Sandbox Reserved 914: Difference between revisions
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[[Image:pymol.png|300px|left|thumb|'''Figure 1:'''Three dimensional structure of Palmitoyl-Protein Thioesterase 1. The blue color represents the α-helices and the purple represents the β-sheets. The pink signifies random coil.]] | [[Image:pymol.png|300px|left|thumb|'''Figure 1:'''Three dimensional structure of Palmitoyl-Protein Thioesterase 1. The blue color represents the α-helices and the purple represents the β-sheets. The pink signifies random coil.]] | ||
Palmitoyl-Protein Thioesterase 1 (PPT1) is a lysosomal enzyme that plays a role in the degradation of lipid-modified proteins<ref name="human">Palmitoyl-Protein Thioesterase 1 Precursor - Homo Sapiens. N.p., 1 Oct. 1996.</ref>. PPT1 derives its catalytic power from its [http://en.wikipedia.org/wiki/Catalytic_triad catalytic triad], [http://en.wikipedia.org/wiki/Alpha/beta_hydrolase_fold α/β hydrolase fold], and hydrophobic groove in order to remove fatty acid acyl groups, typically palmitate from cysteine residues in proteins<ref name="human"/>. PPT1 is able to be modified by cofactor enzymes, which can induce biological changes<ref name="human"/>. Misregulation of PPT1 modifications can cause various diseases, including infantile neuronal ceroid lipofuscinosis<ref name="PPT"/>, kufs disease<ref name="PPT"/>, and late-infantile neuronal ceroid lipofuscinosis<ref name="PPT"/>. Within these diseases, the production of PPT1 is decreased or eliminated completely, which leads to fatty acid buildup primarily in neuronal cells, leading to slowed developmental progress<ref name="PPT"/>. | Palmitoyl-Protein Thioesterase 1 (PPT1) is a lysosomal enzyme that plays a role in the degradation of lipid-modified proteins<ref name="human">Palmitoyl-Protein Thioesterase 1 Precursor - Homo Sapiens. N.p., 1 Oct. 1996.</ref>. PPT1 derives its catalytic power from its [http://en.wikipedia.org/wiki/Catalytic_triad catalytic triad], [http://en.wikipedia.org/wiki/Alpha/beta_hydrolase_fold α/β hydrolase fold], and hydrophobic groove in order to remove fatty acid acyl groups, typically [http://en.wikipedia.org/wiki/Palmitic_acid palmitate] from cysteine residues in proteins<ref name="human"/>. PPT1 is able to be modified by cofactor enzymes, which can induce biological changes<ref name="human"/>. Misregulation of PPT1 modifications can cause various diseases, including infantile neuronal ceroid lipofuscinosis<ref name="PPT"/>, kufs disease<ref name="PPT"/>, and late-infantile neuronal ceroid lipofuscinosis<ref name="PPT"/>. Within these diseases, the production of PPT1 is decreased or eliminated completely, which leads to fatty acid buildup primarily in neuronal cells, leading to slowed developmental progress<ref name="PPT"/>. | ||
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=== Catalytic Triad === | === Catalytic Triad === | ||
The <scene name='57/573128/2/1'>catalytic triad</scene> is composed of Ser115, His289, and Asp233, which is the same as the catalytic triad in chymotrypsin <ref name="human"/>. A water molecule is occupying the <scene name='57/573128/7/1'>oxyanion hole</scene> and it is hydrogen bonded to Ser115 <ref name="Prom"/>. The purpose of the oxyanion hole is to stabilize the oxyanion that is formed after the nucleophilic attack of the transition state. Ser115 acts as a nucleophile, while His289 and Asp233 are coordinated to Ser115 to lower its pKa value so it can undergo catalytic activity<ref name="Prom"/>. The pKa of the nucleophile in the catalytic triad is lowered to allow the nucleophilic attack<ref name="Prom">Branneby, Cecilia. Exploiting Enzyme Promiscuity for Rational Design. KTH Biotechnology. N.p., May 2005</ref>. | The <scene name='57/573128/2/1'>catalytic triad</scene> is composed of Ser115, His289, and Asp233, which is the same as the catalytic triad in [http://en.wikipedia.org/wiki/Chymotrypsin chymotrypsin] <ref name="human"/>. A water molecule is occupying the <scene name='57/573128/7/1'>oxyanion hole</scene> and it is hydrogen bonded to Ser115 <ref name="Prom"/>. The purpose of the oxyanion hole is to stabilize the oxyanion that is formed after the nucleophilic attack of the transition state. Ser115 acts as a nucleophile, while His289 and Asp233 are coordinated to Ser115 to lower its pKa value so it can undergo catalytic activity<ref name="Prom"/>. The pKa of the nucleophile in the catalytic triad is lowered to allow the nucleophilic attack<ref name="Prom">Branneby, Cecilia. Exploiting Enzyme Promiscuity for Rational Design. KTH Biotechnology. N.p., May 2005</ref>. | ||
===Hydrophobic Groove === | ===Hydrophobic Groove === | ||
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===Molecular === | ===Molecular === | ||
The main molecular function of PPT1 is to breakdown lipid-modified proteins and act as a hydrolase of thioester bonds<ref name="RSCB"/>. In the main catalytic reaction for PPT1, a cysteine residue is removed from the palmitoylated protein by PPT, resulting in a free cysteine residue and palmitoyl-CoA<ref name="RSCB"/>. A water molecule was suggested to come in and stabilize the transition state, along with protonating the cysteine residue on the palmitoylated protein, allowing the palmitoyl-CoA to break free. | The main molecular function of PPT1 is to breakdown lipid-modified proteins and act as a hydrolase of thioester bonds<ref name="RSCB"/>. In the main [http://lipidlibrary.aocs.org/Lipids/protlip/index.htm catalytic reaction] for PPT1, a cysteine residue is removed from the palmitoylated protein by PPT, resulting in a free cysteine residue and palmitoyl-CoA<ref name="RSCB"/>. A water molecule was suggested to come in and stabilize the transition state, along with protonating the cysteine residue on the palmitoylated protein, allowing the palmitoyl-CoA to break free. | ||
==Medical Relevance== | ==Medical Relevance== | ||
