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dc.contributor.authorVasudevarao, Mohankrishna Dalvoy
dc.contributor.authorMizar, Pushpak
dc.contributor.authorKumari, Sujata
dc.contributor.authorMandal, Somnath
dc.contributor.authorSiddhanta, Soumik
dc.contributor.authorSwamy, Mahadeva M. M.
dc.contributor.authorKaypee, Stephanie
dc.contributor.authorKodihalli, Ravindra C.
dc.contributor.authorBanerjee, Amrita
dc.contributor.authorNaryana, Chandrabhas
dc.contributor.authorDasgupta, Dipak
dc.contributor.authorKundu, Tapas Kumar
dc.identifier.citationVasudevarao, 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,
dc.identifier.citationJournal of Biological Chemistryen_US
dc.descriptionRestricted Accessen_US
dc.description.abstractBackground: 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.en_US
dc.publisherAmerican Society Biochemistry Molecular Biology Incen_US
dc.rights@American Society Biochemistry Molecular Biology Inc, 2014en_US
dc.subjectBiochemistry & Molecular Biologyen_US
dc.subjectEnzyme Inactivationen_US
dc.subjectEnzyme Inhibitorsen_US
dc.subjectHistone Acetylaseen_US
dc.subjectReactive Oxygen Species (Ros)en_US
dc.subjectLysine Acetyltransferaseen_US
dc.subjectN-Acetyl Cysteineen_US
dc.subjectStructure-Activity Relationshipen_US
dc.subjectSurface-Enhanced Ramanen_US
dc.subjectInduced Histone Hypoacetylationen_US
dc.subjectGlobal Gene-Expressionen_US
dc.subjectTranscriptional Coactivatoren_US
dc.subjectChromatin Transcriptionen_US
dc.subjectSmall Moleculesen_US
dc.subjectCancer Cellsen_US
dc.titleNaphthoquinone-mediated Inhibition of Lysine Acetyltransferase KAT3B/p300, Basis for Non-toxic Inhibitor Synthesisen_US
Appears in Collections:Research Articles (Chandrabhas N.)
Research Papers (Tapas K. Kundu)

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