@misc{10481/59178,
year = {2019},
month = {2},
url = {http://hdl.handle.net/10481/59178},
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.},
organization = {This work was started, and partly supported by a grant from the Spanish Nuclear Council (CSN).},
publisher = {Springer Nature},
title = {Efficacy of aldose reductase inhibitors is affected by oxidative stress induced under X-ray irradiation},
doi = {10.1038/s41598-019-39722-0},
author = {Castellvi, Albert and Gavira Gallardo, José Antonio},
}