Histone deacetylases
| Histone deacetylases | ||
|---|---|---|
| Identifier | ||
| Gene name (s) | HDAC1 , HDAC2 , HDAC3 , HDAC4 , HDAC5 , HDAC6 , HDAC7 , HDAC8 , HDAC9 , HDAC10 , HDAC11 | |
| Enzyme classification | ||
| EC, category | 3.5.1.98 , hydrolase | |
| Response type | Deacetylation of N-acetyllysine in histone | |
| Substrate | Acetyl histone | |
| Products | Histone | |
| Occurrence | ||
| Parent taxon | Creature | |
Histone deacetylases ( HDAC s for short ) are enzymes that change histones . Not only do they directly regulate the transcription of genetic information and epigenetic repression , but they are also involved in controlling the cell cycle and the development of the organism. HDACs are part of larger protein complexes . They occur in all eukaryotes and in humans in all tissue types.
function
HDACs remove acetyl groups from acetylated lysine on the N-terminal histone end . The deacetylation gives the amino acid lysine a positive electrical charge again. This increases the affinity of the histone end for the negatively charged phosphate framework of the DNA . The DNA transcription is downregulated by the subsequent blocking of the DNA for transcription factors . This is usually associated with the formation of primarily inactive heterochromatin .
HDACs play a role in the suppression of cell proliferation induced by the retinoblastoma protein. The retinoblastoma protein is part of a complex that directs HDACs to chromatin in order to deacetylate lysines there.
HDAC classes in higher eukaryotes
The human HDACs are divided into four classes according to sequence and domain relationship to their orthologues in yeast:
- Class I.
- HDAC1
- HDAC2
- HDAC3
- HDAC8
- Class IIa
- HDAC4
- HDAC5
- HDAC7
- HDAC9
- Class IIb
- HDAC6
- HDAC10
- Class III
- Class IV
- HDAC11
Together with the acetyl polyamine amidohydrolases and the azetoin utilization proteins , the histone deacetylases belong to the histone deacetylase superfamily .
HDAC inhibitors
HDAC inhibitors (e.g. entinostat , vorinostat , mocetinostat ) are being investigated as possible drugs in cancer research. Richon et al were able to demonstrate that HDAC inhibitors can induce CDK inhibitor 1 . The latest research has shown that many cancer cells, including cells from breast, liver and kidney cancer, produce an exceptional amount of HDAC11. Investigations are now going into the extent to which HDAC11 could act as a target structure for new cancer therapies.
As an enhancer of proteasome inhibitors, the HDAC inhibitor panobinostat has been approved in the EU for the treatment of multiple myeloma under certain conditions since 2015 .
See also
Web links
- Characterization of the interaction of human histone deacetylase 3 with MAP kinase 11 . (PDF; 1.7 MB) Inaugural dissertation
Individual evidence
- ^ A. Brehm, EA Miska, DJ McCance, JL Reid, AJ Bannister, T. Kouzarides: Retinoblastoma protein recruits histone deacetylase to repress transcription. In: Nature . 391 (6667), 1998, pp. 597-601.
- ^ IV Gregoretti et al: Molecular evolution of the histone deacetylase family: functional implications of phylogenetic analysis. In: J Mol Biol. 2004 Apr 16, 338 (1), pp. 17-31. PMID 15050820 , doi: 10.1016 / j.jmb.2004.02.006
- ↑ Zhengke Wang, Gangjian Qin, Ting C Zhao: HDAC4: mechanism of regulation and biological functions. In: Epigenomics. 6, 2014, p. 139, doi : 10.2217 / epi.13.73 . PMID 24579951 . PMC 4380265 (free full text).
- ↑ DD Leipe, D. Landsman: Histone deacetylases, acetoin utilization proteins and acetylpolyamine amidohydrolases are members of an ancient protein superfamily. In: Nucleic Acids Res. 25, 1997, pp. 3693-3697. PMID 9278492 .
- ↑ InterPro IPR000286 Histone deacetylase superfamily
- ↑ VM Richon, TW Sandhoff, RA Rifkind, PA Marks: Histone deacetylase inhibitor selectively induces p21 (WAF1) expression and gene-associated histone acetylation. In: Proceedings of the National Academy of Sciences . 97 (18), AUG 29 2000, pp. 10014-10019.
- ↑ WS el-Deiry, T. Tokino, Velculescu VE, DB Levy, R. Parsons, JM Trent, D. Lin, WE Mercer, KW Kinzler, B. Vogelstein: WAF1, a potential mediator of p53 tumor suppression. In: Cell , 75 (4), NOV 19 1993, pp. 817-825.
- ↑ Hedwig E. Deubzer, Marie C. Schier, Ina Oehme, Marco Lodrini, Bernard Haendler, Anette Sommer, Olaf Witt: HDAC11 is a novel drug target in carcinomas . In: International Journal of Cancer . tape 132 , no. 1 , 2012, doi : 10.1002 / ijc.27876 .
- ↑ First histone deacetylase inhibitor approved in the EU. In: Pharmaceutical newspaper . September 14, 2015, accessed December 28, 2015 .
- ↑ Kerstin A. Gräfe: Panobinostat - New principle of action in myeloma. In: Pharmaceutical newspaper . 2015, accessed on December 28, 2015 (edition 39/2015).