Histone Lysine deacetylases

Histone acetylation marks are removed by the class of enzymes named 'histone deacetylases' (HDACs). They contain a 'histone deacetylase' catalytic domain that mediates this function. They often exist as a part of multi-subunit complexes.

Eighteen deacetylases are known in humans that are classified into 4 classes based on homology:

Class I: HDAC 1, 2, 3 and 8

Class IIa: HDAC 4, 5, 7 and 9

Class IIb: HDAC 6 and 10

Class III: NAD-dependent deacetylase Sirtuin 1 to 7

Class IV: HDAC 11

The mechanism of catalysis is same for Class I, II and IV wherein a metal ion (Zn/Fe) present at the active site makes a coordinate bond with the oxygen of the carbonyl group and activates a water molecule with the help of nearby histidine/aspartic acid for nucleophilic attack that further causes removal of the acetyl group. Sirtuins have a rather different mechanism wherein they first bind the acetylated substrate followed by NAD+. NAD+ is converted to nicotinamide after attack of carbonyl oxygen. The intermediate formed is alpha-1'-O-alkylamidate that finally deacetylates lysine and gives 2'-O-acetyl-ADP-ribose as the product.

Apart from histones, HDACs have several non-histone targets as well. Histone deacetylation is generally linked to transcriptional repression. Other functions include control of cell motility by modifying tubulin, making critical decisions during immune responses, regulation of organismal aging, DNA damage repair, synaptic plasticity. Sirt1 is an important master molecule that regulates multiple and diverse cellular functions. It also regulates p53 which itself is a master regulator. They are also suggested as biomarkers for benign teratomas. HDACs are implicated in many cancers like human pancreatic adenocarcinoma tissues, hepatocellular carnicomas, blood cancers, gastric cancers and other diseases like Werner syndrome.

Further reading: PMID: 18292778, PMID: 12711221.

Cytogenetic map of Lysine deacetylases coding genes
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Different histone Lysine deacetylases
Enzyme (UniprotKB recommended name) Coding gene/s Site of histone modification
Histone deacetylase 1HDAC1H3K56ac
Histone deacetylase 10HDAC10
Histone deacetylase 11HDAC11
Histone deacetylase 2HDAC2
Histone deacetylase 3HDAC3H3K4ac
Histone deacetylase 4HDAC4
Histone deacetylase 5HDAC5
Histone deacetylase 6HDAC6
Histone deacetylase 7HDAC7
Histone deacetylase 8HDAC8
Histone deacetylase 9HDAC9
NAD-dependent deacetylase sirtuin-1SIRT1H4K16ac, H3K9ac, H1K25ac
NAD-dependent deacetylase sirtuin-2SIRT2H4K16ac, H3K56ac
NAD-dependent deacetylase sirtuin-3, mitochondrialSIRT3H3K56ac
NAD-dependent deacetylase sirtuin-6SIRT6H3K9ac, H3K56ac