We have located links that may give you full text access.
JOURNAL ARTICLE
RESEARCH SUPPORT, NON-U.S. GOV'T
Quinone reductase 2 is an adventitious target of protein kinase CK2 inhibitors TBBz (TBI) and DMAT.
Biochemistry 2015 January 14
Quinone reductase 2 (NQO2) exhibits off-target interactions with two protein kinase CK2 inhibitors, 4,5,6,7-1H-tetrabromobenzimidazole (TBBz) and 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole (DMAT). TBBz and DMAT induce apoptosis in cells expressing an inhibitor-resistant CK2, suggesting that the interaction with NQO2 may mediate some of their pharmacological effects. In this study, we have fully characterized the binding of TBBz and DMAT to NQO2. Fluorescence titrations showed that TBBz and DMAT bind oxidized NQO2 in the low nanomolar range; in the case of TBBz, the affinity for NQO2 was 40-fold greater than its affinity for CK2. A related CK2 inhibitor, 4,5,6,7-tetrabromobenzotriazole (TBB), which failed to cause apoptosis in cells expressing inhibitor-resistant CK2, binds NQO2 with an affinity 1000-fold lower than those of TBBz and DMAT. Kinetic analysis indicated that DMAT inhibits NQO2 by binding with similar affinities to the oxidized and reduced forms. Crystal structure analysis showed that DMAT binds reduced NQO2 in a manner different from that in the oxidized state. In oxidized NQO2, TBBz and DMAT are deeply buried in the active site and make direct hydrogen and halogen bonds to the enzyme. In reduced NQO2, DMAT occupies a more peripheral region and hydrogen and halogen bonds with the enzyme are mediated through three water molecules. Therefore, although TBB, TBBz, and DMAT are all potent inhibitors of CK2, they exhibit different activity profiles toward NQO2. We conclude that the active site of NQO2 is fundamentally different from the ATP binding site of CK2 and the inhibition of NQO2 by CK2 inhibitors is adventitious.
Full text links
Related Resources
Trending Papers
Heart failure with preserved ejection fraction: diagnosis, risk assessment, and treatment.Clinical Research in Cardiology : Official Journal of the German Cardiac Society 2024 April 12
Proximal versus distal diuretics in congestive heart failure.Nephrology, Dialysis, Transplantation 2024 Februrary 30
Efficacy and safety of pharmacotherapy in chronic insomnia: A review of clinical guidelines and case reports.Mental Health Clinician 2023 October
World Health Organization and International Consensus Classification of eosinophilic disorders: 2024 update on diagnosis, risk stratification, and management.American Journal of Hematology 2024 March 30
Get seemless 1-tap access through your institution/university
For the best experience, use the Read mobile app
All material on this website is protected by copyright, Copyright © 1994-2024 by WebMD LLC.
This website also contains material copyrighted by 3rd parties.
By using this service, you agree to our terms of use and privacy policy.
Your Privacy Choices
You can now claim free CME credits for this literature searchClaim now
Get seemless 1-tap access through your institution/university
For the best experience, use the Read mobile app