Sandbox Reserved 333: Difference between revisions

From Proteopedia
Jump to navigationJump to search
← Older edit
No edit summary
Michal Harel (talk | contribs)
32,838 edits
No edit summary
 
(38 intermediate revisions by 2 users not shown)
Line 3: Line 3:
  <!-- PLEASE ADD YOUR CONTENT BELOW HERE -->
  <!-- PLEASE ADD YOUR CONTENT BELOW HERE -->
=Mevalonate Diphosphate Decarboxylase=
=Mevalonate Diphosphate Decarboxylase=
{{STRUCTURE_2hk3|PDB=2hk3|SCENE=}}
__TOC__
<Structure load='2hk3' size='400' frame='true' align='right' caption='Fig 1 Mevalonate diphosphate decarboxylase in the homodimeric form' scene='Insert optional scene name here' />
==Introduction==
:'''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"/>.


==Introduction==
See also [[Mevalonate pathway]]
: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"/>.
<scene name='Sandbox_Reserved_333/Fig2/1'>gggggg</scene>


==Structure==
==Structure==
:Mevalonate diphosphate decarboxylase exists as a symmetrical dimer<ref name = "Byres"/> <ref name = "Voynova"/> <ref name ="ByresMartin"/> . The C-terminal domains of each monomer are symmetrically oriented towards one another around a solvent-filled channel <ref name = "Byres"/>. The dimer is stabilized between alpha helices 6 and 10 on the monomers, and also through salt bridge interactions, tyrosine and proline stacking, and hydrophobic interactions <ref name = "Byres"/>. The interface between the monomers is very small, with only 7% of the total surface area of the monomer engaged in the interface interaction <ref name = "Voynova"/>. This small interface between monomers is a characteristic of GHMP kinases <ref name = "Voynova"/>. Each monomer consists of a single polypeptide chain with 331 amino acid residues. Each polypeptide chain has <scene name='Sandbox_Reserved_333/Mdd/3'>13 alpha helices and 15 beta sheets </scene>.<ref name = "RCSB"> Kabsch W., Sander C. "Sequence/Structure details of Crystal Structure of mevalonate diphosphate decarboxylase from Staphylococcus aureus" RCSB Protein Databank, http://www.rcsb.org/pdb/explore/remediatedSequence.do?structureId=2HK3 </ref>. The active site on each monomer is a deep, highly charged cleft made up seven segments of polypeptide chain, which is located away from the other monomer, and is unaffected by dimerization <ref name = "Byres"/>. An ATP binding polypeptide segment called the P loop is also located near the active site <ref name = "Byres"/>.  A total of 19 amino acid residue side chains are involved with substrate binding in the active site <ref name = "Byres"/>.
:Mevalonate diphosphate decarboxylase exists as a symmetrical dimer<ref name = "Byres"/> <ref name = "Voynova"/> <ref name ="ByresMartin"/> . The C-terminal domains of each monomer are symmetrically oriented towards one another around a solvent-filled channel <ref name = "Byres"/>. The dimer is stabilized between alpha helices 6 and 10 on each monomer, and also through salt bridge interactions, tyrosine stacking, proline stacking, and hydrophobic interactions <ref name = "Byres"/>. The interface between the monomers is very small, with only 7% of the total surface area of the monomer engaged in the interface interaction <ref name = "Voynova"/>. This small interface between monomers is a characteristic of GHMP kinases <ref name = "Voynova"/>. Each monomer consists of a single polypeptide chain with 331 amino acid residues <ref name = "RCSB"> PMID: 6667333  </ref>. Each polypeptide chain has <scene name='Sandbox_Reserved_333/Alpha_helices/1'> 13 alpha helices </scene> and <scene name='Sandbox_Reserved_333/Beta_sheets/1'> 15 beta sheets </scene> <ref name ="RCSB"/>. The active site on each monomer is a deep, highly charged cleft made up seven segments of polypeptide chain <ref name = "Byres"/> . The active sites are located away from the solvent filled channel, and they are unaffected by dimerization <ref name = "Byres"/>. The amino acid residues Tyr19, Trp20, Trp158 and Met203 form a <scene name='Sandbox_Reserved_333/Hydrophobic_surfaces/1'>Hydrophobic surface</scene> that is important in the active site for helping to orient the mevalonate diphosphate properly <ref name = "Byres"/>. One important animo acid in the active site is Tyrosine 19 (Fig 2) because it is strategically placed to interact with the terminal phosphate group of mevalonate diphosphate when it is bound in the active site <ref name = "Byres"/>. An ATP binding polypeptide segment called the P loop is also located near the active site <ref name = "Byres"/>.  A total of 19 amino acid residue side chains are involved with substrate binding in the active site <ref name = "Byres"/>.
 
[[Image:Tyrosine.png|thumb|left| Fig 2 Tyrosine 19 in the active site of mevalonate diphosphate decarboxylase.]]
 


==Reaction==
==Reaction==
: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 (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.
 
[[Image:Protopedia_figures.png|center|frame|Fig. 3 Showing the phosphorylation of mevalonate diphosphate, followed by dephosphorylation and decarboxylation of the unstable intermediate, yielding isopentyl pyrophosphate, inorganic phosphate, carbon dioxide and ADP, all catalyzed by mevalonate diphosphate decarboxylase]]
 


[[Image:Protopedia_figure.png]]
: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 is transmitted to the human bloodstream through the bite of the tsetse fly, that causes [http://en.wikipedia.org/wiki/African_trypanosomiasis African Sleeping sickness] <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 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"/>.
 
 


==References==
==References==
<references/>
<references/>
Retrieved from "https://proteopedia.org/Sandbox_Reserved_333"