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Title: Naphthoquinone-mediated Inhibition of Lysine Acetyltransferase KAT3B/p300, Basis for Non-toxic Inhibitor Synthesis
Authors: Vasudevarao, Mohankrishna Dalvoy
Mizar, Pushpak
Kumari, Sujata
Mandal, Somnath
Siddhanta, Soumik
Swamy, Mahadeva M. M.
Kaypee, Stephanie
Kodihalli, Ravindra C.
Banerjee, Amrita
Naryana, Chandrabhas
Dasgupta, Dipak
Kundu, Tapas Kumar
Keywords: Biochemistry & Molecular Biology
Enzyme Inactivation
Enzyme Inhibitors
Histone Acetylase
Reactive Oxygen Species (Ros)
Lysine Acetyltransferase
N-Acetyl Cysteine
Structure-Activity Relationship
Surface-Enhanced Raman
Induced Histone Hypoacetylation
Global Gene-Expression
Transcriptional Coactivator
Chromatin Transcription
Small Molecules
Cancer Cells
Issue Date: 2014
Publisher: American Society Biochemistry Molecular Biology Inc
Citation: Vasudevarao, MD; Mizar, P; Kumari, S; Mandal, S; Siddhanta, S; Swamy, MMM; Kaypee, S; Kodihalli, RC; Banerjee, A; Naryana, C; Dasgupta, D; Kundu, TK, Naphthoquinone-mediated Inhibition of Lysine Acetyltransferase KAT3B/p300, Basis for Non-toxic Inhibitor Synthesis. Journal of Biological Chemistry 2014, 289 (11) 7702-7717,
Journal of Biological Chemistry
Abstract: Background: 1,4-Naphthoquinone analogs, such as plumbagin, are toxic compounds due to their redox cycling and thiol-reactive properties. Results: The p300 inhibitor PTK1, a plumbagin derivative with greatly reduced toxicity, was synthesized and characterized. Conclusion: PTK1 is a reversible, non-competitive inhibitor of p300 KAT activity with reduced toxicity. Significance: These studies provide insight into naphthoquinone-mediated KAT inhibition and describe the synthesis of a therapeutically important, non-toxic inhibitor. Hydroxynaphthoquinone-based inhibitors of the lysine acetyltransferase KAT3B (p300), such as plumbagin, are relatively toxic. Here, we report that free thiol reactivity and redox cycling properties greatly contribute to the toxicity of plumbagin. A reactive 3rd position in the naphthoquinone derivatives is essential for thiol reactivity and enhances redox cycling. Using this clue, we synthesized PTK1, harboring a methyl substitution at the 3rd position of plumbagin. This molecule loses its thiol reactivity completely and its redox cycling ability to a lesser extent. Mechanistically, non-competitive, reversible binding of the inhibitor to the lysine acetyltransferase (KAT) domain of p300 is largely responsible for the acetyltransferase inhibition. Remarkably, the modified inhibitor PTK1 was a nearly non-toxic inhibitor of p300. The present report elucidates the mechanism of acetyltransferase activity inhibition by 1,4-naphthoquinones, which involves redox cycling and nucleophilic adduct formation, and it suggests possible routes of synthesis of the non-toxic inhibitor.
Description: Restricted Access
ISSN: 0021-9258
Appears in Collections:Research Articles (Chandrabhas N.)
Research Papers (Tapas K. Kundu)

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