The Interaction of Human Glutathione Transferase GSTA1-1 with Reactive Dyes

Human glutathione transferase A1-1 (hGSTA1-1) contributes to developing resistance to anticancer drugs and, therefore, is promising in terms of drug-design targets for coping with this phenomenon. In the present study, the interaction of anthraquinone and diazo dichlorotriazine dyes (DCTD) with hGST...

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Published in:Molecules (Basel, Switzerland) Switzerland), 2021-04, Vol.26 (8), p.2399
Main Authors: Alqarni, Mohammed Hamed, Foudah, Ahmed Ibrahim, Muharram, Magdy Mohamed, Labrou, Nikolaos E
Format: Article
Language:English
Subjects:
1-Chloro-2,4-dinitrobenzene
Anthraquinone
Anthraquinone dyes
Binding sites
Cancer
chemotherapy
Drug development
Drug resistance
Dyes
enzyme inhibitor
Enzymes
Glutathione transferase
Inhibitors
Kinetics
Molecular modelling
Procion
Proteins
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Summary:Human glutathione transferase A1-1 (hGSTA1-1) contributes to developing resistance to anticancer drugs and, therefore, is promising in terms of drug-design targets for coping with this phenomenon. In the present study, the interaction of anthraquinone and diazo dichlorotriazine dyes (DCTD) with hGSTA1-1 was investigated. The anthraquinone dye Procion blue MX-R (PBMX-R) appeared to interact with higher affinity and was selected for further study. The enzyme was specifically and irreversibly inactivated by PBMX-R, following a biphasic pseudo-first-order saturation kinetics, with approximately 1 mol of inhibitor per mol of the dimeric enzyme being incorporated. Molecular modeling and protein chemistry data suggested that the modified residue is the Cys112, which is located at the entrance of the solvent channel at the subunits interface. The results suggest that negative cooperativity exists upon PBMX-R binding, indicating a structural communication between the two subunits. Kinetic inhibition analysis showed that the dye is a competitive inhibitor towards glutathione (GSH) and mixed-type inhibitor towards 1-chloro-2,4-dinitrobenzene (CDNB). The present study results suggest that PBMX-R is a useful probe suitable for assessing by kinetic means the drugability of the enzyme in future drug-design efforts.
ISSN:1420-3049
1420-3049
DOI:10.3390/molecules26082399