diphosphomevalonate decarboxylase | |||||||||
---|---|---|---|---|---|---|---|---|---|
Identifiers | |||||||||
EC no. | 4.1.1.33 | ||||||||
CAS no. | 9024-66-2 | ||||||||
Databases | |||||||||
IntEnz | IntEnz view | ||||||||
BRENDA | BRENDA entry | ||||||||
ExPASy | NiceZyme view | ||||||||
KEGG | KEGG entry | ||||||||
MetaCyc | metabolic pathway | ||||||||
PRIAM | profile | ||||||||
PDB structures | RCSB PDB PDBe PDBsum | ||||||||
Gene Ontology | AmiGO / QuickGO | ||||||||
|
Diphosphomevalonate decarboxylase (EC 4.1.1.33), most commonly referred to in scientific literature as mevalonate diphosphate decarboxylase[citation needed], is an enzyme that catalyzes the chemical reaction
- ATP + (R)-5-diphosphomevalonate ADP + phosphate + isopentenyl diphosphate + CO2
This enzyme converts mevalonate 5-diphosphate (MVAPP) to isopentenyl diphosphate (IPP) through ATP dependent decarboxylation.[1] The two substrates of this enzyme are ATP and mevalonate 5-diphosphate, whereas its 4 products are ADP, phosphate, isopentenyl diphosphate, and CO2.
Mevalonate diphosphate decarboxylase catalyzes the final step in the mevalonate pathway. The mevalonate pathway is responsible for the biosynthesis of isoprenoids from acetate.[2] This pathway plays a key role in multiple cellular processes by synthesizing sterol isoprenoids, such as cholesterol, and non-sterol isoprenoids, such as dolichol, heme A, tRNA isopentenyltransferase, and ubiquinone.[3][4]
This enzyme belongs to the family of lyases, specifically the carboxy-lyases, which cleave carbon-carbon bonds. The systematic name of this enzyme class is ATP:(R)-5-diphosphomevalonate carboxy-lyase (adding ATP isopentenyl-diphosphate-forming). Other names in common use include pyrophosphomevalonate decarboxylase, mevalonate-5-pyrophosphate decarboxylase, pyrophosphomevalonic acid decarboxylase, 5-pyrophosphomevalonate decarboxylase, mevalonate 5-diphosphate decarboxylase, and ATP:(R)-5-diphosphomevalonate carboxy-lyase (dehydrating).
YouTube Encyclopedic
-
1/5Views:24 5503652 775 38445 105120 664
-
Decarboxylation
-
Decarboxylation Mechanism
-
ATP & Respiration: Crash Course Biology #7
-
Organic chemistry: Amino acids and peptides (1)
-
Overview of Amino Acid Metabolism
Transcription
Voiceover: Here's the dot structure for propanedioic acid, or malonic acid and if you heat it up it's going to undergo a decarboxylation reaction, so if we show free rotation about this bond, and it's a sigma bond, so we can show a different confirmation. Let me go ahead and draw in this carboxylic acid on the left, and then we're going to have our carboxylic acid on the right too, this time the carbonyl is going to be going to the right, so let me go ahead and put in those electrons, and the OH will be going to the left, so there we have it. So in this mechanism we're actually going to form a bond between this oxygen and this proton, and it's a cyclic mechanism, so if these electrons in here move in to here that's going to push these electrons in to here, and then these electrons are going to form the bond between the oxygen and the hydrogen, so let's go ahead and show the result of our cyclic mechanism. We would have a carbon bonded to an oxygen, bonded to hydrogen and then we have an OH over here, and then we'd have a double bond between this carbon and another carbon, on the right we could actually form CO2. So let me go ahead and put in lone pairs of electrons on that oxygen so we can see that we would form our carbon dioxide molecule here. So let me go ahead and draw those in. And let's follow some of those electrons, so the electrons in magenta, right in here, are going to move in to form this bond, to form our double bond for CO2. And then these electrons in here in blue, so between this carbon and this carbon are going to move over here to form this double bond between this carbon, and then there's a carbon right here, and then there's also two hydrogens bonded to this carbon. Let me go ahead and draw those in so we can see it a little bit better. And then finally, I want to make these electrons in here red, so these electrons are the ones that are going to form this bond between the oxygen and the hydrogen, so that we formed our CO2 and we've also formed an acid enol. So this right here is called an "acid enol". And we saw in earlier videos how the enol is in equilibrium with the keto form, with keto–enol tautomerization. And so this is actually the enol form of acetic acid, and so that's actually going to be our product. So let me go ahead and draw acetic acid up here, and here we have the OH on the left side, and then we would have our carbon over here with three hydrogens bonded to it, so this would be if we're thinking about the keto-type form. So the difference between the enol and the keto form are the movement of one proton, so there's a proton here and the oxygen in here, it's one of these on the carbon, and then the double bond. Here we have the double bond between the two carbons, and here we've moved the double bond between the carbon and the oxygen. So once again, we've seen how to do that in earlier videos. And then we also produce CO2, so carbon dioxide as the other product for this reaction. So the key to a decarboxylation reaction is having a cabonyl beta to a carboxylic acid. So, for example, here's our carboxylic acid, and we know the carbon next to a carboxylic acid is the alpha carbon, and the carbon next to that is the beta carbon, and we saw how this carbonyl was necessary in the mechanism. And so the fact that there's an OH here isn't really necessary, and what we really need is a cardonyl that's beta to our carboxylic acid in order for a decarboxylation reaction to occur. So let's look at another example where we don't have a dioic acid anymore, we have a carboxylic acid on the right and then over here on the left we have a ketone. But again the key point is here's the alpha carbon and here's the beta carbon, we have a carbonyl that's beta to our carboxylic acid, and so therefore a decarboxylation reaction can take place. So if we heat up this molecule, once again thinking about the mechanism rotating about that single bond. Let's go ahead and redraw this. So we have our benzene ring, and then we have our carbonyl right here, and then we would have once again our carbonyl going off to the right this time, and then our OH over here on the left. So thinking about our mechanism once again, we know it's a cyclic mechanism, we know this oxygen is going to bond to this proton, and so these electrons are going to move in to here, and these electrons move in to here, and these electrons move in to here, so that's our cyclic mechanism and we draw what happens, moving all those electrons around, we have our benzene ring, we would have it bonded to an oxygen, this oxygen was bonded to this proton now, and we have a double bond right in here, and then we also form CO2. So once again let's run through those electrons and try to follow some of those electrons here, so let me draw in these lone pairs of electrons on our oxygens so we can see where the CO2 comes from. So once again, these electrons in here in magenta are going to move in here to form the double bond on CO2. At the same time these electrons in here are going to move in to here to form this double bond, and then finally these electrons in here are going to move out to form the bond between the oxygen and the hydrogen so we've made our CO2. So the oxygen-carbon-oxygen comes from this oxygen-carbon-oxygen right here on the molecule on the left, so hopefully that's a little bit easier to see now. And once again we have an enol, so we form our CO2, we also create our enol, and so we can think about keto-enol tautomerization for our product, so the enol is going to be in equilibrium with the keto form. So let's go ahead and draw the keto form, which we know is moving one proton and moving the double bond. So we move the double bond between the carbon and the oxygen and we move that proton to this carbon right here, so this carbon right here picks up a proton. So down here that carbon had two hyrdogens, and it doesn't have to be this one right here, but we are going to add a hydrogen to that carbon and that gives us our final product, our ketone. So this decarboxylation reaction produces a ketone, and once again it doesn't really matter what this R group is here, here we have a benzene ring instead of the OH in the previous example. And then of course we're also going to make CO2. So decarboxylation reactions are going to be important in future videos where we're synthesizing some complicated molecules, and so this is the cyclic mechanism for it.
Enzyme mechanism
Mevalonate diphosphate decarboxylase recognizes and binds two substrates: ATP and mevalonate 5-diphosphate. After binding, the enzyme performs three types of reactions that can be separated into two main stages. First, phosphorylation occurs. This creates a reactive intermediate, which in the second stage undergoes concerted dephosphorylation and decarboxylation.[5] Many enzyme residues in the active site play important roles in this concerted mechanism. An aspartic acid residue deprotonates the C3 hydroxyl on MVAPP and facilitates the oxygen to attack a phosphate from ATP. As a result, intermediate 1, 3-phosphoMVAPP, now has a much better leaving group, which helps to produce intermediate 2.[1] This third intermediate is a transient beta carboxy carbonium intermediate and provides an "electron sink" that helps drives the decarboxylation reaction.[1]
Enzyme structure
The exact enzyme apparatus of mevalonate diphosphate decarboxylase is not completely understood. Structures of both the yeast and human mevalonate diphosphate decarboxylase have been solved with X-ray crystallography, but scientists have experienced difficulties in obtaining structures of bound metabolites. Scientists have classified mevalonate diphosphate decarboxylase as an enzyme in the GHMP kinase family (galactokinase, homoserine kinase, mevalonate kinase, and phosphomevalonate kinase).[6] Both mevalonate kinase and mevalonate diphosphate decarboxylase probably evolved from a common ancestor since they have a similar fold and catalyze phosphorylation of similar substrates.[6][7] Due to these commonalities, both enzymes are often studied comparatively, and especially in reference to inhibitors.
Though there is limited information, some important residues have been identified and are highlighted in the active site structure and mechanism. Due to the difficulty of obtaining crystal structures of bound substrates, a sulfate ion and water molecules were used to better understand the residues role in substrate binding.[8]
When investigating the human form of mevalonate diphosphate decarboxylase, the following specific residues were identified: arginine-161 (Arg-161), serine-127 (Ser-127), aspartate-305 (Asp-305), and asparagine-17 (Asn-17).[1] Arg-161 interacts with the C1 carbonyl of MVAPP, and Asn-17 is important for hydrogen bonding with this same arginine residue.[1] Asp-305 is positioned about 4 Å from the C3 hydroxyl on MVAPP and acts as a general base catalyst in the active site.[1] Ser-127 aids in orientation of the phosphoryl chain for the phosphate transfer to MVAPP.[1] Mevalonate diphosphate decarboxylase also has a phosphate-binding loop (‘P-loop’) where amino acid residues provide key interactions that stabilize the nucleotide triphosphoryl moiety.[9] The residues from the P-loop are conserved across enzymes in the GHMP kinase family and include Ala-105, Ser-106, Ser-107 and Ala-108.[9]
Biological function
Many different organisms utilize the mevalonate pathway and mevalonate diphosphate decarboxylase, but for different purposes.[9] In gram positive bacteria, isopentenyl diphosphate, the end product of mevalonate diphosphate decarboxylase, is an essential intermediate in peptidoglycan and polyisoprenoid biosynethesis.[9] Therefore, targeting the mevalonate pathway, and mevalonate diphosphate decarboxylase, could be a potential antimicrobial drug.[9]
The mevalonate pathway is also used in higher order eukaryotes and plants. Mevalonate diphosphate decarboxylase is mainly present in the liver of mammals where the majority of mevalonate is converted to cholesterol.[10][11] Some of the cholesterol is converted to steroid hormones, bile acids, and vitamin D.[10] Mevalonate is also converted into many other important intermediates in mammalian cells: dolichols (carriers in the assembly of carbohydrate chains in glycoproteins), ubiquinones (important for electron transport), tRNA isopentenyltransferase (used in protein synthesis), and franesylated and geranylgeranylated proteins (membrane associated proteins that appear to be involved in intracellular signaling).[10] The main point of regulation in cholesterol and nonsterol isoprene biosynethsis is HMGCoA reductase, the third enzyme in the mevalonate pathway.[10]
Disease relevance
Coronary artery disease is the leading cause of death in the US general population.[12] Hypercholesterolemia or high cholesterol is considered a major risk factor in coronary artery disease.[13] Therefore, major efforts are focused toward understanding regulation and developing inhibitors of cholesterol biosynthesis.[13] Mevalonate diphosphate decarboxylase is a potential enzyme to be targeted in the cholesterol synthesis pathway. Scientists discovered a molecule, 6-fluoromevalonate (6-FMVA), to be a strong competitive inhibitor of mevalonate diphosphate decarboxylase.[13] The addition of 6-FMVA results in a decrease in cholesterol levels.[13]
Spontaneously hypertensive rats (stroke-prone) (SHRSP) are affected by severe hypertension and cerebral hemorrhage.[14] Scientists have found a low serum cholesterol level in rats with this condition.[14] In SHRSP, mevalonate diphosphate decarboxylase has a much lower activity while HMG-CoA reductase remains unchanged; therefore, mevalonate diphosphate decarboxylase may be responsible for the lower cholesterol biosynthesis in this condition.[14][15] In humans, it is hypothesized that cholesterol deficiency may make the plasma membranes fragile and, as a result, induce angionecrosis in the brain. Reduced serum cholesterol, resulting from a low activity of mevalonate diphosphate decarboxylase, may be the cause of cerebral hemorrhage in some cases.[14]
Structural studies
As of 2015, at least 15 structures have been solved for this class of enzymes, including PDB accession codes 1FI4, 2HK2, 2HK3, and 2HKE.
References
- ^ a b c d e f g h i j Voynova, NE; Fu, Z; Battaile, KP; Herdendorf, TJ; Kim, JJ; Miziorko, HM (1 December 2008). "Human mevalonate diphosphate decarboxylase: characterization, investigation of the mevalonate diphosphate binding site, and crystal structure". Archives of Biochemistry and Biophysics. 480 (1): 58–67. doi:10.1016/j.abb.2008.08.024. PMC 2709241. PMID 18823933.
- ^ Miziorko, HM (15 January 2011). "Enzymes of the mevalonate pathway of isoprenoid biosynthesis". Archives of Biochemistry and Biophysics. 505 (2): 131–43. doi:10.1016/j.abb.2010.09.028. PMC 3026612. PMID 20932952.
- ^ Buhaescu, I; Izzedine, H (June 2007). "Mevalonate pathway: a review of clinical and therapeutical implications". Clinical Biochemistry. 40 (9–10): 575–84. doi:10.1016/j.clinbiochem.2007.03.016. PMID 17467679.
- ^ Miziorko, HM (15 January 2011). "Enzymes of the mevalonate pathway of isoprenoid biosynthesis". Archives of Biochemistry and Biophysics. 505 (2): 131–43. doi:10.1016/j.abb.2010.09.028. PMC 3026612. PMID 20932952.
- ^ Byres, E; Alphey, MS; Smith, TK; Hunter, WN (10 August 2007). "Crystal structures of Trypanosoma brucei and Staphylococcus aureus mevalonate diphosphate decarboxylase inform on the determinants of specificity and reactivity". Journal of Molecular Biology. 371 (2): 540–53. doi:10.1016/j.jmb.2007.05.094. PMID 17583736.
- ^ a b Qiu, Yongge; Gao, Jinbo; Guo, Fei; Qiao, Yuqin; Li, Ding (November 2007). "Mutation and inhibition studies of mevalonate 5-diphosphate decarboxylase". Bioorganic & Medicinal Chemistry Letters. 17 (22): 6164–6168. doi:10.1016/j.bmcl.2007.09.033. PMID 17888661.
- ^ Qiu, Yongge; Li, Ding (July 2006). "Inhibition of mevalonate 5-diphosphate decarboxylase by fluorinated substrate analogs". Biochimica et Biophysica Acta (BBA) - General Subjects. 1760 (7): 1080–1087. doi:10.1016/j.bbagen.2006.03.009. PMID 16626865.
- ^ Krepkiy, Dmitriy; Miziorko, Henry M. (July 2004). "Identification of active site residues in mevalonate diphosphate decarboxylase: Implications for a family of phosphotransferases". Protein Science. 13 (7): 1875–1881. doi:10.1110/ps.04725204. PMC 2279928. PMID 15169949.
- ^ a b c d e Barta, Michael L.; McWhorter, William J.; Miziorko, Henry M.; Geisbrecht, Brian V. (17 July 2012). "Structural Basis for Nucleotide Binding and Reaction Catalysis in Mevalonate Diphosphate Decarboxylase". Biochemistry. 51 (28): 5611–5621. doi:10.1021/bi300591x. PMC 4227304. PMID 22734632.
- ^ a b c d Hinson, DD; Chambliss, KL; Toth, MJ; Tanaka, RD; Gibson, KM (November 1997). "Post-translational regulation of mevalonate kinase by intermediates of the cholesterol and nonsterol isoprene biosynthetic pathways". Journal of Lipid Research. 38 (11): 2216–23. doi:10.1016/S0022-2275(20)34935-X. PMID 9392419.
- ^ Michihara, A; Akasaki, K; Yamori, Y; Tsuji, H (November 2001). "Tissue distribution of a major mevalonate pyrophosphate decarboxylase in rats". Biological & Pharmaceutical Bulletin. 24 (11): 1231–4. doi:10.1248/bpb.24.1231. PMID 11725954.
- ^ McCullough, P. A. (11 April 2007). "Coronary Artery Disease". Clinical Journal of the American Society of Nephrology. 2 (3): 611–616. doi:10.2215/CJN.03871106. PMID 17699471.
- ^ a b c d Sawamura, M; Nara, Y; Yamori, Y (25 March 1992). "Liver mevalonate 5-pyrophosphate decarboxylase is responsible for reduced serum cholesterol in stroke-prone spontaneously hypertensive rat". The Journal of Biological Chemistry. 267 (9): 6051–5. doi:10.1016/S0021-9258(18)42660-9. PMID 1556116.
- ^ Krepkiy, D; Miziorko, HM (July 2004). "Identification of active site residues in mevalonate diphosphate decarboxylase: implications for a family of phosphotransferases". Protein Science. 13 (7): 1875–81. doi:10.1110/ps.04725204. PMC 2279928. PMID 15169949.
- Bloch K, Chaykin S, Phillips AH, de Waard A (1959). "Mevalonic acid pyrophosphate and isopentenyl pyrophosphate". J. Biol. Chem. 234 (10): 2595–2604. doi:10.1016/S0021-9258(18)69744-3. PMID 13801508.