Sandbox Reserved 333: Difference between revisions

:'''Mevalonate diphosphate decarboxylase''' (MDD) is an important enzyme required by every cell for the biosynthesis of cholesterol and other isoprenoids in mammals, bacteria, yeast and fungi <ref name = "Byres">PMID: 17583736 </ref> <ref name =  "Text" > Nelson, D.L. and Cox, M.M. 2008. Lehninger Principles of Biochemistry, Fifth ed. W.H. Freeman and Company. pp 831 </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 (IPP) 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"/>.

:The mevalonate pathway encompasses 3 different enzymes that convert mevalonate to isopentenyl pyrophosphate (IPP), 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 3) <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 3)<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 3) <ref name = "Byres"/> <ref name = "Voynova"/>. The IPP molecules can react together to make cholesterol or other isoprenoids.

: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 isoprenoid biosynthesis decreases <ref name = "Krepkiy"/>, which can be detrimental to many organisms that rely on the formation of IPP for cholesterol, electron transport, membrane structures, membrane anchors, and signaling pathways <ref name = "ByresMartin"/>.  One such organism that requires MDD is Trypanosoma bruceii, a parasite that causes [http://en.wikipedia.org/wiki/African_trypanosomiasis African Sleeping sickness] after being transmitted to the human bloodstream through the bite of a 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"/>.