Naphthoquinone-mediated inhibition of lysine acetyltransferase KAT3B/p300, basis for non-toxic inhibitor synthesis.
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.
From the Transcription and Disease Laboratory and.
Mohankrishna Dalvoy
MD
Vasudevarao
Pushpak
P
Mizar
Sujata
S
Kumari
Somnath
S
Mandal
Soumik
S
Siddhanta
Mahadeva M M
MM
Swamy
Stephanie
S
Kaypee
Ravindra C
RC
Kodihalli
Amrita
A
Banerjee
Chandrabhas
C
Naryana
Dipak
D
Dasgupta
Tapas K
TK
Kundu
D001665:Binding Sites; D045744:Cell Line, Tumor; D002470:Cell Survival; D050881:E1A-Associated p300 Protein / Q000037:antagonists & inhibitors* / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000737:chemistry*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007700:Kinetics; D008239:Lysine / Q000737:chemistry; D009285:Naphthoquinones / Q000737:chemistry*; D010084:Oxidation-Reduction; D017434:Protein Structure, Tertiary; D017382:Reactive Oxygen Species; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000737:chemistry
D004791:Enzyme Inhibitors; D009285:Naphthoquinones; D017382:Reactive Oxygen Species; D013438:Sulfhydryl Compounds; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; D008239:Lysine; C014758:plumbagin
Enzyme Inactivation; Enzyme Inhibitors; Histone Acetylase; Lysine Acetyltransferase; N-Acetyl Cysteine; Plumbagin; Reactive Oxygen Species (ROS); Structure-Activity Relationship; Thiol; Toxicity