Diphosphomevalonate decarboxylase

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diphosphomevalonate decarboxylase
Overall reaction catalyzed by mevalonate diphosphate decarboxylase.jpg
ATP dependent decarboxylation catalyzed by mevalonate diphosphate decarboxylase [1]
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
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PMC articles
PubMed articles
NCBI proteins
Mevalonate (diphospho) decarboxylase
Identifiers
SymbolMVD
NCBI gene 4597
HGNC 7529
OMIM 603236
RefSeq NM_002461
UniProt P53602
Other data
EC number 4.1.1.33
Locus Chr. 16 q24.3
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Structures Swiss-model
Domains InterPro

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

Contents

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).

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]

Proposed mechanism for human mevalonate diphosphate decarboxylase. Amino acid residues colored to correspond to crystal structure image of active site residues. ATP is brown to show phosphoryl transfer. Mechanism for Mevalonate Diphosphate Decarboxylase.jpg
Proposed mechanism for human mevalonate diphosphate decarboxylase. Amino acid residues colored to correspond to crystal structure image of active site residues. ATP is brown to show phosphoryl transfer.

Enzyme structure

Crystal structure of the active cite of human mevalonate diphosphate decarboxylase, generated from 3D4J. Proposed important residues for mechanism and substrate binding are highlighted: Arg-161 (green), Ser-127 (blue), Asp-305 (orange), and Asn-17 (red). Sulfate ion aided in better understanding the substrate binding. Mevalonate diphosphate is proposed to be positioned so the terminal phosphate is near the sulfate ion in the crystal structure. Important residues of active site of mevalonate diphosphate decarboxylase.png
Crystal structure of the active cite of human mevalonate diphosphate decarboxylase, generated from 3D4J. Proposed important residues for mechanism and substrate binding are highlighted: Arg-161 (green), Ser-127 (blue), Asp-305 (orange), and Asn-17 (red). Sulfate ion aided in better understanding the substrate binding. Mevalonate diphosphate is proposed to be positioned so the terminal phosphate is near the sulfate ion in the crystal 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]

Mevalonate pathway Mevalonate pathway.png
Mevalonate pathway

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.

Related Research Articles

Juvenile hormones (JHs) are a group of acyclic sesquiterpenoids that regulate many aspects of insect physiology. The first discovery of a JH was by Vincent Wigglesworth. JHs regulate development, reproduction, diapause, and polyphenisms. The chemical formula for juvenile hormone is .

<span class="mw-page-title-main">Mevalonate pathway</span>

The mevalonate pathway, also known as the isoprenoid pathway or HMG-CoA reductase pathway is an essential metabolic pathway present in eukaryotes, archaea, and some bacteria. The pathway produces two five-carbon building blocks called isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP), which are used to make isoprenoids, a diverse class of over 30,000 biomolecules such as cholesterol, vitamin K, coenzyme Q10, and all steroid hormones.

<span class="mw-page-title-main">Pyridoxal phosphate</span> Active form of vitamin B6

Pyridoxal phosphate (PLP, pyridoxal 5'-phosphate, P5P), the active form of vitamin B6, is a coenzyme in a variety of enzymatic reactions. The International Union of Biochemistry and Molecular Biology has catalogued more than 140 PLP-dependent activities, corresponding to ~4% of all classified activities. The versatility of PLP arises from its ability to covalently bind the substrate, and then to act as an electrophilic catalyst, thereby stabilizing different types of carbanionic reaction intermediates.

<span class="mw-page-title-main">Prenylation</span> Addition of hydrophobic moieties to proteins or other biomolecules

Prenylation is the addition of hydrophobic molecules to a protein or a biomolecule. It is usually assumed that prenyl groups (3-methylbut-2-en-1-yl) facilitate attachment to cell membranes, similar to lipid anchors like the GPI anchor, though direct evidence of this has not been observed. Prenyl groups have been shown to be important for protein–protein binding through specialized prenyl-binding domains.

Dolichol refers to any of a group of long-chain mostly unsaturated organic compounds that are made up of varying numbers of isoprene units terminating in an α-saturated isoprenoid group, containing an alcohol functional group.

In molecular biology, biosynthesis is a multi-step, enzyme-catalyzed process where substrates are converted into more complex products in living organisms. In biosynthesis, simple compounds are modified, converted into other compounds, or joined to form macromolecules. This process often consists of metabolic pathways. Some of these biosynthetic pathways are located within a single cellular organelle, while others involve enzymes that are located within multiple cellular organelles. Examples of these biosynthetic pathways include the production of lipid membrane components and nucleotides. Biosynthesis is usually synonymous with anabolism.

<span class="mw-page-title-main">Dimethylallyl pyrophosphate</span> Chemical compound

Dimethylallyl pyrophosphate is an isoprenoid precursor. It is a product of both the mevalonate pathway and the MEP pathway of isoprenoid precursor biosynthesis. It is an isomer of isopentenyl pyrophosphate (IPP) and exists in virtually all life forms. The enzyme isopentenyl pyrophosphate isomerase catalyzes isomerization between DMAPP and IPP.

<span class="mw-page-title-main">Isopentenyl pyrophosphate</span> Chemical compound

Isopentenyl pyrophosphate is an isoprenoid precursor. IPP is an intermediate in the classical, HMG-CoA reductase pathway and in the non-mevalonate MEP pathway of isoprenoid precursor biosynthesis. Isoprenoid precursors such as IPP, and its isomer DMAPP, are used by organisms in the biosynthesis of terpenes and terpenoids.

(<i>E</i>)-4-Hydroxy-3-methyl-but-2-enyl pyrophosphate Chemical compound

(E)-4-Hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP or HMB-PP) is an intermediate of the MEP pathway (non-mevalonate pathway) of isoprenoid biosynthesis. The enzyme HMB-PP synthase (GcpE, IspG) catalyzes the conversion of 2-C-methyl-D-erythritol 2,4-cyclodiphosphate (MEcPP) into HMB-PP. HMB-PP is then converted further to isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP) by HMB-PP reductase (LytB, IspH).

The non-mevalonate pathway—also appearing as the mevalonate-independent pathway and the 2-C-methyl-D-erythritol 4-phosphate/1-deoxy-D-xylulose 5-phosphate (MEP/DOXP) pathway—is an alternative metabolic pathway for the biosynthesis of the isoprenoid precursors isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP). The currently preferred name for this pathway is the MEP pathway, since MEP is the first committed metabolite on the route to IPP.

<span class="mw-page-title-main">Farnesyl-diphosphate farnesyltransferase</span> Class of enzymes

Squalene synthase (SQS) or farnesyl-diphosphate:farnesyl-diphosphate farnesyl transferase is an enzyme localized to the membrane of the endoplasmic reticulum. SQS participates in the isoprenoid biosynthetic pathway, catalyzing a two-step reaction in which two identical molecules of farnesyl pyrophosphate (FPP) are converted into squalene, with the consumption of NADPH. Catalysis by SQS is the first committed step in sterol synthesis, since the squalene produced is converted exclusively into various sterols, such as cholesterol, via a complex, multi-step pathway. SQS belongs to squalene/phytoene synthase family of proteins.

<span class="mw-page-title-main">Isopentenyl-diphosphate delta isomerase</span> Class of enzymes

Isopentenyl pyrophosphate isomerase, also known as Isopentenyl-diphosphate delta isomerase, is an isomerase that catalyzes the conversion of the relatively un-reactive isopentenyl pyrophosphate (IPP) to the more-reactive electrophile dimethylallyl pyrophosphate (DMAPP). This isomerization is a key step in the biosynthesis of isoprenoids through the mevalonate pathway and the MEP pathway.

<span class="mw-page-title-main">Mevalonate kinase</span>

Mevalonate kinase is an enzyme that in humans is encoded by the MVK gene. Mevalonate kinases are found in a wide variety of organisms from bacteria to mammals. This enzyme catalyzes the following reaction:

<span class="mw-page-title-main">ATP citrate synthase</span> Class of enzymes

ATP citrate synthase (also ATP citrate lyase (ACLY)) is an enzyme that in animals represents an important step in fatty acid biosynthesis. By converting citrate to acetyl-CoA, the enzyme links carbohydrate metabolism, which yields citrate as an intermediate, with fatty acid biosynthesis, which consumes acetyl-CoA. In plants, ATP citrate lyase generates cytosolic acetyl-CoA precursors of thousands of specialized metabolites, including waxes, sterols, and polyketides.

<span class="mw-page-title-main">Hydroxymethylglutaryl-CoA synthase</span> Class of enzymes

In molecular biology, hydroxymethylglutaryl-CoA synthase or HMG-CoA synthase EC 2.3.3.10 is an enzyme which catalyzes the reaction in which acetyl-CoA condenses with acetoacetyl-CoA to form 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). This reaction comprises the second step in the mevalonate-dependent isoprenoid biosynthesis pathway. HMG-CoA is an intermediate in both cholesterol synthesis and ketogenesis. This reaction is overactivated in patients with diabetes mellitus type 1 if left untreated, due to prolonged insulin deficiency and the exhaustion of substrates for gluconeogenesis and the TCA cycle, notably oxaloacetate. This results in shunting of excess acetyl-CoA into the ketone synthesis pathway via HMG-CoA, leading to the development of diabetic ketoacidosis.

In enzymology, a 1-deoxy-d-xylulose-5-phosphate synthase (EC 2.2.1.7) is an enzyme in the non-mevalonate pathway that catalyzes the chemical reaction

In enzymology, a geranyltranstransferase is an enzyme that catalyzes the chemical reaction

4-Hydroxy-3-methylbut-2-enyl diphosphate reductase (EC 1.17.1.2, isopentenyl-diphosphate:NADP+ oxidoreductase, LytB, (E)-4-hydroxy-3-methylbut-2-en-1-yl diphosphate reductase, HMBPP reductase, IspH, LytB/IspH) is an enzyme in the non-mevalonate pathway. It acts upon (E)-4-Hydroxy-3-methyl-but-2-enyl pyrophosphate (or "HMB-PP").

<span class="mw-page-title-main">Aucubin</span> Chemical compound

Aucubin is an iridoid glycoside. Iridoids are commonly found in plants and function as defensive compounds. Iridoids decrease the growth rates of many generalist herbivores.

Isopentenyl phosphate kinase is an enzyme with systematic name ATP:isopentenyl phosphate phosphotransferase. This enzyme catalyses the following chemical reaction

References

  1. 1 2 3 4 5 6 7 8 9 10 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.
  2. ↑ 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.
  3. ↑ 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.
  4. ↑ 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.
  5. ↑ 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.
  6. 1 2 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.
  7. ↑ 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.
  8. ↑ 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.
  9. 1 2 3 4 5 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.
  10. 1 2 3 4 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.
  11. ↑ 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.
  12. ↑ 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.
  13. 1 2 3 4 Nave, Jean-Franqois; d'Orchymont, Hugues; Ducep, Jean-Bernard; Piriou, Franqois; Jung, Michel J. (1985). "Mechanism of the inhibition of cholesterol biosynthesis by 6-fluoromevalonate". Biochemical Journal. 227 (1): 247–254. doi:10.1042/bj2270247. PMC   1144833 . PMID   2986604.
  14. 1 2 3 4 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.
  15. ↑ 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.
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