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==Introduction==
==Introduction==
The two protein subunits possess dense regions of <scene name='48/483891/Secondary_structure/1'>beta strands and alpha helices.</scene>
Vanin 1, otherwise known as pantetheinase, is an enzyme found throughout the body in various tissues including the liver and kidneys. As an ectoenzyme—any enzyme found on the outside or outer surface of a cell—pantethiense is anchored to the cell wall by a glycosylphosphatidylinositol (GPI) linker, allowing for the it to carry out its enzymatic purpose of hydrolyzing pantetheine to pantothenic acid and cysteamine [1]. The two protein subunits possess dense regions of <scene name='48/483891/Secondary_structure/1'>beta strands and alpha helices</scene> which create binding sites for three types of ligands, the non-polar <scene name='48/483891/Rrv/1'>RRV ligand</scene>, a di(hydroxyethyl)ether compound <scene name='48/483891/Peg/1'>PEG</scene>, and <scene name='48/483891/Nag/1'>NAG</scene> (N-acetyl-d-glucosamine) ligands. The identification of the associated binding sites has led to the investigation of active-site inhibitors (see Additional Features).
Vanin 1, otherwise known as pantetheinase, is an enzyme found throughout the body in various tissues including the liver and kidneys. As an ectoenzyme—any enzyme found on the outside or outer surface of a cell—pantethiense is anchored to the cell wall by a glycosylphosphatidylinositol (GPI) linker, allowing for the it to carry out its enzymatic purpose of hydrolyzing pantetheine to pantothenic acid and cysteamine [1].  


The importance of vanin 1 lies in the products of the enzymatic reaction. Pantothenic acid (vitamin B12) plays a significant role in the maintenance of the nervous system and brain. The compound is also involved in DNA synthesis, as well as fatty acid and amino acid metabolism [2]. Cysteamine—a product of the degradation of the amino acid cysteine—is used to form coenzyme A, a compound that plays a key role in the citric acid cycle and the synthesis of fatty acids. A lack of these biomolecules can lead to significant physiological issues (see Additional Features).  
The importance of vanin 1 lies in the products of the enzymatic reaction. Pantothenic acid (vitamin B12) plays a significant role in the maintenance of the nervous system and brain. The compound is also involved in DNA synthesis, as well as fatty acid and amino acid metabolism [2]. Cysteamine—a product of the degradation of the amino acid cysteine—is used to form coenzyme A, a compound that plays a key role in the citric acid cycle and the synthesis of fatty acids. A lack of these biomolecules can lead to significant physiological issues (see Additional Features).  
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4CYG has three types ligands involved in the structure. There are two <scene name='48/483891/Rrv/1'>RRV</scene> ((2r)-2,4-dihydroxy-n-[(3s)-3-hydroxy-4-phenylbutyl]-3,3-dimethylbutanamide) ligands, two <scene name='48/483891/Peg/1'>PEG</scene> (di(hydroxyethyl) ether) ligands, and eight <scene name='48/483891/Nag/1'>NAG</scene> (N-acetyl-d-glucosamine) ligands.  
4CYG has three types ligands involved in the structure. There are two <scene name='48/483891/Rrv/1'>RRV</scene> ((2r)-2,4-dihydroxy-n-[(3s)-3-hydroxy-4-phenylbutyl]-3,3-dimethylbutanamide) ligands, two <scene name='48/483891/Peg/1'>PEG</scene> (di(hydroxyethyl) ether) ligands, and eight <scene name='48/483891/Nag/1'>NAG</scene> (N-acetyl-d-glucosamine) ligands.  
==Binding Interactions==


==Binding Interactions==
4CYG is a key protein that is involved in the breakdown of pantetheine to panthothenic acid and cysteamine. These proteins are associated with many metabolic diseases like type 2 diabetes. Understanding the binding interaction would give insight into treating these diseases more effectively. 4CYG has three <scene name='48/483891/Binding_site/1'>Catalytic Residues</scene> (Glu79, Lys178 and Cys211) that represents the active site of the enzyme. The purple amino acids represent the three amino acids directly involved in the binding interactions. The active site is located in the center of the enzyme in between the two sub-units. It was discovered that Glu79 and Lys178 were responsible for orienting and activating Cys211 to catalyze the reaction. The substrate forms a covalent bond with Cys211 producing the transition state.[1]
4CYG is a key protein that is involved in the breakdown of pantetheine to panthothenic acid and cysteamine. These proteins are associated with many metabolic diseases like type 2 diabetes. Understanding the binding interaction would give insight into treating these diseases more effectively. 4CYG has three <scene name='48/483891/Binding_site/1'>Catalytic Residues</scene> (Glu79, Lys178 and Cys211) that represents the active site of the enzyme. The purple amino acids represent the three amino acids directly involved in the binding interactions. The active site is located in the center of the enzyme in between the two sub-units. It was discovered that Glu79 and Lys178 were responsible for orienting and activating Cys211 to catalyze the reaction. The substrate forms a covalent bond with Cys211 producing the transition state.[1]


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==Additional Features==
==Additional Features==
The biological importance of Pantetheinase is found in the products Cysteamine and vitamin B5, formed from the hydrolysis reaction shown below. Cysteamine and Vitamin B5 are key components in the synthesis of other necessary biomolecules such as acetylcholine and Coenzyme A.   
The biological importance of pantetheinase is found in the products cysteamine and vitamin B5, formed from the hydrolysis reaction shown below. Cysteamine and vitamin B5 are key components in the synthesis of other necessary bio-molecules such as acetylcholine and coenzyme A.   


[[Image:rxn.png]]
===Inhibition===
===Inhibition===
The importance of Pantetheinase stems from the vitality of the components of the reaction it catalyzes. It is for this reason that Pantetheinase has been a promising point of research in the medical field. Pantetheine analogues known as pantothenamides have been shown to act as effective antibiotics that protect the body from bacterial intruders. The similarity of these analogues to Pantetheine allow for the active sites of pantetheinase to catalyze their breakdown through hydrolysis. The administration of RR6 in the presence of pantetheinase and other antibiotic pantothenamides revealed that RR6 acts as a competitive inhibitor with great affinity for the active sites on pantetheinase, thus preserving desired concentrations of the pantothenamides with antibiotic characteristics.  
The importance of pantetheinase stems from the vitality of the components of the reaction it catalyzes. It is for this reason that pantetheinase has been a promising point of research in the field of medicine. Pantetheine analogues known as pantothenamides have been shown to act as effective antibiotics that protect the body from bacterial intruders. The similarity of these analogues to pantetheine allows for the active sites on pantetheinase to catalyze their breakdown through hydrolysis. The administration of RR6 in the presence of pantetheinase and other antibiotic pantothenamides revealed that RR6 acts as a competitive inhibitor with great affinity for the active site Cys at <scene name='48/483891/Rr6/2'>residue 211</scene> on pantetheinase, thus preserving desired concentrations of the pantothenamides with antibiotic characteristics. The RR6 inhibitor is shown below.  


[[Image:RR6.png]]
===Absence===
===Absence===
Vitamin B5 is the recycled product of the hydrolysis of pantetheine and is a major substrate in the formation of Coenzyme A (CoA). Without Pantetheinase, the hydrolysis of panteheine would occur at a significantly slower rate and would therefore produce the Vitamin B5 and cysteamine at a slower rate. Lower concentrations of Vitamin B5 would result in inadequate prodution of CoA and therefore inadequate production of acetylcholine. Acetylcholine is a neurotransmitter that is needed for proper brain funcion which means an absence of pantetheinase could lead to neurological complications.  
Vitamin B5 is the recycled product of the hydrolysis of pantetheine and is a major substrate in the formation of coenzyme A (CoA). Without pantetheinase, the hydrolysis of pantetheine would occur at a significantly slower rate and would therefore produce vitamin B5 and cysteamine at a slower rate. Lower concentrations of Vitamin B5 would result in inadequate prodution of CoA and therefore inadequate production of acetylcholine. Acetylcholine is a neurotransmitter that is needed for proper brain function which means an absence of pantetheinase could lead to neurological complications.  
   
   
Cysteamine is important in the regulation of cystine levels in lysosomes. A lack of cysteamine due to the absence of pantetheinase would lead to a build up of lysosomal cystine, a disease known as cystinosis.
Cysteamine is important in the regulation of cystine levels in lysosomes. A lack of cysteamine due to the absence of pantetheinase would lead to a build up of lysosomal cystine, a disease known as cystinosis.  


The purple chains represent the polar and therefore hydrophilic regions of 4CYG and the grey chains represent the nonpolar hydrophobic regions of
<scene name='48/483891/Polarity/1'>4CYG</scene>.


==Quiz Question 1==
==Quiz Question 1==
Pantetheinase exhibits an extremely similar sequence to the other proteins in the Vanin family. In addition, <scene name='48/483891/Pantetheinase/1'>pantetheinase</scene> is also sequentially similar to this enzyme, which allows the body to utilize a certain vitamin:
a. gastric lipase
b. biotinidase
c. carboxypeptidase
d. pepsin




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==References==
==References==
<references/>
<references/>
[2] "Pantetheinase." VNN1. UniProt, n.d. Web. 10 Apr. 2016.
[3]Jansen, Patrick, and Joost Schalkwijk. "Chemical Biology Tools to Study Pantetheinases of the Vanin Family." Biochemical Society Transactions. Portland Press, n.d. Web. 10 Apr. 2016.
[4]"Cystinosis." Genetics Home Reference. U.S. National Library of Medicine, 8 Apr. 2016. Web. 10 Apr. 2016.

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OCA, Lynmarie K Thompson, Student
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