User:Madeleine Wilson/Sandbox 1: Difference between revisions
From Proteopedia
Jump to navigationJump to search
No edit summary |
No edit summary |
||
| Line 27: | Line 27: | ||
The active site and binding pocket of KMT contain residues and shape that ensure both catalytic capability as well as optimal stability. First, the lysine of the histone enters the active site via the <scene name='81/811092/Tyrosine_channel_2/3'>Lysine access channel</scene> comprised of Tyr335 and Tyr337. Feeding the histone into the active site is initially difficult; however, the hydrophobicity of the aromatic rings and slight polarity of the alcohol group on the Tyr side chain are essential for facilitating this process. Once in the active site, the alkyl part of the histone chain is stabilized by the <scene name='81/811092/Hydrophobic_binding_pocket/1'>hydrophobic binding pocket</scene>, and polar residues are stabilized by hydrogen bonding interactions on the surface. The Tyr335 and Tyr337 are also essential for stabilization of histone chain via hydrogen bonding. | The active site and binding pocket of KMT contain residues and shape that ensure both catalytic capability as well as optimal stability. First, the lysine of the histone enters the active site via the <scene name='81/811092/Tyrosine_channel_2/3'>Lysine access channel</scene> comprised of Tyr335 and Tyr337. Feeding the histone into the active site is initially difficult; however, the hydrophobicity of the aromatic rings and slight polarity of the alcohol group on the Tyr side chain are essential for facilitating this process. Once in the active site, the alkyl part of the histone chain is stabilized by the <scene name='81/811092/Hydrophobic_binding_pocket/1'>hydrophobic binding pocket</scene>, and polar residues are stabilized by hydrogen bonding interactions on the surface. The Tyr335 and Tyr337 are also essential for stabilization of histone chain via hydrogen bonding. | ||
The <scene name='81/811092/Active_site_w_water/3'>active site</scene> itself contains the cofactor [https://en.wikipedia.org/wiki/S-Adenosyl_methionine S-adenosyl methionine (SAM)] which donates the methyl group in the reaction. <ref name="Xiao" /> In the active site scene, the strict depicts the post-reaction result, where the Lys has been methylated and SAM has been converted to S-adenosyl homocysteine (SAH). | The <scene name='81/811092/Active_site_w_water/3'>active site</scene> itself contains the cofactor [https://en.wikipedia.org/wiki/S-Adenosyl_methionine S-adenosyl methionine (SAM)] which donates the methyl group in the reaction. <ref name="Xiao" /> In the active site scene, the strict depicts the post-reaction result, where the Lys has been methylated and SAM has been converted to S-adenosyl homocysteine (SAH). | ||
[[Image: | [[Image:KMT_Mechanism_jpg.jpeg|200px|left|thumb|Figure 2. KMT Mechanism]] | ||
The reaction is catalyzed by Tyr305, Tyr245, carbonyl oxygens of the main chain in residues 295 and 290. Tyr305 and the carbonyl oxygens stabilize and pull electron density off a water to pull on one of the hydrogens off the nitrogen of the lysine, while oxygen of Tyr245 pulls on the other hydrogen of the nitrogen. Both of these actions allow nitrogen to become more nucleophilic and attack the carbon of the methyl group on the SAM, which is attached to a positively charged sulfur. The methyl group is then transferred and the sulfur is neutral; SAM has been converted to (SAH). <ref name="Xiao" /> | The reaction is catalyzed by Tyr305, Tyr245, carbonyl oxygens of the main chain in residues 295 and 290. Tyr305 and the carbonyl oxygens stabilize and pull electron density off a water to pull on one of the hydrogens off the nitrogen of the lysine, while oxygen of Tyr245 pulls on the other hydrogen of the nitrogen. Both of these actions allow nitrogen to become more nucleophilic and attack the carbon of the methyl group on the SAM, which is attached to a positively charged sulfur. The methyl group is then transferred and the sulfur is neutral; SAM has been converted to (SAH). <ref name="Xiao" /> | ||
==Inhibitors== | ==Inhibitors== | ||
[[Image:Sinefugin.png|200px|left|thumb|Sinefungin]] | [[Image:Sinefugin.png|200px|left|thumb|Figure 3. Sinefungin]] | ||
Sinefungin is a potent methyltransferase inhibitor. It is a structural analog of S-adenosylmethionine that is more stable due to the ability to create two additional hydrogen bonds to its amine group in the active site. It has been used experimentally to inhibit the SET 7/9 protein on peritoneal fibrosis in mice and in human peritoneal mesothelial cells. <ref name="Schluck">PMID: 8995524</ref> Tamura et al. (2018) found that sinefungin suppressed the cell accumulation and thickening in methylglyoxal peritoneal fibrosis. <ref name="Tamura">PMID: 29723250</ref> | Sinefungin is a potent methyltransferase inhibitor. It is a structural analog of S-adenosylmethionine that is more stable due to the ability to create two additional hydrogen bonds to its amine group in the active site. It has been used experimentally to inhibit the SET 7/9 protein on peritoneal fibrosis in mice and in human peritoneal mesothelial cells. <ref name="Schluck">PMID: 8995524</ref> Tamura et al. (2018) found that sinefungin suppressed the cell accumulation and thickening in methylglyoxal peritoneal fibrosis. <ref name="Tamura">PMID: 29723250</ref> | ||
