Human histone deacetylase HDACs

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. 

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]. 

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. 

Bugula collected in the US Virgin Islands produces by culture two cyclic tetrapeptides, microsporins A and B, which are potent inhibitors of histone deacetylase (HDAC) and cytotoxic for several human cancer cell lines (Gu et al., 2007). Microsporin A contains two nonribosomal amino acids o-pipecolic add (Pip) and 2(S)-amino-8-oxo-decanoic... 

R., Gallinari, P. et al. (2004) Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDACS, complexed with a hydroxamic acid inhibitor. Proceedings of the National Academy of Sciences of the United States of America, 101 (42), 15064-15069. 

So far 18 different members of HDACs have been discovered in humans and classified into four classes based on their homology to yeast histone deacetylases [33]. Class I includes four different subtypes (HDACl, 2, 3, 8), class II contains six subtypes tvhich are divided into two subclasses class Ila with subtypes HDAC4, 5, 7, 9 and class Ilb with HDAC6, 10. Class I and class II HDAC share significant structural homology, especially within the highly conserved catalytic domains. HDACs 6 and 10 are unique as they have two catalytic domains. HDACll is referred to as class IV. While the activity of class I, II and IV HDACs depends on a zinc based catalysis mechanism, the class III enzymes, also called sirtuins, require nicotinamide adenine dinucleotide as a cofactor for their catalysis. 

Mol, C., Ho, J.D., Jennings, A.J. et al. (2004) Structural snapshots of human HDACS provide insights into the class 1 histone deacetylases. Structure (London, England 1993), 12, 1325-1334. 

HCG human chorionic gonadotropin HCL hairy cell leukemia Hct hematocrit HCTZ hydrochlorothiazide HD hemodialysis HDAC histone deacetylase Hep hepatitis hepatotox hepatotoxicity HER2 type of cancer gene HF heart failure HFA designation for type of inhalation device Hgb hemoglobin HIT/HITTS heparin-mduced thrombocytopenia... 

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