Sandbox 160: Difference between revisions

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The inorganic phosphate (Pi) that is involved in the reaction functions to attack by phosphorolysis the thioester intermediate that is formed by the substrate on the cysteine reside after NAD+ has been reduced <ref name="reference 1"/>. The attack by Pi on the carbonyl carbon of C1 is simultaneously followed by the replacement of bound NADH for NAD+ so another turn of the cycle can now commence. The final product is released as 1,3 bisphosphoglycerate in which the second Pi molecule has been incorporated.

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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>.

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 bloodstream<ref name="ref 8">PMID:11405646 </ref>.

Research relating oxidative stress to GAPDH has also been conducted and shows very promising results. Nitration of tyrosine residues is a sign that oxidative stress is occuring, and nitration of tyrosine has been known to be linked to neurodegenerative disorders and cancer<ref name="ref 3"/>. It has been documented that nitration of the cysteine (Cys149) residue within the active site of the GAPDH enzyme is responsible for causing loss of enzymatic activity<ref name="ref 3"/>. This loss of enzymatic activity is due to the nitration of two tyrosine residues (Tyr311 and Tyr317) which are in close proximity to the active site cysteine. The ultimate result of this nitration is that it causes the loss of affinity for NAD+ and therefore a loss of NAD+ binding<ref name="ref 3"/>.

Research relating oxidative stress to GAPDH has also been conducted and shows very promising results. Nitration of tyrosine residues is a sign that oxidative stress is occuring, and nitration of tyrosine has been known to be linked to neurodegenerative disorders and cancer<ref name="ref 3"/>. It has been documented that nitration of the cysteine (Cys149) residue within the active site of the GAPDH enzyme is responsible for causing loss of enzymatic activity<ref name="ref 3"/>. This loss of enzymatic activity is due to the nitration of two tyrosine residues (Tyr311 and Tyr317) which are in close proximity to the active site cysteine. The ultimate result of this nitration is that it causes the loss of affinity for NAD+ and therefore a loss of NAD+ binding<ref name="ref 3"/>. Other studies have shown that GAPDH is involved in the death of neuron cells as a result of oxidative stress, and that GAPDH is found to be deposited in protein aggregates containing disulfide bonds<ref name="ref 9">PMID:17613523 </ref>. Oxidative stress causes the oligomerization of proteins such as GAPDH which result from the formation of intramolecular disulfide bonds. The accumulation of GAPDH as insoluble aggregates has been linked to diseases such as Alzheimer's disease and Parkinson's disease, as insoluble aggregates have indeed been found in both<ref name="ref 9" </ref>. Implications of this and other relating studies of GAPDH aggregation due to oxidative stress, can be utilized by experimentation and efficient research in producing possible solutions that can aid in the prevention of diseases such as the ones listed.

== References ==

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 The inorganic phosphate (Pi) that is involved in the reaction functions to attack by phosphorolysis the thioester intermediate that is formed by the substrate on the cysteine reside after NAD+ has been reduced <ref name="reference 1"/>. The attack by Pi on the carbonyl carbon of C1 is simultaneously followed by the replacement of bound NADH for NAD+ so another turn of the cycle can now commence. The final product is released as 1,3 bisphosphoglycerate in which the second Pi molecule has been incorporated.
@@ Line 27: / Line 25: @@
 ==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>.
+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 bloodstream<ref name="ref 8">PMID:11405646 </ref>.
-Research relating oxidative stress to GAPDH has also been conducted and shows very promising results. Nitration of tyrosine residues is a sign that oxidative stress is occuring, and nitration of tyrosine has been known to be linked to neurodegenerative disorders and cancer<ref name="ref 3"/>. It has been documented that nitration of the cysteine (Cys149) residue within the active site of the GAPDH enzyme is responsible for causing loss of enzymatic activity<ref name="ref 3"/>. This loss of enzymatic activity is due to the nitration of two tyrosine residues (Tyr311 and Tyr317) which are in close proximity to the active site cysteine. The ultimate result of this nitration is that it causes the loss of affinity for NAD+ and therefore a loss of NAD+ binding<ref name="ref 3"/>.
+Research relating oxidative stress to GAPDH has also been conducted and shows very promising results. Nitration of tyrosine residues is a sign that oxidative stress is occuring, and nitration of tyrosine has been known to be linked to neurodegenerative disorders and cancer<ref name="ref 3"/>. It has been documented that nitration of the cysteine (Cys149) residue within the active site of the GAPDH enzyme is responsible for causing loss of enzymatic activity<ref name="ref 3"/>. This loss of enzymatic activity is due to the nitration of two tyrosine residues (Tyr311 and Tyr317) which are in close proximity to the active site cysteine. The ultimate result of this nitration is that it causes the loss of affinity for NAD+ and therefore a loss of NAD+ binding<ref name="ref 3"/>. Other studies have shown that GAPDH is involved in the death of neuron cells as a result of oxidative stress, and that GAPDH is found to be deposited in protein aggregates containing disulfide bonds<ref name="ref 9">PMID:17613523 </ref>. Oxidative stress causes the oligomerization of proteins such as GAPDH which result from the formation of intramolecular disulfide bonds. The accumulation of GAPDH as insoluble aggregates has been linked to diseases such as Alzheimer's disease and Parkinson's disease, as insoluble aggregates have indeed been found in both<ref name="ref 9" </ref>. Implications of this and other relating studies of GAPDH aggregation due to oxidative stress, can be utilized by experimentation and efficient research in producing possible solutions that can aid in the prevention of diseases such as the ones listed.
 == References ==
 <references/>