User:Courtney Brown/Sandbox 1
From Proteopedia
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====HDAC8==== | ====HDAC8==== | ||
| - | [https://en.wikipedia.org/wiki/HDAC8 Histone Deacetylase 8] is an enzyme found in ''[https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]''. HDAC8 is 388 residues long and consists of eight-stranded parallel β-sheets surrounded by 11 α-helices <ref name="Vanninni" />. HDAC8 is the only functional HDAC that is found to be a single polypeptide instead of being high-molecular-weight multi-protein complexes <ref name="Vanninni" />. The substrate bound to the HDAC8 includes an acetyl group, one arginine, one histidine, two lysines and MCM, a Coumarin fluorescence tag. | + | [https://en.wikipedia.org/wiki/HDAC8 Histone Deacetylase 8] is an enzyme found in ''[https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]''. HDAC8 is 388 residues long and consists of eight-stranded parallel β-sheets surrounded by 11 α-helices <ref name="Vanninni" />. HDAC8 is the only functional HDAC that is found to be a single polypeptide instead of being high-molecular-weight multi-protein complexes <ref name="Vanninni" />. HDAC8 decreases gene expression by increasing DNA-histone interactions, condensing the DNA tighter. The substrate bound to the HDAC8 includes an acetyl group, one arginine, one histidine, two lysines and MCM, a Coumarin fluorescence tag. |
==Structure== | ==Structure== | ||
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===Active Site=== | ===Active Site=== | ||
| - | Substrates are deacetylated via a classic 2<sup>+</sup> metal ion mechanism. The Zinc ion <scene name='81/811715/Zn_activating_water/1'>activates the water</scene> by withdrawing electron density from the water due to the positive charge, making the water more acidic, therefore a better nucleophile. The Zinc ion also coordinates to the carbonyl oxygen of the acetyl group on the lysine, polarizing the carbonyl carbon, making it more electrophilic. <scene name='81/811715/His_142_and_143/1'>His142</scene> deprotinates the water, the first step of the deacetylation. His 142 is closer to the water molecule than His 143, which was also thought to deprotinate the water. However, a mutation done to His 143 only reduced activity, not abolished it, showing it is important but not crucial. His 143 is thought to orient the substrate by protinating the amine group on the leaving group of the reaction <ref name="Vanninni" />. | + | Substrates are deacetylated via a classic 2<sup>+</sup> metal ion mechanism. The Zinc ion <scene name='81/811715/Zn_activating_water/1'>activates the water</scene> by withdrawing electron density from the water due to the positive charge, making the water more acidic, therefore a better nucleophile. The Zinc ion also coordinates to the carbonyl oxygen of the acetyl group on the lysine, polarizing the carbonyl carbon, making it more electrophilic. <scene name='81/811715/His_142_and_143/1'>His142</scene> deprotinates the water, the first step of the deacetylation (Figure 1). His 142 is closer to the water molecule than His 143, which was also thought to deprotinate the water. However, a mutation done to His 143 only reduced activity, not abolished it, showing it is important but not crucial. His 143 is thought to orient the substrate by protinating the amine group on the leaving group of the reaction <ref name="Vanninni" />. |
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| + | The attack by the deprotinated water forces the carbonyl carbon into a tetrehedral transition state. <scene name='81/811715/Tyr306/4'>Tyr306</scene> acts as the oxyanion hole, stabilizing this transition state via its protruding -OH group hydrogen-bonding with the negatively charged oxygen. | ||
<scene name='81/811715/Residues_coordinating_to_zinc/1'>Asp178, His180 and Asp267</scene> | <scene name='81/811715/Residues_coordinating_to_zinc/1'>Asp178, His180 and Asp267</scene> | ||
| - | <scene name='81/811715/Tyr306/4'>Tyr306</scene> | ||
==Disease== | ==Disease== | ||
Revision as of 02:39, 7 April 2019
The Human Histone H3/K9 Deacetylase, HDAC8
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