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Zinc-dependent Histone Deacetylases

Before our work [39], only one catalytic mechanism for zinc dependent HDACs has been proposed in the literature, which was originated from the crystallographic study of HDLP [47], a histone-deacetylase-like protein that is widely used as a model for class-I HDACs. In the enzyme active site, the catalytic metal zinc is penta-coordinated by two asp residues, one histidine residues as well as the inhibitor [47], Based on their crystal structures, Finnin et al. [47] postulated a catalytic mechanism for HDACs in which the first reaction step is analogous to the hydroxide mechanism for zinc proteases zinc-bound water is a nucleophile and Zn2+ is five-fold coordinated during the reaction process. However, recent experimental studies by Kapustin et al. suggested that the transition state of HDACs may not be analogous to zinc-proteases [48], which cast some doubts on this mechanism. [Pg.345]

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. [Pg.51]

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. [Pg.62]

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. [Pg.101]

Heltweg, B., Dequiedt, F., Verdin, F. and Jung, M. (2003) Nonisotopic substrate for assaying both human zinc and NAD + -dependent histone deacetylases. Analytical Biochemistry, 319, 42 8. [Pg.115]

Structural Aspects of Zinc-Dependent Histone Deacetylases... [Pg.8]

The key to understanding the function of histone deacetylases lies in their three dimensional architecture. As outlined above, the class I, II, and IV enzymes are all metal ion dependent in most cases, a zinc ion is essential for activation and hydrolysis of the amide group, which is located within the active site of the enzyme. However, it has been shown that other metal ions can efficiently adopt the role of the catalytic ion. For instance, the nature of the ion bound to the catalytic site influences the specific activity of HDAC8 in the following order Co2+ > Fe2+ > Zn2+ > Ni2+. These data suggest that Fe2+ rather than Zn2+ may be responsible for the in vivo activity of HDAC8 [33]. [Pg.8]

Histone deacetylases (HDACs, EC number 3.5.1) remove acetyl groups from A -acetyl lysines by hydrolysis, both on histones and non-histone proteins, hence are more generally referred to as lysine deacetylases (KDACs). HDACs are grouped into four classes based on sequence homology and mechanism (Table 5.2). The first two classes, sometimes referred to as classical HDACs, are zinc-dependent and their activity is inhibited by hydroxamic acids, e.g. trichostatin A (TSA). The third class, referred to as Sirtuins, are NAD -dependent proteins and are not inhibited by TSA. The fourth class is also zinc-dependent, but is considered an atypical category based on low sequence homology to classes I and II. Class I and IV HDACs are mainly found in the nucleus and are expressed in many cell types, while the expression of class II HDACs, which are able to shuttle in and out of the nucleus, is tissue specific. Sirtuin localisation depends on the particular isoform (cytoplasm, mitochondria and nucleus). [Pg.164]

Macrocyclic Inhibitors of Zinc-dependent Histone Deacetylases (HDACs)... [Pg.127]


See other pages where Zinc-dependent Histone Deacetylases is mentioned: [Pg.341]    [Pg.344]    [Pg.338]    [Pg.267]    [Pg.292]    [Pg.18]    [Pg.217]    [Pg.5120]    [Pg.645]    [Pg.5]    [Pg.557]    [Pg.5119]    [Pg.16]    [Pg.128]    [Pg.128]   
See also in sourсe #XX -- [ Pg.110 , Pg.111 , Pg.112 , Pg.113 , Pg.114 , Pg.115 ]




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