Histone deacetylase 1300938 223562722 2008-07-04T17:06:21Z DOI bot 6652755 Citation maintenance. Removed redundant parameters. You can [[WP:DOI|use this bot]] yourself! Please [[User:DOI_bot/bugs|report any bugs]]. '''Histone deacetylases (HDAC)''' ([[EC number]] 3.5.1) are a class of [[enzyme]]s that remove [[acetyl group]]s from an ε-N-acetyl [[lysine]] [[amino acid]] on a [[histone]]. Its action is opposite to that of [[histone acetyltransferase]]. ==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.<ref name=Ruijter>{{cite journal |author=Ruijter A.J.M''et al'' |title=Histone deacetylases(HDACs):characterization of the classical HDAC family |journal=Biochem. J. |volume=370 |issue= |pages=737–749 |year=2003|doi=10.1042/BJ20021321}}</ref><ref name=Longworth>{{cite journal |author=Longworth and Laimins |title=Histone deacetylase 3 localizes to the plasma membrane and is a substrate of Src |journal= Oncogene |volume=25|issue= |pages=4495–4500 |year=2006|doi=10.1038/sj.onc.1209473}}</ref> ==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]] [http://www.genome.jp/dbget-bin/show_pathway?ko04330+ko:K06067 PATH:ko04330] * Cellular processes; cell growth and death; [[cell cycle]] [http://www.genome.jp/dbget-bin/show_pathway?ko04110+ko:K06067 PATH:ko04110] * Human diseases; cancers; [[chronic myeloid leukemia]] [http://www.genome.jp/dbget-bin/show_pathway?ko05220+ko:K06067 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.<ref name=Gordin>{{cite journal |author=Zupkovitz G, Tischler J, Posch M, ''et al'' |title=Negative and positive regulation of gene expression by mouse histone deacetylase 1 |journal=Mol. Cell. Biol. |volume=26 |issue=21 |pages=7913–28 |year=2006 |pmid=16940178 |doi=10.1128/MCB.01220-06}}</ref> 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,<ref name="pmid17961987">{{cite journal |author=Sharma RP, Grayson DR, Gavin DP |title=Histone deactylase 1 expression is increased in the prefrontal cortex of schizophrenia subjects: Analysis of the National Brain Databank microarray collection |journal= Schizophrenia Research|volume= 98|issue= |pages= 111|year=2007 |pmid=17961987 |doi=10.1016/j.schres.2007.09.020}}</ref> negatively correlating with the expression of [[GAD67]] mRNA. ==HDAC inhibitors== {{main|Histone deacetylase inhibitor}} 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]].<ref>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</ref><ref>{{cite web |url=http://news.bbc.co.uk/2/hi/health/6606315.stm |title=Scientists 'reverse' memory loss | Health | Scientists 'reverse' memory loss |accessdate=2007-07-08 |format= |work= | publisher = BBC News}}</ref> 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.<ref name="pmid17351388">{{cite journal | author = Monneret C | title = Histone deacetylase inhibitors for epigenetic therapy of cancer | journal = Anticancer Drugs | volume = 18 | issue = 4 | pages = 363–70 | year = 2007 | pmid = 17351388 | doi = 10.1097/CAD.0b013e328012a5db }}</ref> In addition, some clinical trials are studying HDAC inhibitor, valproic acid, on the latent pools of HIV in infected persons.<ref>[http://www.clinicaltrials.gov/ct2/show/NCT00576290?term=HDAC&rank=8 Depletion of Latent HIV in CD4 Cells - Full Text View - ClinicalTrials.gov<!-- Bot generated title -->]</ref> HDAC inhibitors have effects on non-histone proteins that are related to acetylation. ==Family== Together with the [[acetylpolyamine amidohydrolase]]s and the [[acetoin utilization protein]]s, the histone deacetylases form an ancient protein superfamily known as the '''histone deacetylase superfamily'''.<ref name="pmid9278492">{{cite journal | author = Leipe DD, Landsman D | title = Histone deacetylases, acetoin utilization proteins and acetylpolyamine amidohydrolases are members of an ancient protein superfamily | journal = Nucleic Acids Res. | volume = 25 | issue = 18 | pages = 3693–7 | year = 1997 | pmid = 9278492 | doi = 10.1093/nar/25.18.3693 }}</ref> Histone deacetylases, acetoin utilization proteins and acetylpolyamine amidohydrolases are members of an ancient protein superfamily.{{InterPro|IPR000286}} == Classes of HDACs in higher eukaryotes == HDACs, are classified in four classes depending on sequence identity and domain organization:<ref name="pmid17951399">{{cite journal | author = Dokmanovic M, Clarke C, Marks PA | title = Histone deacetylase inhibitors: overview and perspectives | journal = Mol. Cancer Res. | volume = 5 | issue = 10 | pages = 981–9 | year = 2007 | pmid = 17951399 | doi = 10.1158/1541-7786.MCR-07-0324 }}</ref> * Class I ** [[HDAC1]], [[HDAC2]], [[HDAC3]], [[HDAC8]] * Class II ** [[HDAC4]], [[HDAC5]], [[HDAC6]], [[HDAC7A]], [[HDAC9]], [[HDAC10]] * Class III ** Homologs of [[Sir2]] in the yeast ''Saccharomyces cerevisiae'' ** [[sirtuin]]s in mammals ([[Sirtuin 1|SIRT1]], [[SIRT2]], [[SIRT3]], {{gene|SIRT4}}, [[SIRT5]], [[SIRT6]], [[SIRT7]]) * Class IV ** [[HDAC11]] ==See also== *[[Histone deacetylase inhibitor]] *[[Histone methyltransferase]] *[[Histone-modifying enzymes]] *[[RNA polymerase control by chromatin structure]] ==References== {{Reflist|2}} ==External links== * {{MeshName|Histone+deacetylase}} * [http://veille-srv.inist.fr/bin/dilib/AppliHuman2/desc.cgi?/applis/veille/home/apache/users/genomique/human/Server/EN.Human.EC.wsh+EC%203.5.1.-%20Histone%20Deacetylases Literature list on histone deacetylases, EC 3.5.1] * [http://www.targethdac.com/hdac/targethdac/histone_deacetylase/index.jsp?WT.srch=1&WT.mc_id=ZL016 Animation] at [[Merck & Co.|Merck]] {{Carbon-nitrogen non-peptide hydrolases}} [[Category:EC 3.5.1]] [[de:Histon-Deacetylase]] [[hu:Hiszton deacetiláz]] [[ja:ヒストン脱アセチル化酵素]] [[pt:Histona deacetilase]]