Histone deacetylase
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Histone deacetylases (HDAC) (EC number 3.5.1) are a class of enzymes that remove acetyl groups from an ε-N-acetyl lysine amino acid on a histone. Its action is opposite to that of histone acetyltransferase.
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[edit] Locations
Within the class I HDACs, HDAC 1,2 and 8 are primarily found in the nucleus, whereas HDAC 3 is found both in the nucleus, cytoplasm and also membrane associated. Class II HDACs (HDAC 4, 5, 6, 7 9 and 10) are able to shuttle in and out of the nucelus depending on different signals.[1][2]
[edit] Functions
Histone tails are normally positively charged due to amine groups present on their lysine and arginine amino acids. These positive charges help the histone tails to interact with and bind to the negatively charged phosphate groups on the DNA backbone. Acetylation, which occurs normally in a cell, neutralizes the positive charges on the histone by changing amines into amides and decreases the ability of the histones to bind to DNA. This process allows chromatin expansion, allowing for genetic transcription to take place. Histone deacetylase removes those acetyl groups, increasing positive charges to the histone tails and encourages high-affinity binding between the histones and DNA backbone. This process condenses DNA structure, preventing transcription.
Histone deacetylase is involved in a series of pathways within the living system. According to the Kyoto Encyclopedia of Genes and Genomes (KEGG), these are:
- Environmental information processing; signal transduction; notch signaling pathway PATH:ko04330
- Cellular processes; cell growth and death; cell cycle PATH:ko04110
- Human diseases; cancers; chronic myeloid leukemia PATH:ko05220
Histone acetylation plays an important role in the regulation of gene expression. Hyperacetylated chromatin is transcriptionally active, and hypoacetylated chromatin is silent. A study on mice found that a specific subset of mouse genes (7%) was deregulated in the absence of HDAC1.[3] Their study also found a regulatory cross talk between HDAC1 and HDAC2 and suggest a novel function for HDAC1 as a transcriptional coactivator.
HDAC1 expression was found to be increased in the prefrontal cortex of schizophrenia subjects,[4] negatively correlating with the expression of GAD67 mRNA.
[edit] HDAC inhibitors
HDIs have a long history of use in psychiatry and neurology as mood stabilizers and anti-epilectics, for example, valproic acid. More recently, HDIs are being studied as a mitigator or treatment for neurodegenerative diseases.[5][6] Also in recent years, there has been an effort to develop HDIs for cancer therapy, and vorinostat has recently been approved for treatment of cutaneous T cell lymphoma (CTCL). The exact mechanisms by which the compounds may work are unclear, but epigenetic pathways are proposed.[7] In addition, some clinical trials are studying HDAC inhibitor, valproic acid, on the latent pools of HIV in infected persons.[8]
HDAC inhibitors have effects on non-histone proteins that are related to acetylation -- see histone deacetylase inhibitor.
[edit] Family
Together with the acetylpolyamine amidohydrolases and the acetoin utilization proteins, the histone deacetylases form an ancient protein superfamily known as the histone deacetylase superfamily.[9] Histone deacetylases, acetoin utilization proteins and acetylpolyamine amidohydrolases are members of an ancient protein superfamily.IPR000286
[edit] Classes of HDACs in higher eukaryotes
HDACs, are classified in four classes depending on sequence identity and domain organization:[10]
- Class I
- Class II
- Class III
- Class IV
[edit] See also
- Histone deacetylase inhibitor
- Histone methyltransferase
- Histone-modifying enzymes
- RNA polymerase control by chromatin structure
[edit] References
- ^ Ruijter A.J.Met al (2003). "Histone deacetylases(HDACs):characterization of the classical HDAC family". Biochem. J. 370: 737-749. doi:.
- ^ Longworth and Laimins (2006). "Histone deacetylase 3 localizes to the plasma membrane and is a substrate of Src". Oncogene 25: 4495-4500. doi:.
- ^ Zupkovitz G, Tischler J, Posch M, et al (2006). "Negative and positive regulation of gene expression by mouse histone deacetylase 1". Mol. Cell. Biol. 26 (21): 7913-28. doi:. PMID 16940178.
- ^ Sharma RP, Grayson DR, Gavin DP (2007). "Histone deactylase 1 expression is increased in the prefrontal cortex of schizophrenia subjects: Analysis of the National Brain Databank microarray collection". Schizophrenia Research 98: 111. doi:. PMID 17961987.
- ^ Hahnen E, Hauke J, Tränkle C, Eyüpoglu IY, Wirth B, Blümcke I (2008). Histone deacetylase inhibitors: possible implications for neurodegenerative disorders. Expert Opin Investig Drugs, 17(2):169-184
- ^ Scientists 'reverse' memory loss. BBC News. Retrieved on 2007-07-08.
- ^ Monneret C (2007). "Histone deacetylase inhibitors for epigenetic therapy of cancer". Anticancer Drugs 18 (4): 363–70. doi:. PMID 17351388.
- ^ Depletion of Latent HIV in CD4 Cells - Full Text View - ClinicalTrials.gov
- ^ Leipe DD, Landsman D (1997). "Histone deacetylases, acetoin utilization proteins and acetylpolyamine amidohydrolases are members of an ancient protein superfamily". Nucleic Acids Res. 25 (18): 3693–7. doi:. PMID 9278492.
- ^ Dokmanovic M, Clarke C, Marks PA (2007). "Histone deacetylase inhibitors: overview and perspectives". Mol. Cancer Res. 5 (10): 981–9. doi:. PMID 17951399.
[edit] External links
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