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==Palmitoyl-Protein Thioesterase 1 ==
==Palmitoyl-Protein Thioesterase 1 ==
<Structure load='1EH5' size='350' frame='true' align='right' caption='Insert caption here' scene='57/573128/1/1' />
<StructureSection load='1EH5' size='350' frame='true' align='right' caption='Insert caption here' scene='57/573128/1/1' >
[[Image:sandbox1.png|300px|left|thumb|Three dimensional structure of Palmitoyl-Protein Thioesterase 1.]]
[[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. PPT1 receives its catalytic power from its catalytic triad, the α/β hydrolase fold, and its hydrophobic groove in order to remove fatty acid acyl groups, typically palmitate from cysteine residues in proteins. PPT1 demonstrates how proteins can be modified by different enzymes and induce biological changes. Misregulation of PPT1 modifications can cause various diseases, including infantile neuronal ceroid lipofuscinosis, kufs disease, and late-infantile neuronal ceroid lipofuscinosis. Within these diseases, the production of PPT1 is decreased or eliminated completely, which leads to fatty acid buildup.  
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." UniProt. N.p., 1 Oct. 1996. Web. 10 Apr. 2014.</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"/>.  




== Structure ==
== Structure ==
The secondary structure of PPT1 contains several α-helices and few β-sheets.
The secondary structure of PPT1 contains several α-helices and few β-sheets (Figure 1). PPT1 includes residues 28-306, after the 27-residue signal peptide has been removed <ref name="RSCB">PMID:10781062</ref>. An insertion is found between β6 and β7, residues 140-223, and that forms a <scene name='57/573128/9/1'>second domain</scene>, shown in blue, that is compromised almost entirely of the fatty acid binding site. This second domain region contains six helices, α2-α7<ref name="RSCB"/>.  
   
   
=== α/β Hydrolase Fold ===
The α/β hydrolase fold is common to many other hydrolases <ref name="RSCB"/>. The α/β hydrolase fold has a central 6 stranded parallel β-sheet consisting of <scene name='57/573128/4/1'>β3-β8</scene> and α-helices <scene name='57/573128/5/1'>αA, αB, αC, and αF</scene><ref name="RSCB"/>. A catalytic triad and an oxyanion hole are also common features to the PPT1 protein family. None of the enzymes within the α/β hydrolase fold family require a cofactor for catalytic activity.
The α/β Hydrolase Fold is common to many other hydrolases. This fold consists of β3-β8, αA, αB, αC, and αF. The α/β hydrolase fold has a central 6 stranded parallel Beta sheet. There is also a helix that is roughly perpendicular to the direction of the beta sheet. There is also a large insertion, containing 6 helices, that forms a second domain that encompasses most of the fatty acid binding site.


=== 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.
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 (2005): Web. 10 Apr. 2013.</ref>.  
A water molecule is occupying the oxyanion hole and it is hydrogen bonded to ser115.
   
   
===Hydrophobic Groove ===
===Hydrophobic Groove ===
 
The <scene name='57/573128/3/1'>hydrophobic binding groove</scene> is located in the second domain of PPT1, where palmitate mainly binds. The fact that palmitate has to <scene name='57/573128/6/1'>bend</scene> to fit into the binding pocket suggests that this pocket is designed to bind an unsaturated fatty acid, with a possible cis-double bond between C4 and C5<ref name="RSCB"/>. The top portion of the groove is formed by the residues from α2 to α3. Several residues that are present near the active site create the rest of the groove, including <scene name='57/573128/10/1'>Ile235, Val236, Gln116, Gly40, and Met41</scene><ref name="RSCB"/>.
The <scene name='57/573128/3/1'>hydrophobic binding groove</scene> is located in the second domain of PPT1, where palmitate mainly binds. The fact that palmitate has to bend to fit into the binding pocket suggests that this pocket is designed to bind an unsaturated fatty acid.  


== Function ==
== Function ==


===Biological ===
===Biological ===
PPT1 is biologically involved in sensory transduction and the vision process.
PPT1 is biologically involved in sensory transduction and the vision process<ref name="human"/>. Within sensory tranduction, PPT1 is involved in the process of converting extracellular signals, such as light, taste, touch, or smell, into electric signals that are then sent throughout the body<ref name="human"/>. With vision, PPT1 is involved in the process of seeing images and then processing them into information that is then interpreted by the brain<ref name="human"/>.  
   
   
===Molecular ===
===Molecular ===
The main molecular function of PPT1 is to breakdown lipid-modified proteins.  
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==
PPT1 mutations are the root cause of several diseases, specifically those where mutations cause a decrease or depletion of PPT1. Infantile neuronal ceroid lipofuscinosis (INCF) is characterized by impaired mental and motor development, including difficulty with walking, speaking, and intellectual function, beginning around the first or second year of life. The PPT1 mutation involved in INCF replaces an arginine with a stop signal in the instructions to make the enzyme. This mutation leads to a vast reduction in the production of PPT1, which impairs the removal of fatty acids from proteins. This impaired removal leads to fatty acid accumulations throughout the body, particularly in neuronal cells in the brain. Late-infantile neuronal ceroid lipofuscinosis has the same characteristics as INCF, but the mutation varies slightly. This leads to a slight reduction in the activity of PPT1 instead of completely wiping it out.   
PPT1 mutations and a decrease or depletion of PPT1 are the root cause of several diseases. Infantile neuronal ceroid lipofuscinosis (INCF) is characterized by impaired mental and motor development, including difficulty with walking, speaking, and intellectual function, beginning around the first or second year of life<ref name="PPT">"PPT1." Genetics Home Reference. N.p., Aug. 2013. Web. 10 Apr. 2014.</ref>. The PPT1 mutation involved in INCF replaces an arginine with a stop signal in the instructions to make the enzyme. This mutation leads to a vast reduction in the production of PPT1, which impairs the removal of fatty acids from proteins. This impaired removal leads to fatty acid accumulations throughout the body, particularly in neuronal cells in the brain<ref name="PPT"/>. Late-infantile neuronal ceroid lipofuscinosis has the same characteristics as INCF, but the mutation varies slightly. This leads to a slight reduction in the activity of PPT1 instead of completely wiping it out<ref name="PPT"/>.  
Mutations can also cause premature stop signals to be added to the instructions to create PPT1, resulting in Kufs disease. This is characterized by seizures, problems with movement, and a decline of intellectual function, usually beginning in early adulthood. Although premature stop signals are added, these mutations allow enough PPT1 to be produced so that the onset is later on in life and the life expectancy is higher.   
   
Mutations can also cause premature stop signals to be added to the instructions to create PPT1, resulting in Kufs disease<ref name="PPT"/>. This is characterized by seizures, problems with movement, and a decline of intellectual function, usually beginning in early adulthood<ref name="PPT"/>. Although premature stop signals are added, these mutations allow enough PPT1 to be produced so that the onset is later on in life and the life expectancy is higher.   
</StructureSection>


== References ==
<references/>




== External Resources ==


http://en.wikipedia.org/wiki/Palmitoyl_protein_thioesterase


== External Resources ==
https://www.counsyl.com/diseases/ppt1-related-neuronal-ceroid-lipofuscinosis/
 
http://en.wikipedia.org/wiki/Alpha/beta_hydrolase_fold
 
http://en.wikipedia.org/wiki/Catalytic_triad
 
http://www.biomedcentral.com/1471-2121/8/22


http://www.genecards.org/cgi-bin/carddisp.pl?gene=PPT1


http://www.ebi.ac.uk/pdbe-srv/view/entry/1pja/summary.html


</StructureSection>
http://www.ncbi.nlm.nih.gov/gene/5538

Latest revision as of 15:45, 22 April 2014

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Palmitoyl-Protein Thioesterase 1Palmitoyl-Protein Thioesterase 1

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[1]. PPT1 derives its catalytic power from its catalytic triad, α/β hydrolase fold, and hydrophobic groove in order to remove fatty acid acyl groups, typically palmitate from cysteine residues in proteins[1]. PPT1 is able to be modified by cofactor enzymes, which can induce biological changes[1]. Misregulation of PPT1 modifications can cause various diseases, including infantile neuronal ceroid lipofuscinosis[2], kufs disease[2], and late-infantile neuronal ceroid lipofuscinosis[2]. 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[2].


Structure

The secondary structure of PPT1 contains several α-helices and few β-sheets (Figure 1). PPT1 includes residues 28-306, after the 27-residue signal peptide has been removed [3]. An insertion is found between β6 and β7, residues 140-223, and that forms a , shown in blue, that is compromised almost entirely of the fatty acid binding site. This second domain region contains six helices, α2-α7[3].

The α/β hydrolase fold is common to many other hydrolases [3]. The α/β hydrolase fold has a central 6 stranded parallel β-sheet consisting of and α-helices [3]. A catalytic triad and an oxyanion hole are also common features to the PPT1 protein family. None of the enzymes within the α/β hydrolase fold family require a cofactor for catalytic activity.

Catalytic Triad

The is composed of Ser115, His289, and Asp233, which is the same as the catalytic triad in chymotrypsin [1]. A water molecule is occupying the and it is hydrogen bonded to Ser115 [4]. 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[4]. The pKa of the nucleophile in the catalytic triad is lowered to allow the nucleophilic attack[4].

Hydrophobic Groove

The is located in the second domain of PPT1, where palmitate mainly binds. The fact that palmitate has to to fit into the binding pocket suggests that this pocket is designed to bind an unsaturated fatty acid, with a possible cis-double bond between C4 and C5[3]. The top portion of the groove is formed by the residues from α2 to α3. Several residues that are present near the active site create the rest of the groove, including [3].

Function

Biological

PPT1 is biologically involved in sensory transduction and the vision process[1]. Within sensory tranduction, PPT1 is involved in the process of converting extracellular signals, such as light, taste, touch, or smell, into electric signals that are then sent throughout the body[1]. With vision, PPT1 is involved in the process of seeing images and then processing them into information that is then interpreted by the brain[1].

Molecular

The main molecular function of PPT1 is to breakdown lipid-modified proteins and act as a hydrolase of thioester bonds[3]. 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[3]. 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

PPT1 mutations and a decrease or depletion of PPT1 are the root cause of several diseases. Infantile neuronal ceroid lipofuscinosis (INCF) is characterized by impaired mental and motor development, including difficulty with walking, speaking, and intellectual function, beginning around the first or second year of life[2]. The PPT1 mutation involved in INCF replaces an arginine with a stop signal in the instructions to make the enzyme. This mutation leads to a vast reduction in the production of PPT1, which impairs the removal of fatty acids from proteins. This impaired removal leads to fatty acid accumulations throughout the body, particularly in neuronal cells in the brain[2]. Late-infantile neuronal ceroid lipofuscinosis has the same characteristics as INCF, but the mutation varies slightly. This leads to a slight reduction in the activity of PPT1 instead of completely wiping it out[2].

Mutations can also cause premature stop signals to be added to the instructions to create PPT1, resulting in Kufs disease[2]. This is characterized by seizures, problems with movement, and a decline of intellectual function, usually beginning in early adulthood[2]. Although premature stop signals are added, these mutations allow enough PPT1 to be produced so that the onset is later on in life and the life expectancy is higher.

Insert caption here

Drag the structure with the mouse to rotate

ReferencesReferences

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 "Palmitoyl Protein Thioesterase 1." UniProt. N.p., 1 Oct. 1996. Web. 10 Apr. 2014.
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 "PPT1." Genetics Home Reference. N.p., Aug. 2013. Web. 10 Apr. 2014.
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 Bellizzi JJ 3rd, Widom J, Kemp C, Lu JY, Das AK, Hofmann SL, Clardy J. The crystal structure of palmitoyl protein thioesterase 1 and the molecular basis of infantile neuronal ceroid lipofuscinosis. Proc Natl Acad Sci U S A. 2000 Apr 25;97(9):4573-8. PMID:10781062 doi:10.1073/pnas.080508097
  4. ↑ 4.0 4.1 4.2 Branneby, Cecilia. "Exploiting Enzyme Promiscuity for Rational Design." KTH Biotechnology (2005): Web. 10 Apr. 2013.


External ResourcesExternal Resources

http://en.wikipedia.org/wiki/Palmitoyl_protein_thioesterase

https://www.counsyl.com/diseases/ppt1-related-neuronal-ceroid-lipofuscinosis/

http://en.wikipedia.org/wiki/Alpha/beta_hydrolase_fold

http://en.wikipedia.org/wiki/Catalytic_triad

http://www.biomedcentral.com/1471-2121/8/22

http://www.genecards.org/cgi-bin/carddisp.pl?gene=PPT1

http://www.ebi.ac.uk/pdbe-srv/view/entry/1pja/summary.html

http://www.ncbi.nlm.nih.gov/gene/5538

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