Sandbox 160: Difference between revisions

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{{STRUCTURE_1vc2| PDB=1vc2 | Scene =Sandbox_160/Newscene/1'>active site }}

Glyceraldehyde 3-Phosphate dehydrogenase (GAPDH) is an Oxidoreductase enzyme involved in many important biochemical reactions and belongs to the Aldehyde Dehydrogenase superfamily<ref name="ref 6">PMID:9497334 </ref>. GAPDH has been divided into two large classes and subsequent subclasses. Class 1 consists of eukaryotes and eubacteria whereas class 2 contains archael GAPDHs <ref name="ref 2">PMID:11846565 </ref>. It is involved in glycolysis, gluconeogenesis and in the case of photosynthetic organism, the carbon reduction cycle <ref name="ref 2"/>. This protein is responsible for catalyzing the conversion of glyceraldeyde 3-Phosphate into 1,3-Biphosphoglycerate in a two step coupled mechanism. This conversion occurs during step 6 or the beginning of the "payoff phase" of glycolysis (the second half of the entire process) in which ATP and NADH is produced. A total of 2 NADH and 4 ATP are produced during this phase for a net gain of 2 NADH and 2 ATP for the entire glycolysis pathway per glucose.A number of disease causing parasites particularly protists such as ''Trypanosoma brucei'' rely on glycolysis to provide the energy for their biochemical functions. Due to this, such parasites will heavily rely on GAPDH due to its intrinsic role in the glycolytic pathway and therefore targeting this enzyme complex can be a promising field of research. Subsequent pharmaceutical drug development and testing can then be conducted to provide protection against deadly viruses and disease. This protein has also been linked as acting as a nitric oxide sensor and plays roles in transcriptional regulation of genes along with translational silencing <ref name="ref 3">PMID:20014444 </ref>.

Glyceraldehyde 3-Phosphate dehydrogenase (GAPDH) is an Oxidoreductase enzyme involved in many important biochemical reactions and belongs to the Aldehyde Dehydrogenase superfamily<ref name="ref 6">PMID:9497334 </ref>. GAPDH has been divided into two large classes and subsequent subclasses. Class 1 consists of eukaryotes and eubacteria whereas class 2 contains archael GAPDHs <ref name="ref 2">PMID:11846565 </ref>. It is involved in glycolysis, gluconeogenesis and in the case of photosynthetic organism, the carbon reduction cycle <ref name="ref 2"/>. This protein is responsible for catalyzing the conversion of glyceraldeyde 3-Phosphate into 1,3-Biphosphoglycerate in a two step coupled mechanism. This conversion occurs during step 6 or the beginning of the "payoff phase" of glycolysis (the second half of the entire process) in which ATP and NADH is produced. A total of 2 NADH and 4 ATP are produced during this phase for a net gain of 2 NADH and 2 ATP for the entire glycolysis pathway per glucose.A number of disease causing parasites particularly protists such as ''Trypanosoma brucei'' rely on glycolysis to provide the energy for their biochemical functions. Due to this, such parasites will heavily rely on GAPDH due to its intrinsic role in the glycolytic pathway and therefore targeting this enzyme complex can be a promising field of research. Subsequent pharmaceutical drug development and testing can then be conducted to provide protection against deadly viruses and disease. This protein has also been linked as acting as a nitric oxide sensor and plays roles in transcriptional regulation of genes along with translational silencing <ref name="ref 3">PMID:20014444 </ref>. Although the exact mechanism of these roles are unknown at the moment it is believed that posttranslational modifications play a part in determining these other functions<ref name="ref 3"/>.

== Structure & Function ==

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==Relations to Medicine==

Strong structural analysis and in depth studies of parasitic protozoans has allowed the determination of conservation and differences between the parasite and human forms of GAPDH. ''Trypanosoma cruzi'', a protozoan parasite is responsible for causing Chagas' disease in approximately 16-18 million people from southern and central America<ref name="ref 7">PMID:9580189 </ref>. This parasite is responsible for causing up to 45,000 deaths per year and can cause severe complications such as neurological disorders and chronic cardiopathy<ref name="ref 7"/>. Although there are preexisting drugs on the market that do show some effectiveness, they are all known to cause severe side effects which defeats the purpose of their production. The role of Glyceraldehyde 3-Phosphate Dehydrogenase in this case is that it has been found that the bloodstream forms of the related protozoan ''T. brucei''are shown to lack a functional tricarboxylic acid cycle and thus its ultimate ATP source must come from glycolysis<ref name="ref 7"/>. It is this finding that has intrigued scientists to find solutions to the diseases caused by these protozoans. At the moment the most relevant target is the binding site of the adenosine ring of the NAD+ cofactor. It has been studied in great detail and its differences from the human form have been well recorded to allow the outcome of a possible solution<ref name="ref 7"/>. The NAD+ binding region is homologous in both ''T. brucei'' and ''T. cruzi'' and this site is therefore a suitable target for inhibitors that will provide a solution to Chagas' disease<ref name="ref 7"/>. This step will be advantageous because several adenosine analogues have already been designed and applied as selective and competitive inhibitors to trypanosomatid GAPDHs and have shown to stop the growth of ''T. brucei'' within the bloodstram<ref name="ref 8">PMID:11405646 </ref>.

== References ==

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@@ Line 6: / Line 6: @@
 {{STRUCTURE_1vc2|  PDB=1vc2  | Scene =Sandbox_160/Newscene/1'>active site }}
-Glyceraldehyde 3-Phosphate dehydrogenase (GAPDH) is an Oxidoreductase enzyme involved in many important biochemical reactions and belongs to the Aldehyde Dehydrogenase superfamily<ref name="ref 6">PMID:9497334 </ref>. GAPDH has been divided into two large classes and subsequent subclasses. Class 1 consists of eukaryotes and eubacteria whereas class 2 contains archael GAPDHs <ref name="ref 2">PMID:11846565 </ref>. It is involved in glycolysis, gluconeogenesis and in the case of photosynthetic organism, the carbon reduction cycle <ref name="ref 2"/>. This protein is responsible for catalyzing the conversion of glyceraldeyde 3-Phosphate into 1,3-Biphosphoglycerate in a two step coupled mechanism. This conversion occurs during step 6 or the beginning of the "payoff phase" of glycolysis (the second half of the entire process) in which ATP and NADH is produced. A total of 2 NADH and 4 ATP are produced during this phase for a net gain of 2 NADH and 2 ATP for the entire glycolysis pathway per glucose.A number of disease causing parasites particularly protists such as ''Trypanosoma brucei'' rely on glycolysis to provide the energy for their biochemical functions. Due to this, such parasites will heavily rely on GAPDH due to its intrinsic role in the glycolytic pathway and therefore targeting this enzyme complex can be a promising field of research. Subsequent pharmaceutical drug development and testing can then be conducted to provide protection against deadly viruses and disease. This protein has also been linked as acting as a nitric oxide sensor and plays roles in transcriptional regulation of genes along with translational silencing <ref name="ref 3">PMID:20014444 </ref>.
+Glyceraldehyde 3-Phosphate dehydrogenase (GAPDH) is an Oxidoreductase enzyme involved in many important biochemical reactions and belongs to the Aldehyde Dehydrogenase superfamily<ref name="ref 6">PMID:9497334 </ref>. GAPDH has been divided into two large classes and subsequent subclasses. Class 1 consists of eukaryotes and eubacteria whereas class 2 contains archael GAPDHs <ref name="ref 2">PMID:11846565 </ref>. It is involved in glycolysis, gluconeogenesis and in the case of photosynthetic organism, the carbon reduction cycle <ref name="ref 2"/>. This protein is responsible for catalyzing the conversion of glyceraldeyde 3-Phosphate into 1,3-Biphosphoglycerate in a two step coupled mechanism. This conversion occurs during step 6 or the beginning of the "payoff phase" of glycolysis (the second half of the entire process) in which ATP and NADH is produced. A total of 2 NADH and 4 ATP are produced during this phase for a net gain of 2 NADH and 2 ATP for the entire glycolysis pathway per glucose.A number of disease causing parasites particularly protists such as ''Trypanosoma brucei'' rely on glycolysis to provide the energy for their biochemical functions. Due to this, such parasites will heavily rely on GAPDH due to its intrinsic role in the glycolytic pathway and therefore targeting this enzyme complex can be a promising field of research. Subsequent pharmaceutical drug development and testing can then be conducted to provide protection against deadly viruses and disease. This protein has also been linked as acting as a nitric oxide sensor and plays roles in transcriptional regulation of genes along with translational silencing <ref name="ref 3">PMID:20014444 </ref>. Although the exact mechanism of these roles are unknown at the moment it is believed that posttranslational modifications play a part in determining these other functions<ref name="ref 3"/>.
 == Structure & Function ==
@@ Line 28: / Line 28: @@
 ==Relations to Medicine==
 Strong structural analysis and in depth studies of parasitic protozoans has allowed the determination of conservation and differences between the parasite and human forms of GAPDH. ''Trypanosoma cruzi'', a protozoan parasite is responsible for causing Chagas' disease in approximately 16-18 million people from southern and central America<ref name="ref 7">PMID:9580189 </ref>. This parasite is responsible for causing up to 45,000 deaths per year and can cause severe complications such as neurological disorders and chronic cardiopathy<ref name="ref 7"/>. Although there are preexisting drugs on the market that do show some effectiveness, they are all known to cause severe side effects which defeats the purpose of their production. The role of Glyceraldehyde 3-Phosphate Dehydrogenase in this case is that it has been found that the bloodstream forms of the related protozoan ''T. brucei''are shown to lack a functional tricarboxylic acid cycle and thus its ultimate ATP source must come from glycolysis<ref name="ref 7"/>. It is this finding that has intrigued scientists to find solutions to the diseases caused by these protozoans. At the moment the most relevant target is the binding site of the adenosine ring of the NAD+ cofactor. It has been studied in great detail and its differences from the human form have been well recorded to allow the outcome of a possible solution<ref name="ref 7"/>. The NAD+ binding region is homologous in both ''T. brucei'' and ''T. cruzi'' and this site is therefore a suitable target for inhibitors that will provide a solution to Chagas' disease<ref name="ref 7"/>. This step will be advantageous because several adenosine analogues have already been designed and applied as selective and competitive inhibitors to trypanosomatid GAPDHs and have shown to stop the growth of ''T. brucei'' within the bloodstram<ref name="ref 8">PMID:11405646 </ref>.
 == References ==
 <references/>