Histone deacetylase

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histone deacetylase
2vqj.png
Catalytic domain of Human histone deacetylase 4 with bound inhibitor. PDB rendering based on 2vqj.[1]
Identifiers
EC number3.5.1.98
CAS number9076-57-7
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / EGO
 
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histone deacetylase
2vqj.png
Catalytic domain of Human histone deacetylase 4 with bound inhibitor. PDB rendering based on 2vqj.[1]
Identifiers
EC number3.5.1.98
CAS number9076-57-7
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / EGO
Histone deacetylase superfamily
Identifiers
SymbolHist_deacetyl
PfamPF00850
InterProIPR000286
SCOP1c3s
SUPERFAMILY1c3s

Histone deacetylases (EC 3.5.1.98, HDAC) are a class of enzymes that remove acetyl groups (O=C-CH3) from an ε-N-acetyl lysine amino acid on a histone, allowing the histones to wrap the DNA more tightly. This is important because DNA is wrapped around histones, and DNA expression is regulated by acetylation and de-acetylation. Its action is opposite to that of histone acetyltransferase. HDAC proteins are now also called lysine deacetylases (KDAC), to describe their function rather than their target, which also includes non-histone proteins.[2]

HDAC super family[edit]

Together with the acetylpolyamine amidohydrolases and the acetoin utilization proteins, the histone deacetylases form an ancient protein superfamily known as the histone deacetylase superfamily.[3]

Classes of HDACs in higher eukaryotes[edit]

HDACs, are classified in four classes depending on sequence homology to the yeast original enzymes and domain organization:[4]

ClassMembersCatalytic sitesSubcellular localizationTissue distributionSubstratesBinding partnersKnockout phenotype
IHDAC11NucleusUbiquitousAndrogen receptor, SHP, p53, MyoD, E2F1, STAT3embryonic lethal, increased histone acetylation, increase in p21 and p27
HDAC21NucleusUbiquitousGlucocorticoid receptor, YY1, BCL6, STAT3Cardiac defect
HDAC31NucleusUbiquitousSHP, YY1, GATA1, RELA, STAT3, MEF2D
HDAC81Nucleus/cytoplasmUbiquitous?EST1B
IIAHDAC41Nucleus / cytoplasmheart, skeletal muscle, brainGCMA, GATA1, HP1RFXANKDefects in chondrocyte differentiation
HDAC51Nucleus / cytoplasmheart, skeletal muscle, brainGCMA, SMAD7, HP1REA, estrogen receptorCardiac defect
HDAC71Nucleus / cytoplasm / mitochondriaheart, skeletal muscle, pancreas, placentaPLAG1, PLAG2HIF1A, BCL6, endothelin receptor, ACTN1, ACTN4, androgen receptor, Tip60Maintenance of vascular integrity, increase in MMP10
HDAC91Nucleus / cytoplasmbrain, skeletal muscleFOXP3Cardiac defect
IIBHDAC62Mostly cytoplasmheart, liver, kidney, placentaα-Tubulin, HSP90, SHP, SMAD7RUNX2
HDAC101Mostly cytoplasmliver, spleen, kidney
IIIsirtuins in mammals (SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6, SIRT7)
Sir2 in the yeast S. cerevisiae
IVHDAC112Nucleus / cytoplasmbrain, heart, skeletal muscle, kidney

HDAC (except class III) contain zinc and are known as Zn-dependent histone deacetylases.[5]

Subtypes[edit]

HDAC proteins occur in four groups (see above) based on function and DNA sequence similarity. The first two groups are considered "classical" HDACs whose activities are inhibited by trichostatin A (TSA), whereas the third group is a family of NAD+-dependent proteins not affected by TSA. Homologues to these three groups are found in yeast having the names: reduced potassium dependency 3 (Rpd3), which corresponds to Class I; histone deacetylase 1 (hda1), corresponding to Class II; and silent information regulator 2 (Sir2); corresponding to Class III.[6] The fourth group is considered an atypical category of its own, based solely on DNA sequence similarity to the others.

Subcellular distribution[edit]

Within the Class I HDACs, HDAC 1, 2, and 8 are found primarily in the nucleus, whereas HDAC3 is found in both the nucleus and the cytoplasm, and is also membrane-associated. Class II HDACs (HDAC4, 5, 6, 7 9, and 10) are able to shuttle in and out of the nucleus, depending on different signals.[7][8]

HDAC6 is a cytoplasmic, microtuble-associated enzyme. HDAC6 deacetylates tubulin, Hsp90, and cortactin, and forms complexes with other partner proteins, and is, therefore, involved in a variety of biological processes.[9]

Function[edit]

Histone modification[edit]

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 decreased binding allows chromatin expansion, permitting genetic transcription to take place. Histone deacetylases remove those acetyl groups, increasing the positive charge of histone tails and encouraging high-affinity binding between the histones and DNA backbone. The increased DNA binding 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:

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.[10] Their study also found a regulatory crosstalk 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,[11] negatively correlating with the expression of GAD67 mRNA.

Non-histone effects[edit]

It is a mistake to regard HDACs solely in the context of regulating gene transcription by modifying histones and chromatin structure, although that appears to be the predominant function. The function, activity, and stability of proteins can be controlled by post-translational modifications. Protein phosphorylation is perhaps the most widely studied and understood modification in which certain amino acid residues are phosphorylated by the action of protein kinases or dephosphorylated by the action of phosphatases. The acetylation of lysine residues is emerging as an analogous mechanism, in which non-histone proteins are acted on by acetylases and deacetylases.[12] It is in this context that HDACs are being found to interact with a variety of non-histone proteins—some of these are transcription factors and co-regulators, some are not. Note the following four examples:

These are just some examples of constantly emerging non-histone, non-chromatin roles for HDACs.

HDAC inhibitors[edit]

Histone deacetylase inhibitors (HDIs) have a long history of use in psychiatry and neurology as mood stabilizers and anti-epileptics, for example, valproic acid. In more recent times, HDIs are being studied as a mitigator or treatment for neurodegenerative diseases.[19][20] Also in recent years, there has been an effort to develop HDIs for cancer therapy.[21][22] Vorinostat (SAHA) was approved in 2006 for the treatment of cutaneous manifestations in patients with cutaneous T cell lymphoma (CTCL) that have failed previous treatments. A second HDI, Istodax (romidepsin), was approved in 2009 for patients with CTCL. The exact mechanisms by which the compounds may work are unclear, but epigenetic pathways are proposed.[23] In addition, a clinical trial is studying valproic acid effects on the latent pools of HIV in infected persons.[24] HDIs are currently being investigated as chemosensitizers for cytotoxic chemotherapy or radiation therapy, or in association with DNA methylation inhibitors based on in vitro synergy.[25] Recent research has focused on developing isoform selective HDIs which can aid in elucidating role of individual HDAC isoforms and device strategy for effective treatment of diseases related to relevant HDAC isoform.[26][27][28]

HDAC inhibitors have effects on non-histone proteins that are related to acetylation. HDIs can alter the degree of acetylation of these molecules and, therefore, increase or repress their activity. For the four examples given above (see Function) on HDACs acting on non-histone proteins, in each of those instances the HDAC inhibitor Trichostatin A (TSA) blocks the effect. HDIs have been shown to alter the activity of many transcription factors, including ACTR, cMyb, E2F1, EKLF, FEN 1, GATA, HNF-4, HSP90, Ku70, NFκB, PCNA, p53, RB, Runx, SF1 Sp3, STAT, TFIIE, TCF, YY1.[29][30]

Research has shown that histone deacetylase inhibitors may modulate the latency of some viruses, resulting in reactivation.[31] This has been shown to occur, for instance, with a latent human herpesvirus-6 infection.

See also[edit]

References[edit]

  1. ^ Bottomley, M. J.; Lo Surdo, P.; Di Giovine, P.; Cirillo, A.; Scarpelli, R.; Ferrigno, F.; Jones, P.; Neddermann, P.; De Francesco, R.; Steinkühler, C.; Gallinari, P.; Carfí, A. (2008). "Structural and Functional Analysis of the Human HDAC4 Catalytic Domain Reveals a Regulatory Structural Zinc-binding Domain". Journal of Biological Chemistry 283 (39): 26694–26704. doi:10.1074/jbc.M803514200. PMC 3258910. PMID 18614528.  edit
  2. ^ Choudhary C et al. (August 2009). "Lysine acetylation targets protein complexes and co-regulates major cellular functions". Science 325 (5942): 834–40. doi:10.1126/science.1175371. ISSN 1095-9203. PMID 19608861. 
  3. ^ 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:10.1093/nar/25.18.3693. PMC 146955. PMID 9278492. 
  4. ^ Dokmanovic M, Clarke C, Marks PA (2007). "Histone deacetylase inhibitors: overview and perspectives". Mol. Cancer Res. 5 (10): 981–9. doi:10.1158/1541-7786.MCR-07-0324. PMID 17951399. 
  5. ^ Marks PA, Xu WS (July 2009). "Histone Deacetylase Inhibitors: Potential in Cancer Therapy". J. Cell. Biochem. 107 (4): 600–8. doi:10.1002/jcb.22185. PMC 2766855. PMID 19459166. 
  6. ^ Sengupta N, Seto E (September 2004). "Regulation of histone deacetylase activities". J. Cell. Biochem. 93 (1): 57–67. doi:10.1002/jcb.20179. PMID 15352162. 
  7. ^ de Ruijter AJ, van Gennip AH, Caron HN, Kemp S, van Kuilenburg AB (March 2003). "Histone deacetylases (HDACs): characterization of the classical HDAC family". Biochem. J. 370 (Pt 3): 737–49. doi:10.1042/BJ20021321. PMC 1223209. PMID 12429021. 
  8. ^ Longworth MS, Laimins LA (July 2006). "Histone deacetylase 3 localizes to the plasma membrane and is a substrate of Src". Oncogene 25 (32): 4495–500. doi:10.1038/sj.onc.1209473. PMID 16532030. 
  9. ^ Valenzuela-Fernández A, Cabrero JR, Serrador JM, Sánchez-Madrid F (June 2008). "HDAC6: a key regulator of cytoskeleton, cell migration and cell-cell interactions error". Trends Cell Biol. 18 (6): 291–7. doi:10.1016/j.tcb.2008.04.003. PMID 18472263. 
  10. ^ 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:10.1128/MCB.01220-06. PMC 1636735. PMID 16940178. 
  11. ^ 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 (1–3): 111–7. doi:10.1016/j.schres.2007.09.020. PMC 2254186. PMID 17961987. 
  12. ^ Glozak MA, Sengupta N, Zhang X, Seto E (2005). "Acetylation and deacetylation of non-histone proteins". Gene 363: 15–23. doi:10.1016/j.gene.2005.09.010. PMID 16289629. 
  13. ^ Rodriguez-Gonzalez A, Lin T, Ikeda AK, Simms-Waldrip T, Fu C, Sakamoto KM (2008). "Role of the aggresome pathway in cancer: targeting histone deacetylase 6-dependent protein degradation". Cancer Res. 68 (8): 2557–60. doi:10.1158/0008-5472.CAN-07-5989. PMID 18413721. 
  14. ^ Ikenoue T, Inoki K, Zhao B, Guan KL (2008). "PTEN acetylation modulates its interaction with PDZ domain". Cancer Res. 68 (17): 6908–12. doi:10.1158/0008-5472.CAN-08-1107. PMID 18757404. 
  15. ^ Yao XH, Nyomba BL (2008). "Hepatic insulin resistance induced by prenatal alcohol exposure is associated with reduced PTEN and TRB3 acetylation in adult rat offspring". Am J Physiol Regul Integr Comp Physiol 294 (6): R1797–806. doi:10.1152/ajpregu.00804.2007. PMID 18385463. 
  16. ^ Bhakat KK, Izumi T, Yang SH, Hazra TK, Mitra S (2003). "Role of acetylated human AP-endonuclease (APE1/Ref-1) in regulation of the parathyroid hormone gene". EMBO J. 22 (23): 6299–309. doi:10.1093/emboj/cdg595. PMC 291836. PMID 14633989. 
  17. ^ Fantini D, Vascotto C, Deganuto M, Bivi N, Gustincich S, Marcon G, Quadrifoglio F, Damante G, Bhakat KK, Mitra S, Tell G (2008). "APE1/Ref-1 regulates PTEN expression mediated by Egr-1". Free Radic Res. 42 (1): 20–9. doi:10.1080/10715760701765616. PMC 2677450. PMID 18324520. 
  18. ^ Hasselgren PO (2007). "Ubiquitination, phosphorylation, and acetylation--triple threat in muscle wasting". J Cell Physiol. 213 (3): 679–89. doi:10.1002/jcp.21190. PMID 17657723. 
  19. ^ Hahnen E, Hauke J, Tränkle C, Eyüpoglu IY, Wirth B, Blümcke I (February 2008). "Histone deacetylase inhibitors: possible implications for neurodegenerative disorders". Expert Opin Investig Drugs 17 (2): 169–84. doi:10.1517/13543784.17.2.169. PMID 18230051. 
  20. ^ "Scientists 'reverse' memory loss". BBC News. 2007-04-29. Retrieved 2007-07-08. 
  21. ^ Mwakwari S. C., Patil V., Guerrant W., Oyelere A. K. “Macrocyclic histonedeacetylase inhibitors” Curr. Top. Med. Chem. (2010), 10, 1423-1440.
  22. ^ Miller, T. A.; Witter, D. J.; Belvedere, S. J. Med. Chem.2003, 46, 5097–5116.
  23. ^ Monneret C (2007). "Histone deacetylase inhibitors for epigenetic therapy of cancer". Anticancer Drugs 18 (4): 363–70. doi:10.1097/CAD.0b013e328012a5db. PMID 17351388. 
  24. ^ Depletion of Latent HIV in CD4 Cells - Full Text View - ClinicalTrials.gov
  25. ^ Batty N; Malouf, GG; Issa, JP (August 2009). "Histone deacetylase inhibitors as anti-neoplastic agents". Cancer Letters 280 (2): 190–200. doi:10.1016/j.canlet.2009.03.013. PMID 19345475.  Unknown parameter |unused_data= ignored (help)
  26. ^ Patil V., Sodji Q., Kornacki J., MrksichM., Oyelere A. K. “3-Hydroxypyridin-2-thiones as a novel zinc binding group for selective HDAC inhibition” J. Med. Chem. 2013, 56, 3492-3506.
  27. ^ Mwakwari S. C., Guerrant W., Patil V., Khan S., Tekwani B., Gurard-Levin Z., Mrksich M.; Oyelere A. K. “Non-peptide macrocyclic histone deacetylase inhibitorsderived from tricyclic ketolide skeleton” J.Med Chem. 2010, 53, 6100-6111
  28. ^ Kyle V. Butler, Jay Kalin, Camille Brochier, Guilio Vistoli, Brett Langley, and Alan P. Kozikowski "Rational Design and Simple Chemistry Yield a Superior,Neuroprotective HDAC6 Inhibitor, Tubastatin A" J. Am. Chem. Soc. 2010, 132(31), 10842.
  29. ^ Drummond DC, Noble CO, Kirpotin DB, Guo Z, Scott GK, Benz CC (2005). "Clinical development of histone deacetylase inhibitors as anticancer agents". Annu Rev Pharmacol Toxicol 45: 495–528. doi:10.1146/annurev.pharmtox.45.120403.095825. PMID 15822187. 
  30. ^ Yang XJ, Seto E (2007). "HATs and HDACs: from structure, function and regulation to novel strategies for therapy and prevention". Oncogene 26 (37): 5310–5318. doi:10.1038/sj.onc.1210599. PMID 17694074. 
  31. ^ Arbuckle, Jesse. "The molecular biology of human herpesvirus-6 latency and telomere integration". Microbes and infection 13 (8-9). doi:10.1016/j.micinf.2011.03.006. PMC 3130849. PMID 21458587. 

External links[edit]