Histone acetyltransferases HATs

One of the most-studied covalent modifications is the acetylation of the lysine residues of histone tails. The acetylation state of lysines of nucleosomal histones modulates chromatin structure and regulates gene transcriptional activity. The balance of lysine acetylation is controlled by the antagonistic action of two enzyme families histone deacetylases (HDACs) and histone acetyltransferases (HATs). In humans there are essentially three main HDAC subclasses [6]. 

Table 1. List of known histone acetyltransferases (HATs)...

Acetylation of internal lysine residues of core histone N-terminal domains has been found correlatively associated with gene transcription in eukaryotes for more than four decades. Histone acetylation levels are the result of a competition between two families of enzymes histone acetyltransferases (HATs) and histone deacetylases (HDACs). 

Histone acetylation is a reversible amidation reaction involving defined e-amino groups of lysine residues (see Fig. 6) at the N-terminal tails of core histones. The highly dynamic equilibrium between the acetylated and non-acetylated states of lysine is maintained by two enzymatic groups, referred to as histone acetyltransferases (HATs) and histone deacetylases (HDACs). 

A state of equilibrium of histone acetyltransferases (HATS) and deacetylases (HDACs) between a chromatin-bound domain and a protein-based domain in the... 

Histone acetyltransferases (HATs) are enzymes that acetylate specific lysine residues in histones through the transfer of an acetyl group from an acetyl-coenzymeA (AcCoA) molecule, causing profound effects on chromatin structure and assembly as well as gene transcription. HATs are found in most, if not all, eukaryotic organisms as multiprotein complexes, some HAT catalytic subunits even being shared between various complexes that display different substrate specificities based on their subunit composition [12]. Despite their name, HATs do not restrict themselves to the acetylation of histones, since these enzymes have also been shown to act on nonhistone proteins, broadening their scope of action [13]. 

Figure 2.1 Structures of histone acetyltransferases (HATs). Ribbon representation of the structures of the HAT domains of (a) Tetrahymena thermophila CcnS (PDBcode Iqsr), (b) Saccharomyces cerevisiae Hatl (PDB code Ibob), (c) S. cerevisiae Esal (PDB code Imja),...

Figure 2.2 Structures of CcnS histone acetyltransferase (HAT) bound to coenzymeA and various peptides. Schematic representation of Tetrahymena thermophiia CcnS HAT domain (ribbon representation) bound to coenzymeA and 19mers (both shown as ball and sticks) from (a) histone H3 (PDB code lpu9),...

Histone acetyltransferase (HAT) enzymes are divided into several families based on conserved sequence motifs. The two major families are named GNAT (Gcn5-related... 

Souto, J.A., Conte, M., Alvarez, R., Nebbioso, A., Carafa, V., Altucci, L. et al. (2008) Synthesis ofbenzamides related to anacardic acid and their histone acetyltransferase (HAT) inhibitory activities. ChemMedChem, 3, 1435-1442. 

Fig. 4 Co-activator and co-repressor complexes are required for nuclear hormone receptor-mediated transcriptional regulation. The tissue-selective fine-tuning of gene transcription by nuclear hormone receptors is due to different co-regulatory complexes that have various functions and enzymatic activities. Co-activator complexes include factors that contain ATP-dependent chromatin remodelling activity often associated with histone acetyltransferase (HAT) activity. Co-repressors include ATP-dependent chromatin remodelling complexes, which function as platforms for the recruitment of several subcomplexes that often contain histone deacetylase (HDAC) activity...

The acetylation and deacetylation of histones figure prominently in the processes that activate chromatin for transcription. As noted above, the amino-terminal domains of the core histones are generally rich in Lys residues. Particular Lys residues are acetylated by histone acetyltransferases (HATs). Cytosolic (type B) HATs acetylate newly synthesized histones before the histones are imported into the nucleus. The subsequent assembly of the histones into chromatin is facilitated by additional proteins CAF1 for H3 and H4, and NAP1 for H2A and H2B. (See Table 28-2 for an explanation of some of these abbreviated names.)... 

Curcumin has also been found to interrupt the cell cycle, to have cytotoxic effects, and to have a role in antiproliferation and the induction of apoptosis in a hepatocarcinoma cell line. Curcumin is a potent inhibitor of phenol sulfotransferase (SULT1A1) in human liver and extrahepatic tissues [Vietri et al., 2003]. Curcumin inhibited the interleukin-6 (IL-6) production, histone acetyltransferase (HAT) activity, and API activation [Chen et al., 2003a] and prevented cell death and apoptotic biochemical changes, such as the... 

Toleman C, Paterson AJ, Whisenhunt TR, Kudlow JE. Characterization of the histone acetyltransferase (HAT) domain of a bifunctional protein with activable O-GIcNAcase and HAT activities. J. Biol. Chem. 2004 279 53665-53673. 

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