proceedings of the National Academy of Sciences of the United States of America·S K SrivastavaB Das
May 12, 1972·Biochimica Et Biophysica Acta·G RotilioE M Fielden
Mar 1, 1996·Archives of Biochemistry and Biophysics·C E Grimshaw, C J Lai
Dec 27, 1996·The Journal of Biological Chemistry·M CappielloU Mura
Mar 21, 1998·Archives of Biochemistry and Biophysics·A Del CorsoU Mura
May 7, 1954·Science·R GERSCHMANW O FENN
May 1, 1959·Archives of Biochemistry and Biophysics·G L ELLMAN
Dec 22, 2005·Acta Crystallographica. Section D, Biological Crystallography·Philip Evans
Mar 29, 2006·The Journal of Biological Chemistry·Karin KaiserovaAruni Bhatnagar
Nov 7, 2006·Bioorganic Chemistry·June M BrownleeDavid H T Harrison
May 17, 2007·Acta Crystallographica. Section D, Biological Crystallography·Marianna BiadeneThomas R Schneider
Sep 13, 2007·Nature Reviews. Molecular Cell Biology·Benoît D'Autréaux, Michel B Toledano
Jan 29, 2008·The Journal of Biological Chemistry·Karin KaiserovaAruni Bhatnagar
Aug 1, 2007·Journal of Applied Crystallography·Airlie J McCoyRandy J Read
Feb 4, 2010·Acta Crystallographica. Section D, Biological Crystallography·Wolfgang Kabsch
Apr 13, 2010·Acta Crystallographica. Section D, Biological Crystallography·Elspeth F Garman
Apr 13, 2010·Acta Crystallographica. Section D, Biological Crystallography·P EmsleyK Cowtan
Nov 19, 2010·The Journal of Biological Chemistry·Ganesaratnam K BalendiranDuilio Cascio
Apr 29, 2011·Journal of Synchrotron Radiation·Eugenio De la MoraElspeth F Garman
Nov 8, 2011·Cell Metabolism·Karin E Bornfeldt, Ira Tabas
May 15, 2012·Frontiers in Pharmacology·Wai Ho TangJohn Hwa
Sep 25, 2012·Expert Opinion on Therapeutic Patents·Maria ChatzopoulouVassilis J Demopoulos
Dec 21, 2012·Journal of Synchrotron Radiation·Elspeth F Garman, Martin Weik
Dec 7, 2013·Acta Crystallographica. Section D, Biological Crystallography·Kristin A SuttonWilliam A Bernhard
Oct 12, 2014·Chemico-biological Interactions·Trevor M Penning
Apr 1, 2012·Journal of Applied Crystallography·Maxim V PetoukhovDmitri I Svergun
Jan 9, 2015·Acta Crystallographica. Section C, Structural Chemistry·George M Sheldrick
Jan 24, 2015·Acta Crystallographica. Section D, Biological Crystallography·Thomas D GrantEdward H Snell
Jan 24, 2015·Acta Crystallographica. Section D, Biological Crystallography·Adam RoundFlorent Cipriani
Apr 8, 2016·Cell Reports·Devi ThiagarajanRavichandran Ramasamy
May 14, 2016·Nature Reviews. Endocrinology·Rabii Ameziane-El-HassaniCorinne Dupuy

❮ Previous
Next ❯

Methods Mentioned

BETA
X-ray

Software Mentioned

ATSAS
PRIMUS
SHELXL
Thermo Xcalibur
AIMLESS
MR
PDBSET
SCALEIT
XDS
RADDOSE

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.

Related Papers

Proceedings of the National Academy of Sciences of the United States of America
C ChangC C Shih
Biochemical and Biophysical Research Communications
Takashi FurutaniHisataka Shikama
© 2022 Meta ULC. All rights reserved