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

DOI: 10.1038/s41598-019-39722-0 DOI Help

Authors: Albert Castellví (Alba Synchrotron) , Isidro Crespo (Alba Synchrotron) , Eva Crosas (Alba Synchrotron) , Ana Cámara-Artigas (Universidad de Almería) , Jose A. Gavira (CSIC-Universidad de Granada) , Miguel A. G. Aranda (Alba Synchrotron) , Xavier Parés (Universitat Autònoma de Barcelona) , Jaume Farrés (Universitat Autònoma de Barcelona) , Judith Juanhuix (Alba Synchrotron)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Scientific Reports , VOL 9

State: Published (Approved)
Published: February 2019
Diamond Proposal Number(s): 10166

Open Access Open Access

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 oxidative stress, the described irradiation method can be applied to other relevant proteins under oxidative stress environments.

Journal Keywords: Diabetes complications; Post-translational modifications; SAXS; X-ray crystallography

Diamond Keywords: Diabetes

Subject Areas: Biology and Bio-materials, Medicine


Instruments: B21-High Throughput SAXS

Other Facilities: ALBA

Added On: 11/04/2019 11:05

Documents:
s41598-019-39722-0.pdf

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Scattering Small Angle X-ray Scattering (SAXS)