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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 | 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). | ||
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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 protein 4CYG has a two chain structure. The chains have identical sequences, consisting of 506 total residues each. The structure of only Chain A has been isolated <scene name='48/483891/Chain_a_rainbow/4'>here</scene> in order to provide a more simple view. | ==Overall Structure== | ||
The protein 4CYG has a two chain structure. The chains have identical sequences, consisting of 506 total residues each. There are 87 residues missing from the model, which have been replace with spherical basket-like structures. The structure of only Chain A has been isolated <scene name='48/483891/Chain_a_rainbow/4'>here</scene> in order to provide a more simple view. Chain A is colored to show the sequence direction <scene name='48/483891/Chain_a_rainbow/5'>here</scene> | |||
The secondary structure of 4CYG is made up of both beta sheets and alpha helices. The alpha helices of one chain are isolated <scene name='48/483891/Alphas_only/2'>here</scene>, where the polar side of the helix is pink and the hydrophobic side is gray. | The secondary structure of 4CYG is made up of both beta sheets and alpha helices. The alpha helices of one chain, of which there are 11, are isolated <scene name='48/483891/Alphas_only/2'>here</scene>, where the polar side of the helix is pink and the hydrophobic side is gray. The beta sheets of one chain, colored by polarity, can be viewed <scene name='48/483891/Betas_only_polar/1'>here</scene>. The polar portions are colored pink and nonpolar portions are colored grey, allowing for a visual representation of the alternating sequence. | ||
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== | ||
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[[Image:rxn.png]] | [[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 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 | 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]] | [[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 | 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. | ||
==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 | |||
==See Also== | ==See Also== | ||
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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. | |||