@article{ddd.uab.cat:223869,
      author = {Castellví Toledo, Albert and Crespo, Isidro and Crosas, Eva and
               Cámara-Artigas, Ana and Gavira, José A. and Aranda, Miguel A.
               G. and Parés, Xavier and Farrés, Jaume and Juanhuix, Judith},
       title = {Efficacy of aldose reductase inhibitors is affected by oxidative
               stress induced under X-ray irradiation},
     journal = {Scientific reports},
        year = {2019},
      volume = {9},
       pages = {3177--},
       month = {2},
    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 K increases dramatically while the k 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.},
         doi = {10.1038/s41598-019-39722-0},
         url = {https://ddd.uab.cat/record/223869},
}