Sandbox Reserved 466: Difference between revisions

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The tetanus toxin is composed of 468 amino acid residues. The secondary structures present are alpha helices, 3^10 helices, and beta sheets. Twenty-seven percent of the secondary structures are <scene name='Sandbox_Reserved_466/Alpha_and_3-10_helices/1'>alpha helices and 3^10 helices</scene>, which includes a total of 13 helices (127 residues). The <scene name='Sandbox_Reserved_466/Beta_sheets/1'>beta sheets</scene> make up 17% of the secondary structures in this neurotoxin. This includes 25 strands ~~consists~~ 81 residues [PDB]. The <scene name='Sandbox_Reserved_466/Hydrophobic_residues/1'>hydrophobic residues</scene> exist throughout the protein and on the exterior surface to interact with the lipid molecules of the vesicles.

The tetanus toxin is composed of 468 amino acid residues. The secondary structures present are alpha helices, 3^10 helices, and beta sheets. Twenty-seven percent of the secondary structures are <scene name='Sandbox_Reserved_466/Alpha_and_3-10_helices/1'>alpha helices and 3^10 helices</scene>, which includes a total of 13 helices (127 residues). The <scene name='Sandbox_Reserved_466/Beta_sheets/1'>beta sheets</scene> make up 17% of the secondary structures in this neurotoxin. This includes 25 strands consisting of 81 residues [PDB]. The <scene name='Sandbox_Reserved_466/Hydrophobic_residues/1'>hydrophobic residues</scene> exist throughout the protein and on the exterior surface to interact with the lipid molecules of the vesicles.

Tetanus toxin has three functional domains: binding, translocation, and catalytic. The heavy chain is responsible for binding the toxin to the presynaptic neuron membrane and translocating the catalytic light chain domain into the neural cytosol. The light chain is the zinc-dependent catalytic domain containing a zinc-binding motif. This metalloprotease activity causes toxicity [Rao et al., 2005]. The light chain forms a dimer with about 10% of the protein surface existing between the two monomers. Each monomer binds one <scene name='Sandbox_Reserved_466/Zinc_ion/1'>zinc ion</scene>. The active sites of the light chain tetanus toxin interact with the solvent region and are embedded inside a cavity centered around a zinc cation and the conserved zinc-dependent motif. Zinc directly coordinates with His232, His236, and Glu271 within the zinc-dependent <scene name='Sandbox_Reserved_466/Active_site/1'>active site</scene>. Water is another ligand that forms a hydrogen bond with ~~Glu233~~. The formation of the nucleophilic water molecule and the three other amino acid residues in the [http://ars.els-cdn.com/content/image/1-s2.0-S004101010000252X-gr1.jpg tetanus toxin active site] [Rossetto et al., 2001] form a tetrahedral configuration around the catalytic zinc ion. There is also a secondary layer important to the functionality of the active site. These residues are in the surrounding structure, approximately 10 Angstroms from the zinc ion, and they include ~~Glu233~~, His239, Phe274, Arg371, and Tyr374. These residues reinforce the stability and conformation of the active site [Rao et al., 2005].

Tetanus toxin has three functional domains: binding, translocation, and catalytic. The heavy chain is responsible for binding the toxin to the presynaptic neuron membrane and translocating the catalytic light chain domain into the neural cytosol. The light chain is the zinc-dependent catalytic domain containing a zinc-binding motif. This metalloprotease activity causes toxicity [Rao et al., 2005]. The light chain forms a dimer with about 10% of the protein surface existing between the two monomers. Each monomer binds one <scene name='Sandbox_Reserved_466/Zinc_ion/1'>zinc ion</scene>. The active sites of the light chain tetanus toxin interact with the solvent region and are embedded inside a cavity centered around a zinc cation and the conserved zinc-dependent motif. Zinc directly coordinates with His232, His236, and Glu271 within the zinc-dependent <scene name='Sandbox_Reserved_466/Active_site/1'>active site</scene>. Water is another ligand that forms a hydrogen bond with Glu234. The formation of the nucleophilic water molecule and the three other amino acid residues in the [http://ars.els-cdn.com/content/image/1-s2.0-S004101010000252X-gr1.jpg tetanus toxin active site] (Figure b)[Rossetto et al., 2001] form a tetrahedral configuration around the catalytic zinc ion. There is also a secondary layer important to the functionality of the active site. These residues are in the surrounding structure, approximately 10 Angstroms from the zinc ion, and they include Glu234, His239, Phe274, Arg371, and Tyr374. These residues reinforce the stability and conformation of the active site [Rao et al., 2005].

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== Mechanism of Action ==

The tetanus toxin acts in the [http://thebrain.mcgill.ca/flash/i/i_01/i_01_m/i_01_m_ana/i_01_m_ana_1a.jpg synaptic cleft] of neuronal cells and prevents the release of neurotransmitters from the presynaptic neuron terminal [Link et al., 1992]. Neurotransmitters are released from the presynaptic terminal of a neuron into the synaptic cleft and received by endocytosis by the postsynaptic terminal of the next neuron. Nerve terminals are filled with vesicles, which are specialized storage components that contain neurotransmitters, and are released from the terminal into the synaptic cleft by exocytosis. The surface of the postsynaptic terminal has many specialized receptors, which bind with specific ~~vesicles~~. The neurotransmitters are then endocytized into the postsynaptic neuron for transmission of the synapse to facilitate a response to the nerve stimuli.

The tetanus toxin acts in the [http://thebrain.mcgill.ca/flash/i/i_01/i_01_m/i_01_m_ana/i_01_m_ana_1a.jpg synaptic cleft] of neuronal cells and prevents the release of neurotransmitters from the presynaptic neuron terminal [Link et al., 1992]. Neurotransmitters are released from the presynaptic terminal of a neuron into the synaptic cleft and received by endocytosis by the postsynaptic terminal of the next neuron. Nerve terminals are filled with vesicles, which are specialized storage components that contain neurotransmitters, and are released from the terminal into the synaptic cleft by exocytosis. The surface of the postsynaptic terminal has many specialized receptors, which bind with specific neurotransmitters. The neurotransmitters are then endocytized into the postsynaptic neuron for transmission of the synapse to facilitate a response to the nerve stimuli [Dasgupta, 1993].

Tetanus toxin enters the bloodstream or directly binds with a neuronal cell after entering the body from a cut or abrasion. It binds to the neural cells through gangliosides and a protein receptor. Once bound, they enter the cytosol of the synaptic cleft of muscle fiber neurons via a vesicle membrane. Here, they attack and cleave the protein that forms the synaptic vesicle fusion apparatus, particularly [http://en.wikipedia.org/wiki/Synaptobrevin synaptobrevin] [Rao et al., 2005]. Synaptobrevin is a protein that forms [http://en.wikipedia.org/wiki/SNARE_proteins SNARE proteins], which mediate the fusion of synaptic vesicles to the presynaptic terminal. The clostridial neurotoxins each have unique binding sites and substrate cleavage specificity. Tetanus toxin cleaves vesicle-associated membrane proteins of synaptobrevin and inactivates it. The VAMP protein is cleaved at the peptide bond Gln76-Phe77 requiring a amino-terminal extension of 22 residues and a peptide of 33-97 residues in length [Rao et al., 2005].

This interaction between the residues, water, and zinc are essential for the formation of nucleophilic water, which hydrolyzes the peptide bonds of the ~~substrate~~. The three amino acids His232, His236, and Glu271 directly coordinate with the zinc ion. A water molecule, which is the fourth ligand, forms a strong hydrogen bond with another glutamate residue (~~Glu233~~) that is part of the secondary surrounding active residues. The delta-carbonyl of ~~Glu233~~ orients the nucleophilic water molecule into a tetrahedral formation around the [http://ars.els-cdn.com/content/image/1-s2.0-S0041010105000929-gr1.jpg catalytic zinc ion] [Rao et al., 2005]. This formation around the zinc is essential to the formation of the nucleophilic water, which hydrolyzes the peptide bond Gln76-Phe77 of the synaptobrevin VAMP protein.

This interaction between the residues, water, and zinc are essential for the formation of nucleophilic water, which hydrolyzes the peptide bonds of the synaptobrevin VAMP. The three amino acids His232, His236, and Glu271 directly coordinate with the zinc ion. A water molecule, which is the fourth ligand, forms a strong hydrogen bond with another glutamate residue (Glu234) that is part of the secondary surrounding active residues. The delta-carbonyl of Glu234 orients the nucleophilic water molecule into a tetrahedral formation around the [http://ars.els-cdn.com/content/image/1-s2.0-S0041010105000929-gr1.jpg catalytic zinc ion] [Rao et al., 2005]. This formation around the zinc is essential to the formation of the nucleophilic water, which hydrolyzes the peptide bond Gln76-Phe77 of the synaptobrevin VAMP protein [Rossetto et al., 2001].

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== Medical Implications or Possible Applications ==

The tetanus toxin effects the central nervous system by inhibiting the release of neurotransmitters, glycine and gamma-aminobutyric acid, into the synaptic cleft of the spinal cord affecting the transmission of nerve impulses throughout the body. This toxin causes tetanus, which is characterized by rigidity, spasms, and paralysis of the voluntary muscles of the body [Rao et al., 2005]. Tetanus is often referred to as "lockjaw" because a large majority of the patients experience rigidity of the jaw muscles. The toxin enters the body by way of a cut and ~~into~~ the bloodstream, where it spreads rapidly throughout the body, or by a nerve, which transports the toxin directly to the central nervous system. Tetanus toxin attacks motor nerve cells and hyper-activates them. The overactive nerve impulses cause muscles to go into convulsive spasms. The toxin is most commonly known to affect the muscles of the jaw causing rigidity of the muscles of the jaw and face. This toxin also causes severe spasms in the throat and chest making swallowing and breathing extremely difficult. These are the most common causes of death if tetanus is untreated. Tetanus also causes adverse effects on various muscles throughout the body, notably on the heart, blood pressure, and vital brain centers that cause death later in the disease.

The tetanus toxin effects the central nervous system by inhibiting the release of neurotransmitters, glycine and gamma-aminobutyric acid, into the synaptic cleft of the spinal cord affecting the transmission of nerve impulses throughout the body. This toxin causes tetanus, which is characterized by rigidity, spasms, and paralysis of the voluntary muscles of the body [Rao et al., 2005]. Tetanus is often referred to as "lockjaw" because a large majority of the patients experience rigidity of the jaw muscles. The toxin enters the body by way of a cut and enters the bloodstream, where it spreads rapidly throughout the body, or by a nerve, which transports the toxin directly to the central nervous system. Tetanus toxin attacks motor nerve cells and hyper-activates them. The overactive nerve impulses cause muscles to go into convulsive spasms. The toxin is most commonly known to affect the muscles of the jaw causing rigidity of the muscles of the jaw and face. This toxin also causes severe spasms in the throat and chest making swallowing and breathing extremely difficult. These are the most common causes of death if tetanus is untreated. Tetanus also causes adverse effects on various muscles throughout the body, notably on the heart, blood pressure, and vital brain centers that cause death later in the disease [Montecucco, 1995].

Tetanus toxin is still a main concern to public health taking several hundred lives each year. It mainly affects subtropical and tropical regions where hygiene levels are low and treatment and vaccines is not readily available. The most commonly used human vaccine is the chemically modified form of the tetanus neurotoxin. This tetanus ~~toxoid~~ is an effective ~~prevention~~ treatment ~~that is normally distributed to infants over a few months period~~.

Tetanus toxin is still a main concern to public health taking several hundred lives each year [Bizzini, 1979, Dasgupta, 1993, Rao et al., 2005]. It mainly affects subtropical and tropical regions where hygiene levels are low and treatment and vaccines is not readily available. The most commonly used human vaccine is the chemically modified form of the tetanus neurotoxin called the tetanus toxoid. This immunization is a slow process treatment and requires several weeks or months to become effective. A passive treatment for those potentially infected with clostridial spores is the tetanus antitoxin. This is a more supportive treatment of tetanus that contains antibodies generated from a person's blood who have been immunized against the toxin. This antitoxin helps to neutralize the toxin in the bloodstream. However, once the toxin as reached the neural cells, the antitoxin has little effect on the treatment of tetanus. Penicillin is an effective treatment if given intravenously immediately after the cut or skin abrasion has occurred for it kills the bacteria [Montecucco, 1995].

Sandbox Reserved 466: Difference between revisions

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@@ Line 17: / Line 17: @@
-The tetanus toxin is composed of 468 amino acid residues. The secondary structures present are alpha helices, 3^10 helices, and beta sheets. Twenty-seven percent of the secondary structures are <scene name='Sandbox_Reserved_466/Alpha_and_3-10_helices/1'>alpha helices and 3^10 helices</scene>, which includes a total of 13 helices (127 residues). The <scene name='Sandbox_Reserved_466/Beta_sheets/1'>beta sheets</scene> make up 17% of the secondary structures in this neurotoxin. This includes 25 strands consists 81 residues [PDB]. The <scene name='Sandbox_Reserved_466/Hydrophobic_residues/1'>hydrophobic residues</scene> exist throughout the protein and on the exterior surface to interact with the lipid molecules of the vesicles.
+The tetanus toxin is composed of 468 amino acid residues. The secondary structures present are alpha helices, 3^10 helices, and beta sheets. Twenty-seven percent of the secondary structures are <scene name='Sandbox_Reserved_466/Alpha_and_3-10_helices/1'>alpha helices and 3^10 helices</scene>, which includes a total of 13 helices (127 residues). The <scene name='Sandbox_Reserved_466/Beta_sheets/1'>beta sheets</scene> make up 17% of the secondary structures in this neurotoxin. This includes 25 strands consisting of 81 residues [PDB]. The <scene name='Sandbox_Reserved_466/Hydrophobic_residues/1'>hydrophobic residues</scene> exist throughout the protein and on the exterior surface to interact with the lipid molecules of the vesicles.
-Tetanus toxin has three functional domains: binding, translocation, and catalytic. The heavy chain is responsible for binding the toxin to the presynaptic neuron membrane and translocating the catalytic light chain domain into the neural cytosol. The light chain is the zinc-dependent catalytic domain containing a zinc-binding motif. This metalloprotease activity causes toxicity [Rao et al., 2005]. The light chain forms a dimer with about 10% of the protein surface existing between the two monomers. Each monomer binds one <scene name='Sandbox_Reserved_466/Zinc_ion/1'>zinc ion</scene>. The active sites of the light chain tetanus toxin interact with the solvent region and are embedded inside a cavity centered around a zinc cation and the conserved zinc-dependent motif. Zinc directly coordinates with His232, His236, and Glu271 within the zinc-dependent <scene name='Sandbox_Reserved_466/Active_site/1'>active site</scene>. Water is another ligand that forms a hydrogen bond with Glu233. The formation of the nucleophilic water molecule and the three other amino acid residues in the [http://ars.els-cdn.com/content/image/1-s2.0-S004101010000252X-gr1.jpg tetanus toxin active site] [Rossetto et al., 2001] form a tetrahedral configuration around the catalytic zinc ion. There is also a secondary layer important to the functionality of the active site. These residues are in the surrounding structure, approximately 10 Angstroms from the zinc ion, and they include Glu233, His239, Phe274, Arg371, and Tyr374. These residues reinforce the stability and conformation of the active site [Rao et al., 2005].
+Tetanus toxin has three functional domains: binding, translocation, and catalytic. The heavy chain is responsible for binding the toxin to the presynaptic neuron membrane and translocating the catalytic light chain domain into the neural cytosol. The light chain is the zinc-dependent catalytic domain containing a zinc-binding motif. This metalloprotease activity causes toxicity [Rao et al., 2005]. The light chain forms a dimer with about 10% of the protein surface existing between the two monomers. Each monomer binds one <scene name='Sandbox_Reserved_466/Zinc_ion/1'>zinc ion</scene>. The active sites of the light chain tetanus toxin interact with the solvent region and are embedded inside a cavity centered around a zinc cation and the conserved zinc-dependent motif. Zinc directly coordinates with His232, His236, and Glu271 within the zinc-dependent <scene name='Sandbox_Reserved_466/Active_site/1'>active site</scene>. Water is another ligand that forms a hydrogen bond with Glu234. The formation of the nucleophilic water molecule and the three other amino acid residues in the [http://ars.els-cdn.com/content/image/1-s2.0-S004101010000252X-gr1.jpg tetanus toxin active site] (Figure b)[Rossetto et al., 2001] form a tetrahedral configuration around the catalytic zinc ion. There is also a secondary layer important to the functionality of the active site. These residues are in the surrounding structure, approximately 10 Angstroms from the zinc ion, and they include Glu234, His239, Phe274, Arg371, and Tyr374. These residues reinforce the stability and conformation of the active site [Rao et al., 2005].
@@ Line 28: / Line 28: @@
 == Mechanism of Action ==
-The tetanus toxin acts in the [http://thebrain.mcgill.ca/flash/i/i_01/i_01_m/i_01_m_ana/i_01_m_ana_1a.jpg synaptic cleft] of neuronal cells and prevents the release of neurotransmitters from the presynaptic neuron terminal [Link et al., 1992]. Neurotransmitters are released from the presynaptic terminal of a neuron into the synaptic cleft and received by endocytosis by the postsynaptic terminal of the next neuron. Nerve terminals are filled with vesicles, which are specialized storage components that contain neurotransmitters, and are released from the terminal into the synaptic cleft by exocytosis. The surface of the postsynaptic terminal has many specialized receptors, which bind with specific vesicles. The neurotransmitters are then endocytized into the postsynaptic neuron for transmission of the synapse to facilitate a response to the nerve stimuli.
+The tetanus toxin acts in the [http://thebrain.mcgill.ca/flash/i/i_01/i_01_m/i_01_m_ana/i_01_m_ana_1a.jpg synaptic cleft] of neuronal cells and prevents the release of neurotransmitters from the presynaptic neuron terminal [Link et al., 1992]. Neurotransmitters are released from the presynaptic terminal of a neuron into the synaptic cleft and received by endocytosis by the postsynaptic terminal of the next neuron. Nerve terminals are filled with vesicles, which are specialized storage components that contain neurotransmitters, and are released from the terminal into the synaptic cleft by exocytosis. The surface of the postsynaptic terminal has many specialized receptors, which bind with specific neurotransmitters. The neurotransmitters are then endocytized into the postsynaptic neuron for transmission of the synapse to facilitate a response to the nerve stimuli [Dasgupta, 1993].
 Tetanus toxin enters the bloodstream or directly binds with a neuronal cell after entering the body from a cut or abrasion. It binds to the neural cells through gangliosides and a protein receptor. Once bound, they enter the cytosol of the synaptic cleft of muscle fiber neurons via a vesicle membrane. Here, they attack and cleave the protein that forms the synaptic vesicle fusion apparatus, particularly [http://en.wikipedia.org/wiki/Synaptobrevin synaptobrevin] [Rao et al., 2005]. Synaptobrevin is a protein that forms [http://en.wikipedia.org/wiki/SNARE_proteins SNARE proteins], which mediate the fusion of synaptic vesicles to the presynaptic terminal. The clostridial neurotoxins each have unique binding sites and substrate cleavage specificity. Tetanus toxin cleaves vesicle-associated membrane proteins of synaptobrevin and inactivates it. The VAMP protein is cleaved at the peptide bond Gln76-Phe77 requiring a amino-terminal extension of 22 residues and a peptide of 33-97 residues in length [Rao et al., 2005].
-This interaction between the residues, water, and zinc are essential for the formation of nucleophilic water, which hydrolyzes the peptide bonds of the substrate. The three amino acids His232, His236, and Glu271 directly coordinate with the zinc ion. A water molecule, which is the fourth ligand, forms a strong hydrogen bond with another glutamate residue (Glu233) that is part of the secondary surrounding active residues. The delta-carbonyl of Glu233 orients the nucleophilic water molecule into a tetrahedral formation around the [http://ars.els-cdn.com/content/image/1-s2.0-S0041010105000929-gr1.jpg catalytic zinc ion] [Rao et al., 2005]. This formation around the zinc is essential to the formation of the nucleophilic water, which hydrolyzes the peptide bond Gln76-Phe77 of the synaptobrevin VAMP protein.
+This interaction between the residues, water, and zinc are essential for the formation of nucleophilic water, which hydrolyzes the peptide bonds of the synaptobrevin VAMP. The three amino acids His232, His236, and Glu271 directly coordinate with the zinc ion. A water molecule, which is the fourth ligand, forms a strong hydrogen bond with another glutamate residue (Glu234) that is part of the secondary surrounding active residues. The delta-carbonyl of Glu234 orients the nucleophilic water molecule into a tetrahedral formation around the [http://ars.els-cdn.com/content/image/1-s2.0-S0041010105000929-gr1.jpg catalytic zinc ion] [Rao et al., 2005]. This formation around the zinc is essential to the formation of the nucleophilic water, which hydrolyzes the peptide bond Gln76-Phe77 of the synaptobrevin VAMP protein [Rossetto et al., 2001].
@@ Line 38: / Line 40: @@
 == Medical Implications or Possible Applications ==
-The tetanus toxin effects the central nervous system by inhibiting the release of neurotransmitters, glycine and gamma-aminobutyric acid, into the synaptic cleft of the spinal cord affecting the transmission of nerve impulses throughout the body. This toxin causes tetanus, which is characterized by rigidity, spasms, and paralysis of the voluntary muscles of the body [Rao et al., 2005]. Tetanus is often referred to as "lockjaw" because a large majority of the patients experience rigidity of the jaw muscles. The toxin enters the body by way of a cut and into the bloodstream, where it spreads rapidly throughout the body, or by a nerve, which transports the toxin directly to the central nervous system. Tetanus toxin attacks motor nerve cells and hyper-activates them. The overactive nerve impulses cause muscles to go into convulsive spasms. The toxin is most commonly known to affect the muscles of the jaw causing rigidity of the muscles of the jaw and face. This toxin also causes severe spasms in the throat and chest making swallowing and breathing extremely difficult. These are the most common causes of death if tetanus is untreated. Tetanus also causes adverse effects on various muscles throughout the body, notably on the heart, blood pressure, and vital brain centers that cause death later in the disease.
+The tetanus toxin effects the central nervous system by inhibiting the release of neurotransmitters, glycine and gamma-aminobutyric acid, into the synaptic cleft of the spinal cord affecting the transmission of nerve impulses throughout the body. This toxin causes tetanus, which is characterized by rigidity, spasms, and paralysis of the voluntary muscles of the body [Rao et al., 2005]. Tetanus is often referred to as "lockjaw" because a large majority of the patients experience rigidity of the jaw muscles. The toxin enters the body by way of a cut and enters the bloodstream, where it spreads rapidly throughout the body, or by a nerve, which transports the toxin directly to the central nervous system. Tetanus toxin attacks motor nerve cells and hyper-activates them. The overactive nerve impulses cause muscles to go into convulsive spasms. The toxin is most commonly known to affect the muscles of the jaw causing rigidity of the muscles of the jaw and face. This toxin also causes severe spasms in the throat and chest making swallowing and breathing extremely difficult. These are the most common causes of death if tetanus is untreated. Tetanus also causes adverse effects on various muscles throughout the body, notably on the heart, blood pressure, and vital brain centers that cause death later in the disease [Montecucco, 1995].
-Tetanus toxin is still a main concern to public health taking several hundred lives each year. It mainly affects subtropical and tropical regions where hygiene levels are low and treatment and vaccines is not readily available. The most commonly used human vaccine is the chemically modified form of the tetanus neurotoxin. This tetanus toxoid is an effective prevention treatment that is normally distributed to infants over a few months period.
+Tetanus toxin is still a main concern to public health taking several hundred lives each year [Bizzini, 1979, Dasgupta, 1993, Rao et al., 2005]. It mainly affects subtropical and tropical regions where hygiene levels are low and treatment and vaccines is not readily available. The most commonly used human vaccine is the chemically modified form of the tetanus neurotoxin called the tetanus toxoid. This immunization is a slow process treatment and requires several weeks or months to become effective. A passive treatment for those potentially infected with clostridial spores is the tetanus antitoxin. This is a more supportive treatment of tetanus that contains antibodies generated from a person's blood who have been immunized against the toxin. This antitoxin helps to neutralize the toxin in the bloodstream. However, once the toxin as reached the neural cells, the antitoxin has little effect on the treatment of tetanus. Penicillin is an effective treatment if given intravenously immediately after the cut or skin abrasion has occurred for it kills the bacteria [Montecucco, 1995].