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

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_M increases dramatically while the k_cat is not much affected. Consistently, the catalytic tetrad is not showing any modif

SUBMITTER: Castellvi A 

PROVIDER: S-EPMC6395642 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature