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Bisubstrate inhibitors to target histone acetyltransferase 1
Author(s) -
Ngo Liza,
Brown Tyler,
Zheng Yujun G.
Publication year - 2019
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.13476
Subject(s) - enzyme , acetyltransferase , histone acetyltransferase , biochemistry , peptide , histone , chemistry , cofactor , acetylation , biology , stereochemistry , computational biology , gene
Developing selective enzyme inhibitors allows for the expansion of molecular toolboxes to investigate functions and activities of target enzymes. The histone acetyltransferase 1 ( HAT 1) 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 other HAT s. Although HAT 1 has been linked to various disease states, no inhibitors have been reported to target HAT 1. Here, we designed a set of peptide‐CoA conjugates as bisubstrate inhibitors of HAT 1 with submicromolar potency. In particular, the bisubstrate inhibitor H4K12CoA exhibited a low K i value of 1.1 nM for HAT 1. In addition, H4K12CoA was shown to be a competitive inhibitor with respect to both AcCoA and H4 peptide, suggesting a unique kinetic mechanism of HAT 1 catalysis. Creating these submicromolar inhibitors offers mechanistic tools to better understand how HAT 1 recognizes substrates and cofactors, as well as provides chemical leads to further develop therapeutic agents to target this important enzyme for disease therapy.