Sandbox Reserved 1546: Difference between revisions
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==Function== | ==Function== | ||
In order to better understand the function of this | In order to better understand the function of this 5h86 enzyme, we have to understand the basic processes of Fatty Acid Degradation. Fatty Acid Degradation is the procedure that fatty acids go through to be broken down into their metabolites and it takes place in the mitochondrial matrix <ref name = "Section 22.4 Fatty Acids Are Synthesized and Degraded by Different Pathways">Berg JM, Tymoczko JL, Stryer L. Biochemistry. 5th edition. New York: W H Freeman; 2002. Section 22.4, Fatty Acids Are Synthesized and Degraded by Different Pathways. Available from: https://www.ncbi.nlm.nih.gov/books/NBK22554/</ref>. Intermediates in the fatty acid breakdown are covalently attached to the sulfhydryl group of coenzyme A <ref name = "Section 22.4 Fatty Acids Are Synthesized and Degraded by Different Pathways"/>. | ||
<p>Fatty Acid Degradation happens in three steps:</p> | <p>Fatty Acid Degradation happens in three steps:</p> | ||
<p> 1. '''Lipolysis and release from adipose tissue''': In the initial steps of degradation, fatty acids are stored in the adipocytes <ref name = "Section 22.4 Fatty Acids Are Synthesized and Degraded by Different Pathways"/>. The breakdown of adipocytes is called lipolysis where they are then released into the bloodstream to circulate through the body <ref name = "Section 22.4 Fatty Acids Are Synthesized and Degraded by Different Pathways"/>.</p> | <p> 1. '''Lipolysis and release from adipose tissue''': In the initial steps of degradation, fatty acids are stored in the adipocytes <ref name = "Section 22.4 Fatty Acids Are Synthesized and Degraded by Different Pathways"/>. The breakdown of adipocytes is called lipolysis where they are then released into the bloodstream to circulate through the body <ref name = "Section 22.4 Fatty Acids Are Synthesized and Degraded by Different Pathways"/>.</p> | ||
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<p>[[Image:Thiolase_reaction.PNG|400px|center]]</p> | <p>[[Image:Thiolase_reaction.PNG|400px|center]]</p> | ||
<p><center>'''Figure 1''': Reaction mechanism of Acetoacetyl-CoA to two Acetyl-CoAs with the enzyme thiolase. Image obtained from class powerpoints.</center></p> | <p><center>'''Figure 1''': Reaction mechanism of Acetoacetyl-CoA to two Acetyl-CoAs with the enzyme thiolase. Image obtained from class powerpoints.</center></p> | ||
<p>The specific acetyltransferase we are particularly interested in is known as | <p>The specific acetyltransferase we are particularly interested in is known as 5h86 which is a Human Gcn5 bound to butyryl-CoA <ref name = "Structural basis for acyl-group discrimination by human Gcn5L2"/>. Gcn5 is a conserved acetyltransferase that regulates transcription by acetylating the N-terminal tails of histones <ref name = "Structural basis for acyl-group discrimination by human Gcn5L2"/>. To better understand how 5h86 is related to fatty acid degradation, we have to understand how they operate as a histone acetyltransferase (HATs). HATs are enzymes that acetylate conserved lysine amino acids on histone proteins <ref name = "Structural basis for acyl-group discrimination by human Gcn5L2"/>. This occurs by transferring an acetyl group from acetyl-CoA to form ε-N-acetyllysine <ref name = "Structural basis for acyl-group discrimination by human Gcn5L2"/>. When DNA is wrapped around histones, an acetyl group is transferred to the histones, allowing genes to be turned on and off <ref name = "Structural basis for acyl-group discrimination by human Gcn5L2"/>. In conclusion, histone acetylation contribute to the increase of gene expression <ref name = "Structural basis for acyl-group discrimination by human Gcn5L2"/>.</p> | ||
<p>HATs also have a role in transcription regulation and are regulated through phosphorylation <ref name = "Regulating histone acetyltransferases and deacetylases">doi: 10.1038/sj.embor.embor941</ref>. For example, the HAT activity of the CREB-binding protein (CBP) is stimulated by the phosphorylation of a cyclin E/cyclin-dependent kinase 2 <ref name = "Regulating histone acetyltransferases and deacetylases"/>. HATs also participate in the genome-wide yield of acetyl groups on histones <ref name = "Regulating histone acetyltransferases and deacetylases"/>. Some HATs also target specific promoters through their physical interaction with sequence-specific transcription factors, sectionally modifying histones or transcription components to regulate gene transcription <ref name = "Regulating histone acetyltransferases and deacetylases"/>.</p> | <p>HATs also have a role in transcription regulation and are regulated through phosphorylation <ref name = "Regulating histone acetyltransferases and deacetylases">doi: 10.1038/sj.embor.embor941</ref>. For example, the HAT activity of the CREB-binding protein (CBP) is stimulated by the phosphorylation of a cyclin E/cyclin-dependent kinase 2 <ref name = "Regulating histone acetyltransferases and deacetylases"/>. HATs also participate in the genome-wide yield of acetyl groups on histones <ref name = "Regulating histone acetyltransferases and deacetylases"/>. Some HATs also target specific promoters through their physical interaction with sequence-specific transcription factors, sectionally modifying histones or transcription components to regulate gene transcription <ref name = "Regulating histone acetyltransferases and deacetylases"/>.</p> | ||
<p> In all, the function of the 5H68 Human Gcn5 acetyltransferase can be represented through histone acetylation to assist in the activation of transcription <ref name = "Regulating histone acetyltransferases and deacetylases"/>. Histone acetylation functions as the main switch that allows the interchange between permissive and repressive chromatin domains during transcription <ref name = "Role of histone acetylation in the control of gene expression">DOI: 10.1139/o05-041</ref>. The histone acetylation-dependent control of gene expression has mechanisms underlying a direct effect on the solidity of nucleosomal arrays and the creation of key sites for the regulatory binding proteins <ref name = "Role of histone acetylation in the control of gene expression"/>. The enzymes devoted to the addition and removal of acetyl groups are histone acetyltransferases, such as the 5H68 Human Gcn5 acetyltransferase, and deacetylases, in which both enzymes complete acetyl group removal or addition by removing the lysine residues on the N-terminals of histone tails <ref name = "Role of histone acetylation in the control of gene expression"/>.</p> | <p> In all, the function of the 5H68 Human Gcn5 acetyltransferase can be represented through histone acetylation to assist in the activation of transcription <ref name = "Regulating histone acetyltransferases and deacetylases"/>. Histone acetylation functions as the main switch that allows the interchange between permissive and repressive chromatin domains during transcription <ref name = "Role of histone acetylation in the control of gene expression">DOI: 10.1139/o05-041</ref>. The histone acetylation-dependent control of gene expression has mechanisms underlying a direct effect on the solidity of nucleosomal arrays and the creation of key sites for the regulatory binding proteins <ref name = "Role of histone acetylation in the control of gene expression"/>. The enzymes devoted to the addition and removal of acetyl groups are histone acetyltransferases, such as the 5H68 Human Gcn5 acetyltransferase, and deacetylases, in which both enzymes complete acetyl group removal or addition by removing the lysine residues on the N-terminals of histone tails <ref name = "Role of histone acetylation in the control of gene expression"/>.</p> | ||
== Structural Highlights & Disease | == Structural Highlights & Disease == | ||
<StructureSection load='1stp' size='340' side='right' caption='5H86 Structure' scene='80/806432/5h86_molecule/2'>Our enzyme, 5h86, can be expressed in ''E. coli'' and is found in humans <ref name = "Structural basis for acyl-group discrimination by human Gcn5L2"/>. The characteristics of this | <StructureSection load='1stp' size='340' side='right' caption='5H86 Structure' scene='80/806432/5h86_molecule/2'>Our enzyme, 5h86, can be expressed in ''E. coli'' and is found in humans <ref name = "Structural basis for acyl-group discrimination by human Gcn5L2"/>. The characteristics of this 5h86 Huamn Gcn5 enzyme bound to butyrl-coA can be summarized below: | ||
<p>• '''Found in These Organisms''': ''Homo sapiens''</p> | <p>• '''Found in These Organisms''': ''Homo sapiens''</p> | ||
<p>• '''Expressed in This System''': ''Escherichia coli''</p> | <p>• '''Expressed in This System''': ''Escherichia coli''</p> | ||
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<p>• '''Number of Ligands''': 2</p> | <p>• '''Number of Ligands''': 2</p> | ||
<p>• '''Enzymatic Activity''': histone acetyltransferase</p> | <p>• '''Enzymatic Activity''': histone acetyltransferase</p> | ||
<p>More importantly, the active site of Gcn5 contains two grooves where acetyl-CoA and peptide bind.</p> | |||
</StructureSection> | </StructureSection> | ||
==Relevance== | ==Relevance== | ||
It is known that the 5h86 Human Gcn5 enzyme functions as an acetyltransferase that regulates transcription by acetylating the N-terminal tails of histones <ref name = "Structural basis for acyl-group discrimination by human Gcn5L2"/>. The experiment was tested on Gcn5 (Gcn5L2), more specifically the lysine acetylation of this enzyme <ref name = "Structural basis for acyl-group discrimination by human Gcn5L2"/>. This is important to understand because the acyltransferase activity of the Gcn5L2 becomes much weaker with increasing acyl chain length <ref name = "Structural basis for acyl-group discrimination by human Gcn5L2"/>. The researchers were inspired by previous studies that identified a chemically diverse array of lysine acyl modification in vivo, and more specifically - the acyl chain of acetyltransferase specificity in the human Gcn5 <ref name = "Structural basis for acyl-group discrimination by human Gcn5L2"/>. In short, they want to experiment and test which acyl-chain donor had the highest enzymatic activity and to characterize the specificity of the acyl-chain of the human Gcn5, which catalyzes the acetylation of histone peptides much quicker than other methods like propionylation or butyrylation <ref name = "Structural basis for acyl-group discrimination by human Gcn5L2"/>. Through the experiment, it was found that via this method, the active sites of Gcn5 can accommodate longer acyl chains without many structural rearrangements <ref name = "Structural basis for acyl-group discrimination by human Gcn5L2"/>. | |||
<p></p> | |||
== References == | == References == | ||
<references/> | <references/> | ||
