Sandbox Reserved 333: Difference between revisions
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:The mevalonate pathway encompasses 3 different enzymes that convert mevalonate to isopentenyl pyrophosphate, which is an important building block for all isoprenoids <ref name = "Andreassi"> PMID: 19485344 </ref>. Mevalonate diphosphate decarboxylase is the last enzyme in this pathway, and it converts mevalonate diphosphate to IPP (Fig 2) <ref name = "Andreassi"/>. The conversion of mevalonate diphosphate to isopentenyl pyrophosphate is a two-stage reaction <ref name = "Byres"/>. First, MDD binds an ATP molecule to the P loop near the active site, and the mevalonate diphosphate in the active site <ref name = "Byres"/>. Specifically, the Asp293 residue in the active site of MDD abstracts a proton from the C3 hydroxyl group of mevalonate diphosphate, creating a nucleophile that attacks the γ-phosphoryl group of ATP <ref name = "Byres"/>. The phosphorylation of the C3 carbon creates an unstable intermediate and a good leaving group on C3 (Fig 2)<ref name = "Byres"/>. The second stage of the reaction is when MDD dephosphorylates and decarboxylates the substrate, releasing isopentenyl pyrophosphate, inorganic phosphate, ADP and a CO2 molecule (Fig 2) <ref name = "Byres"/><ref name = "Voynova"/>. The IPP molecules can be joined together to make cholesterol or other isoprenoids. | :The mevalonate pathway encompasses 3 different enzymes that convert mevalonate to isopentenyl pyrophosphate, which is an important building block for all isoprenoids <ref name = "Andreassi"> PMID: 19485344 </ref>. Mevalonate diphosphate decarboxylase is the last enzyme in this pathway, and it converts mevalonate diphosphate to IPP (Fig 2) <ref name = "Andreassi"/>. The conversion of mevalonate diphosphate to isopentenyl pyrophosphate is a two-stage reaction <ref name = "Byres"/>. First, MDD binds an ATP molecule to the P loop near the active site, and the mevalonate diphosphate in the active site <ref name = "Byres"/>. Specifically, the Asp293 residue in the active site of MDD abstracts a proton from the C3 hydroxyl group of mevalonate diphosphate, creating a nucleophile that attacks the γ-phosphoryl group of ATP <ref name = "Byres"/>. The phosphorylation of the C3 carbon creates an unstable intermediate and a good leaving group on C3 (Fig 2)<ref name = "Byres"/>. The second stage of the reaction is when MDD dephosphorylates and decarboxylates the substrate, releasing isopentenyl pyrophosphate, inorganic phosphate, ADP and a CO2 molecule (Fig 2) <ref name = "Byres"/><ref name = "Voynova"/>. The IPP molecules can be joined together to make cholesterol or other isoprenoids. | ||
[[Image:Protopedia_figure.png | [[Image:Protopedia_figure.png|center|frame|Fig. 2 Phosphorylation of mevalonate diphosphate, followed by dephosphorylation and decarboxylation of the unstable intermeditae, yeilding isopentyl pyrophosphate, inorganic phosphate, carbon dioxide and ADP,catalyzed by mevalonate diphosphate decarboxylase]] | ||
==Significance== | ==Significance== | ||
:Mevalonate diphosphate decarboxylase is a necessary enzyme in the cholesterol and isoprenoid biosynthesis pathway <ref name = "Byres"/><ref name = "Krepkiy"> PMID: 15169949 </ref> <ref name = "Voynova"/> <ref name = "ByresMartin"/>. Without this enzyme, the cholesterol synthesis production decreases <ref name = "Krepkiy"/>, which can be detrimental to many organisms that rely on the formation of IPP for cholesterol, electron transport, membrane structures and anchors, and signaling pathways <ref name = "ByresMartin"/>. One such organism that requires MDD is the Trypanosoma bruceii, a parasite that causes [http://en.wikipedia.org/wiki/African_trypanosomiasis African Sleeping sickness] and is transmitted to the human bloodstream through the bite of the tsetse fly <ref name = "ByresMartin"/>. MDD was thought to be a potential target enzyme for an inhibitor that would disable the catalytic activity of MDD, thereby stopping IPP production and effectively killing the parasite <ref name = "ByresMartin"/>. It is believed now that the MDD found in Trypanosoma bruceii resembles human MDD too closely, and so it would be difficult to make a species specific inhibitor for MDD <ref name = "Byres"/>. | :Mevalonate diphosphate decarboxylase is a necessary enzyme in the cholesterol and isoprenoid biosynthesis pathway <ref name = "Byres"/> <ref name ="Krepkiy"> PMID: 15169949 </ref> <ref name = "Voynova"/> <ref name = "ByresMartin"/>. Without this enzyme, the cholesterol synthesis production decreases <ref name = "Krepkiy"/>, which can be detrimental to many organisms that rely on the formation of IPP for cholesterol, electron transport, membrane structures and anchors, and signaling pathways <ref name = "ByresMartin"/>. One such organism that requires MDD is the Trypanosoma bruceii, a parasite that causes [http://en.wikipedia.org/wiki/African_trypanosomiasis African Sleeping sickness] and is transmitted to the human bloodstream through the bite of the tsetse fly <ref name = "ByresMartin"/>. MDD was thought to be a potential target enzyme for an inhibitor that would disable the catalytic activity of MDD, thereby stopping IPP production and effectively killing the parasite <ref name = "ByresMartin"/>. It is believed now that the MDD found in Trypanosoma bruceii resembles human MDD too closely, and so it would be difficult to make a species specific inhibitor for MDD <ref name = "Byres"/>. | ||
{{STRUCTURE_2hk3|PDB=2hk3|SCENE=}} | {{STRUCTURE_2hk3|PDB=2hk3|SCENE=}} | ||
==References== <references/> | ==References== | ||
<references/> | |||
