Class IV HDAC

Histone Deacetylases (HDACs) catalyze the removal of the acetyl groups from lysines (see Fig. 1). Together with the HATs they are responsible for maintaining the level of histone acetylation throughout the genome. The family of HDAC proteins has been divided into four classes based on phylogenetic analysis and sequence comparison. HDACs of the classes I and II share the same Zn2+-based reaction and are evolutionary related. Class IV HDACs also possess a Zn2+-based reaction... 

Class IV HDAC 11 is most closely related to the class I family but also displays common characteristics with class II HDACs. The low overall homology to either of these classes has resulted in a separate classification. HDAC 11 is highly expressed in heart, brain, testis, muscle, and kidney cells and is predominantly located in the nucleus [28]. This deacetylase has short N- and C-terminal extensions little is known about its function. 

The human genome contains 18 HDACs that are classified according to their catalytic mechanism. The focus of this chapter is the eleven zinc-dependent HDACs 1-11, which contain a zinc cation as the active site catalyst. In addition, there are seven sirtuins, SIRTs 1-7, which instead employ the cofactor NAD for amide bond hydrolysis. The zinc-dependent HDACs are further subdivided into elass I (HDACs 1, 2, 3 and 8), class Ila (HDACs 4, 5, 7 and 9), class Ilb (HDACs 6 and 10) and class IV (HDAC 11) based on sequence homology and cellular loealization. The class I HDACs are ubiquitously expressed and primarily located in the cell nucleus, where... 

Histone deacetylase (HDAC) are often divided into various classes, (I, II, and IV) which are Zn " dependent (Table 1). Please note this chapter does not discuss the class HI HDACs which are NAD dependent, Sir-2-like deacetylases. The importance of class or isoform selective inhibition over pan-HD AC inhibition is currently being explored for its clinical relevance and thus, we will not explore in detail. However, a few natural products do demonstrate this type of class and isozyme selective inhibition which we will discuss briefly. 

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. 

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. 

In humans, 18 HDACs have been identified and classified according to their homology to yeast HDACs [6]. Class I, II and IV HDACs are zinc-dependent enzymes, whereas the third class (sirtuins) are NAD -dependent enzymes and are covered elsewhere in this book. Class I (H DACs 1, 2, 3, 8) are closely related to yeast Rpd3 class Ila (HDACs 4, 5, 7, 9) and class Ilb (HDACs 6, 10) are related to yeast Hdal and this latter subclass contains two catalytic sites. Finally, class IV H DACs contain just one member (HDAC 11). Whilst classes I and IV HDACs are mainly found in the nucleus of cells, class II H DACs are free to shuttle between the nucleus and the cytoplasm. The exact physiological role of each of the individual H DAC isoforms in cells is far from fully understood, yet it is known that these enzymes act on many other nonhistone substrates. They also often function as part of larger multiprotein complexes and are frequently associated with other HDAC isoforms and/or require the presence of several coregulators. 

The HDAC superfamily consists of 18 members originating from two different evolutionary starting points which exhibit a common lysine deacetylase activity. The classical HDAC family is characterized by a well-conserved Zn2+ catalytic domain (Table 1 classes I, Ha, lib, and IV). The sirtuins (class III HDACs) comprise a distinct subfamily of HDACs, which use NAD+ as cofactor. 

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). 

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. 

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