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Bisubstrate inhibitors to target histone acetyltransferase 1
- Source :
- Chem Biol Drug Des
- Publication Year :
- 2018
-
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 to the other HATs. Although HAT1 has been linked to various disease states, no inhibitors have been reported to target HAT1. Here we designed a set of peptide-CoA conjugates as bisubstrate inhibitors of HAT1 with submicromolar potency. In particular, the bisubstrate inhibitor H4K12CoA exhibited a low K(i) value of 1.1 nM for HAT1. In addition, H4K12CoA was shown to be a competitive inhibitor with respect to both AcCoA and H4 peptide, suggesting a unique kinetic mechanism of HAT1 catalysis. Creating these submicromolar inhibitors offers a mechanistic tools to better understand how HAT1 recognizes substrates and cofactors, as well as provides chemical leads to further develop therapeutic agents to target this important enzyme for disease therapy.
- Subjects :
- Peptide
01 natural sciences
Biochemistry
Binding, Competitive
Cofactor
Article
Substrate Specificity
Disease therapy
Inhibitory Concentration 50
Drug Discovery
Humans
Epigenetics
Amino Acid Sequence
Enzyme Inhibitors
Histone Acetyltransferases
Pharmacology
chemistry.chemical_classification
biology
010405 organic chemistry
Organic Chemistry
Histone acetyltransferase
Recombinant Proteins
0104 chemical sciences
010404 medicinal & biomolecular chemistry
Kinetics
Enzyme
chemistry
biology.protein
Molecular Medicine
HAT1
Competitive inhibitor
Subjects
Details
- ISSN :
- 17470285
- Volume :
- 93
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- Chemical biologydrug design
- Accession number :
- edsair.doi.dedup.....d7d791330217417cdf2171e9c1b78c07