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| Enzyme (UniprotKB recommended name) | Coding gene/s | Site of histone modification |
|---|---|---|
| Histone deacetylase 1 | HDAC1 | H3K56ac |
| Histone deacetylase 10 | HDAC10 | |
| Histone deacetylase 11 | HDAC11 | |
| Histone deacetylase 2 | HDAC2 | |
| Histone deacetylase 3 | HDAC3 | H3K4ac |
| Histone deacetylase 4 | HDAC4 | |
| Histone deacetylase 5 | HDAC5 | |
| Histone deacetylase 6 | HDAC6 | |
| Histone deacetylase 7 | HDAC7 | |
| Histone deacetylase 8 | HDAC8 | |
| Histone deacetylase 9 | HDAC9 | |
| NAD-dependent deacetylase sirtuin-1 | SIRT1 | H4K16ac, H3K9ac, H1K25ac |
| NAD-dependent deacetylase sirtuin-2 | SIRT2 | H4K16ac, H3K56ac |
| NAD-dependent deacetylase sirtuin-3, mitochondrial | SIRT3 | H3K56ac |
| NAD-dependent deacetylase sirtuin-6 | SIRT6 | H3K9ac, H3K56ac |