User:Asif Hossain/Sandbox 1: Difference between revisions

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== Medical Relevance ==

[[Image:Hydroxamic inhibitor.PNG‎|300px||~~left~~||thumb|Figure 1: Hydroxamic Inhibitor]]

[[Image:Hydroxamic inhibitor.PNG‎|300px||right||thumb|Figure 1: Hydroxamic Inhibitor]]

Besides controlling gene regulation through deacetylation of histones, HDAC8 also regulates the post-transcriptional acetylation status of many non-histone proteins, including transcription factors, chaperones, hormone receptors and signaling molecules. Thus, it has influences on protein stability, protein-protein interactions and protein-DNA interactions. HDAC8 can therefore affect the regulation of cell proliferation and cell death. These processes are typically being altered in cancer cells and that makes HDAC enzymes an interesting potential target for cancer drugs. HDAC inhibitors have been shown to be promising cancer drug agent as the HDAC inhibitors (HDACi) cease tumor growth in cancer cells by either making them differentiate, undergo apoptosis or upregulate cell cycle arrest proteins. <ref name="Eckschlager">Eckschlager T, Plch, J, Stiborova M, Hrabeta J.Histone deacetylase inhibitors as anticancer drugs. International journal of molecular sciences, 18(7), 1414. 2017. https://dx.doi.org/10.3390%2Fijms18071414</ref> One way the HDAC inhibitors cease tumor growth is by the reactivation of the transcription factor, [https://en.wikipedia.org/wiki/RUNX3 RUNX3], a known tumor suppressor. HDACi increases the acetylation of the protein and as the stability of RUNX3 is dependent on the acetylation status of the protein, the increased acetylation or HDAC inhibition will enhance the protein stability. A number of HDAC inhibitors have been purified from natural sources or synthesized and at least four structurally different inhibitor classes have been characterized: hydroxamates, cyclic peptides, aliphatic acids and benzamides. The Vorinostat (within the hydroxamate class) has been FDA-approved for treatment of cancer. The hydroxamate HDAC inhibitors consists of a metal-binding domain, a linker domain and a hydrophobic capping group. The HDAC class 1 hydroxamic acid, compound 1,<scene name='81/811087/Inhibitor_and_zinc_binding/7'>binds to the zinc ion</scene> in a bidendate fashion while making hydrogen bonds to important residues as <scene name='81/811087/Inhibitor_and_zinc_binding/6'> His142, His143 and Tyr306</scene> at the active site of HDAC8. Thus, the HDAC inhibitors can be used as antagonists to prevent the functioning of HDAC8 in cancer treatment. <ref name="Vannini, A., Volpari, C., Filocamo, G.">Vannini, A., Volpari, C., Filocamo, G., Casavola, E. C., Brunetti, M., Renzoni, D., ... & Steinkühler, C. (2004). Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor. Proceedings of the National Academy of Sciences, 101(42), 15064-15069. https://dx.doi.org/10.1073%2Fpnas.0404603101</ref>

</StructureSection>

== References ==

@@ Line 37: / Line 37: @@
 == Medical Relevance ==
-[[Image:Hydroxamic inhibitor.PNG‎|300px||left||thumb|Figure 1: Hydroxamic Inhibitor]]
+[[Image:Hydroxamic inhibitor.PNG‎|300px||right||thumb|Figure 1: Hydroxamic Inhibitor]]
 Besides controlling gene regulation through deacetylation of histones, HDAC8 also regulates the post-transcriptional acetylation status of many non-histone proteins, including transcription factors, chaperones, hormone receptors and signaling molecules. Thus, it has influences on protein stability, protein-protein interactions and protein-DNA interactions. HDAC8 can therefore affect the regulation of cell proliferation and cell death. These processes are typically being altered in cancer cells and that makes HDAC enzymes an interesting potential target for cancer drugs. HDAC inhibitors have been shown to be promising cancer drug agent as the HDAC inhibitors (HDACi) cease tumor growth in cancer cells by either making them differentiate, undergo apoptosis or upregulate cell cycle arrest proteins. <ref name="Eckschlager">Eckschlager T, Plch, J, Stiborova M, Hrabeta J.Histone deacetylase inhibitors as anticancer drugs. International journal of molecular sciences, 18(7), 1414. 2017. https://dx.doi.org/10.3390%2Fijms18071414</ref> One way the HDAC inhibitors cease tumor growth is by the reactivation of the transcription factor, [https://en.wikipedia.org/wiki/RUNX3 RUNX3], a known tumor suppressor. HDACi increases the acetylation of the protein and as the stability of RUNX3 is dependent on the acetylation status of the protein, the increased acetylation or HDAC inhibition will enhance the protein stability. A number of HDAC inhibitors have been purified from natural sources or synthesized and at least four structurally different inhibitor classes have been characterized: hydroxamates, cyclic peptides, aliphatic acids and benzamides. The Vorinostat (within the hydroxamate class) has been FDA-approved for treatment of cancer. The hydroxamate HDAC inhibitors consists of a metal-binding domain, a linker domain and a hydrophobic capping group. The HDAC class 1 hydroxamic acid, compound 1,<scene name='81/811087/Inhibitor_and_zinc_binding/7'>binds to the zinc ion</scene> in a bidendate fashion while making hydrogen bonds to important residues as <scene name='81/811087/Inhibitor_and_zinc_binding/6'> His142, His143 and Tyr306</scene> at the active site of HDAC8. Thus, the HDAC inhibitors can be used as antagonists to prevent the functioning of HDAC8 in cancer treatment. <ref name="Vannini, A., Volpari, C., Filocamo, G.">Vannini, A., Volpari, C., Filocamo, G., Casavola, E. C., Brunetti, M., Renzoni, D., ... & Steinkühler, C. (2004). Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor. Proceedings of the National Academy of Sciences, 101(42), 15064-15069. https://dx.doi.org/10.1073%2Fpnas.0404603101</ref>
 </StructureSection>
 == References ==
 <references/>