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=Mevalonate Diphosphate Decarboxylase= | =Mevalonate Diphosphate Decarboxylase= | ||
<Structure load='2hk3' size='500' frame='true' align='right' caption='Fig 1 | <Structure load='2hk3' size='500' frame='true' align='right' caption='Fig 1 Mevalonate diphosphate decarboxylase in the homodimeric form' scene='Insert optional scene name here' /> | ||
==Introduction== | ==Introduction== | ||
:Mevalonate diphosphate decarboxylase (MDD) is an important enzyme required for the biosynthesis of cholesterol and other isoprenoids in mammals, bacteria, yeast and fungi <ref name = "Byres">PMID: 17583736 </ref>. MDD is a member of the GHMP (Galactokinase, Homoserine kinase, mevalonate kinase and phosphomevalonate kinase) enzyme family, and is responsible for the conversion of mevalonate diphosphate to isopentenyl pyrophosphate with the help of 1 ATP molecule<ref name = "Byres"/> <ref name = "Voynova"> PMID: 18823933 </ref>. Even though the kinases in the GHMP family differ in quaternary structure and ability to bind a wide variety of substrates, they share a characteristic alpha/beta fold and similar sequences <ref name = "Byres"/> <ref name = "ByresMartin"> PMID: 16511101 </ref>. Some GHMP kinases exist as dimers, some as tetramers and some as monomers <ref name = "Byres"/>. The amino acid residues in MDD are highly conserved across all species, indicating the specific important activity of the enzyme <ref name = "Byres"/>. | :Mevalonate diphosphate decarboxylase (MDD) is an important enzyme required for the biosynthesis of cholesterol and other isoprenoids in mammals, bacteria, yeast and fungi <ref name = "Byres">PMID: 17583736 </ref>. MDD is a member of the GHMP (Galactokinase, Homoserine kinase, mevalonate kinase and phosphomevalonate kinase) enzyme family, and is responsible for the conversion of mevalonate diphosphate to isopentenyl pyrophosphate with the help of 1 ATP molecule<ref name = "Byres"/> <ref name = "Voynova"> PMID: 18823933 </ref>. Even though the kinases in the GHMP family differ in quaternary structure and ability to bind a wide variety of substrates, they share a characteristic alpha/beta fold and similar sequences <ref name = "Byres"/> <ref name = "ByresMartin"> PMID: 16511101 </ref>. Some GHMP kinases exist as dimers, some as tetramers and some as monomers <ref name = "Byres"/>. The amino acid residues in MDD are highly conserved across all species, indicating the specific important activity of the enzyme <ref name = "Byres"/>. | ||
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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|center|frame|Fig. 2 | [[Image:Protopedia_figure.png|center|frame|Fig. 2 Showing the phosphorylation of mevalonate diphosphate, followed by dephosphorylation and decarboxylation of the unstable intermeditae, yielding isopentyl pyrophosphate, inorganic phosphate, carbon dioxide and ADP, all catalyzed by mevalonate diphosphate decarboxylase]] | ||
==Significance== | ==Significance== | ||
