Human histone deacetylase

Fischle W, EmUiani S, Hendzel Ml, Nagase T, Nomura N, Voelter W, Verdin E (1999) A new family of human histone deacetylases related to Saccharomyces cerevisiae HDAlp. J Biol Chem 274(17) 11713-11720... 

Buggy JJ, Sideris ML, Mak P, Lorimer DD, McIntosh B, Clark JM (2000) Cloning and characterization of a novel human histone deacetylase, HDAC8. Biochem J 350(R 1) 199-205 Candido EP, Reeves R, Davie JR (1978) Sodium butyrate inhibits histone deacetylation in cultured cells. Cell 14(1) 105-113... 

Gao L, Cueto MA, Asselbergs F, Atadja P (2002) Cloning and functional characterization of HDACl Is, a novel member of the human histone deacetylase family. J Biol Chem 277(28) 25748-25755... 

Gray SG, Ekstrom TJ (2001) The human histone deacetylase family. Exp Cell Res 262(2) 75-83... 

Wang AH, Bertos NR, Vezmar M, Pelletier N, Crosato M, Heng HH, Th ng J, Han J, Yang XJ (1999) HDAC4, a human histone deacetylase related to yeast HDAl, is a transcriptional corepressor. Mol Cell Biol 19(ll) 7816-7827... 

Gray SG, Ekstrom TJ (2001) The human histone deacetylase family. Exp Cell Res 262 75—83 Greiner D, Bonaldi T, Eskeland R, Roemer E, Imhof A (2005) Identification of a specific inhibitor of the histone methyltransferase SU(VAR)3-9. Nat Chem BioH 143-145 Grozinger CM, Chao ED, Blackwell HE, Moazed D, Schreiber SL (2001) Identification of a class of small molecule inhibitors of the sirtuin family of NAD-dependent deacetylases by phenotypic screening. J Biol Chem 276(42) 38837-38843... 

Remiszewski, S.W., Samhucetti, L.C., Atadja, P., Bair, KW., Cornell, W.D., Green, M.A. et al. (2002) Inhihitors of human histone deacetylase Synthesis and enzyme and cellular activity of straight chain hydroxamates. Journal of Medicinal Chemistry, 45, 753—757. 

The equilibrium of reversible histone lysine acetylation is maintained by histone deacetylases (H D ACs) on one hand and histone acetyltransferases on the other hand. Human histone deacetylases can be separated into four classes [15]. HDACs of class I, II and IV are zinc-dependent amidohydrolases, whereas class III HDACs, also referred to as sirtuins, have a mechanism that is dependent on NAD [16]. As histone deacetylases have been widely studied, it is not surprising that there are also a large number of assays existing that have helped to characterize modulators of these enzymes and subsequently the enzymes themselves. 

Suzuki, T., Nagano, Y, Kouketsu, A., Matsuura, A., Maruyama, S., Kurotaki, M. et al. (2005) Novel Inhibitors of human histone deacetylases design, synthesis, enzyme inhibition, and cancer cell growth inhibition of SAHA-based non-hydroxamates. Journal of Medicinal Chemistry, 48, 1019—1032. 

In our recent studies we were fortunate to recruit experimental collaborators who have validated computational hits identified by virtual screening of commercially available compound libraries using rigorously validated QSAR models. Examples include anticonvulsants (25), HIV-1 reverse transcriptase inhibitors (32), D1 antagonists (33), antitumor compounds (34), beta-lactamase inhibitors (35), human histone deacetylase (HDAC) inhibitors... 

B. L., Butler, . V., Kozikowski, A. P., Jung, M., Tropsha, A. (2009) Novel inhibitors of human histone deacetylase (HDAC) identified by QSARmodeling of known inhibitors, virtual screening, and experimental validation. J Chem Inf Model 49,461—476. 

Gantt SL, Gattis SG, Fierke CA (2006) Catalytic activity and inhibition of human histone deacetylase 8 is dependent on the identity of the active site metal ion. Biochemistry 45 (19) 6170-6178... 

Muraglia E et al (2008) 2-Trifluoroacetylthiophene oxadiazoles as potent and selective class II human histone deacetylase inhibitors. Bioorg Med Chem Lett 18(23) 6083-6087... 

Many proteins rely upon post-translational modification for activity, subcellular localisation or to alter their structure and/or stabiltiy and some of these modifications are reversible. Reversible acetylation for esunple requires the combined action of acetylases (aka acetyltransfoiases) and deacetylases which work n ether to maintain the appropriate acetylation level. It was only just over ten years ago when these enzymes were first identified and in the case of the first deacetylase an inhibitor of the enzyme was used as a probe to purify the protein itself Reversible protein acetylation has been the subject of intense investigation ever since. Although re-seardi has focussed on histone (de)acetylation and its consequences, it is important to consider alternative in vivo substrates. Human histone deacetylase 6 (HDAC6) is a mbulin deacetylase for example (see ref. 2). 

Chemical Biology of Histone Modifications Table 5.2 Human histone deacetylases. 

Singh, R. K. Mandal, T. Balsubramanian, N. Viaene, T. Leedahl, T. Sule, N. Cook, G. Srivastava, D. K. Histone deacetylase activators N-acetylthioureas serve as highly potent and isozyme selective activators for human histone deacetylase-8 on a fluorescent substrate. Bioorg. Med. Chem. Lett. 2011,27,5920-5923. 

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