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Title: Bisubstrate inhibitors to target histone acetyltransferase 1
Abstract

Developing selective enzyme inhibitors allows for the expansion of molecular toolboxes to investigate functions and activities of target enzymes. The histone acetyltransferase 1 (HAT1) is among the first histone acetyltransferase (HAT) enzymes that were discovered in the mid‐1990s; however, it remains one of the poorly studied enzymes in comparison with the otherHATs. AlthoughHAT1 has been linked to various disease states, no inhibitors have been reported to targetHAT1. Here, we designed a set of peptide‐CoA conjugates as bisubstrate inhibitors ofHAT1 with submicromolar potency. In particular, the bisubstrate inhibitor H4K12CoA exhibited a lowKivalue of 1.1 nM forHAT1. In addition, H4K12CoA was shown to be a competitive inhibitor with respect to both AcCoA and H4 peptide, suggesting a unique kinetic mechanism ofHAT1 catalysis. Creating these submicromolar inhibitors offers mechanistic tools to better understand howHAT1 recognizes substrates and cofactors, as well as provides chemical leads to further develop therapeutic agents to target this important enzyme for disease therapy.

 
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NSF-PAR ID:
10084502
Author(s) / Creator(s):
 ;  ;  
Publisher / Repository:
Wiley-Blackwell
Date Published:
Journal Name:
Chemical Biology & Drug Design
Volume:
93
Issue:
5
ISSN:
1747-0277
Page Range / eLocation ID:
p. 865-873
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
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