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Lysine deacetylation

Different oxidation states of sulfur have also been explored, particularly sulf-ones and sulfonamides as transition state analogs of lysine deacetylation, but without much success. The monodentate SAHA-like methyl sulfoxide 7 proved most potent, but still with an enzyme IC50 of only 48 pM and indications of HDAC/TDAC selectivity in cellular assays [28]. [Pg.340]

PDB code 1T69) (b) outline catalytic mechanism of hydrolytic lysine deacetylation by Class I, II and IV HDACs (c) representative HDAC inhibitor chemotypes, including two clinically approved inhibitors, the hydroxamic acid SAHA/Vorinostat, and the depsipeptide FK228/ Romidepsin. [Pg.167]

SIRT2) in complex with carba-NAD and a histone H4 acetyllysine peptide (PDB code ISZD) (b) outline catalytic mechanism of lysine deacetylation by SIRT deacetylases, which proceeds by activation of the acetyl group by 0-glycosylation (c) representative SIRT inhibitor chemotypes. [Pg.168]

Histone Acetylation. Figure 1 Histone acetylation is a posttranslational modification of lysine residues of histones. This modification is catalyzed by histone actyl transferases (HATs), which transfer an acetyl group (yellow) from acetyl-Coenzyme A onto the E-amino group of the lysine residue. Histone deacetylation is catalyzed by histone deacetylases (HDACs), which hydrolyze the lysine bound acetyl group. HDAC inhibitors like Trichostatin A (TSA) are known to inhibit the deacetylation reaction in vivo and in vitro. [Pg.593]

In addition to histone deacetylation, histone lysine methylation can also lead to gene silencing which is not blocked by the HDAC inhibitors [6, 51], Several lines of evidence have suggested a connection between cancer and histone lysine methyltrans-ferases (HKMTs) [52], HKMTs catalyze the transfer of methyl group(s) from the cofactor. S -adenosyI-methionine (AdoMet) to some specific lysine residues in the N-terminal histone tails [53, 54], With one exception of Dotl [55], all known HKMTs contain the SET domain which represents a novel structural fold [53, 56], Among SET-domain HKMTs, SET7/9 is one of the best characterized experimentally. It is a... [Pg.345]

The phenylselenocysteine has also been used successfully to chemically append analogues of methyl- or acetyl-lysine, important histone modifications that can contribute to chromatin structure and accessibility of transcriptional machinery in eukaryotes. By introducing phenylselenocysteine into the Xenopus histone H3, both acetyl-lysine and mono-, di-, and trimethyl-lysine analogues were appended to the purified unnatural amino acid-containing FI 3 protein (Figure 10). " Additionally, the H3 protein with a modification mimicking acetylation of lysine 9 can be deactylated by a histone deacetylation complex and is also a substrate for phosphorylation by Aurora B kinase. Such purified and chemically labeled histones are likely functional in nucleosomes, and preparation of specifically modified histones for comprehensive analysis of chromatin structure and accessibility is particularly suited to this chemical labeling technique. [Pg.605]

Thus, Xi exemplifies both extremes of the histone code, namely the general deacetylation of all four core histones and the specific retention of H3 dimethylated at lysine 9/27. It also illustrates the great stability of epigenetic signals carried by the histone tails. The general underacetylation of Xi, the undermethylation of H3 lysine 4 and the selective retention of H3 dimethylated at lysine 9/27, are all maintained in human x hamster somatic cell hybrids in which Xi is the only human chromosome and therefore exists in an almost completely foreign (i.e., hamster) cellular environment [73]. [Pg.300]

Histone deacetylases (HDAGs) catalyze the removal of acetyl groups from the Ne atom of histone lysines in a nucleosomal context, ensuring the reversibility of histone acetylation. Histone deacetylation is often associated vdth transcriptional repression and silencing since it promotes chromatin higher order structures and the recruitment of silencers [34]. As other enzymes involved in chromatin... [Pg.29]

The sirtuins (silent information regulator 2-related proteins class III HDACs) form a specific class of histone deacetylases. First, they do not share any sequence or structural homology with the other HDACs. Second, they do not require zinc for activity, but rather use the oxidized form of nicotinamide adenine dinucleotide (NAD ) as cofactor. The reaction catalyzed by these enzymes is the conversion of histones acetylated at specific lysine residues into deacetylated histones, the other products of the reaction being nicotinamide and the metabolite 2 -0-acetyl-adenosine diphosphate ribose (OAADPR) [51, 52]. As HATs and other HDACs, sirtuins not only use acetylated histones as substrates but can also deacetylate other proteins. Intriguingly, some sirtuins do not display any deacetylase activity but act as ADP-ribosyl transferases. [Pg.34]

Histone acetyltransferases (H ATs) catalyze the transfer of an acetyl moiety from acetyl-CoA to the E-amino group of certain lysine residues within core histone proteins. This transferase reaction produces acetylated histones and the deacetylated cofactor CoA-SH. As HATs are important enzymes in the regulation of gene expression, there are also a number of assays available to detect acetyltransferases activity. [Pg.107]


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