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diphosphomevalonate decarboxylase

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Target not currently curated in GtoImmuPdb

Target id: 642

Nomenclature: diphosphomevalonate decarboxylase

Family: Lanosterol biosynthesis pathway

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 400 16q24.2 MVD mevalonate diphosphate decarboxylase
Mouse - 401 8 E1 Mvd mevalonate (diphospho) decarboxylase
Rat - 401 19q12 Mvd mevalonate diphosphate decarboxylase
Previous and Unofficial Names Click here for help
5-Pyrophosphomevalonate decarboxylase | MDD | MDP | mevalonate 5'-diphosphate decarboxylase | Mevalonate 5-diphosphate decarboxylase | mevalonate diphosphate decarboxylase | MPD | Pyrophosphomevalonate decarboxylase | mevalonate pyrophosphate decarboxylase | Pyrophosphomevalonic acid decarboxylase | MDDase | Mvpd | mevalonate (diphospho) decarboxylase
Database Links Click here for help
Alphafold P53602 (Hs), Q99JF5 (Mm), Q62967 (Rn)
BRENDA 4.1.1.33
CATH/Gene3D 3.30.70.890, 3.30.230.10
ChEMBL Target CHEMBL4340 (Hs), CHEMBL4296309 (Rn)
Ensembl Gene ENSG00000167508 (Hs), ENSMUSG00000006517 (Mm), ENSRNOG00000013376 (Rn)
Entrez Gene 4597 (Hs), 192156 (Mm), 81726 (Rn)
Human Protein Atlas ENSG00000167508 (Hs)
KEGG Enzyme 4.1.1.33
KEGG Gene hsa:4597 (Hs), mmu:192156 (Mm), rno:81726 (Rn)
OMIM 603236 (Hs)
Pharos P53602 (Hs)
RefSeq Nucleotide NM_002461 (Hs), NM_138656 (Mm), NM_031062 (Rn)
RefSeq Protein NP_002452 (Hs), NP_619597 (Mm), NP_112324 (Rn)
UniProtKB P53602 (Hs), Q99JF5 (Mm), Q62967 (Rn)
Wikipedia MVD (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of Human mevalonate diphosphate decarboxylase
PDB Id:  3D4J
Resolution:  2.4Å
Species:  Human
References:  9
Enzyme Reaction Click here for help
EC Number: 4.1.1.33 ATP + (R)-5-diphosphomevalonate -> ADP + isopentenyl diphosphate + CO2 + PO34-
Substrates and Reaction Kinetics Click here for help
Substrate Sp. Property Value Units Standard property Standard value Assay description Assay conditions Comments Reference
ATP Substrate is endogenous in the given species Rn Km 5.3x10-4 M pKm 3.3 in vitro spectrophotometric assay, extracted from rat liver pH 7.0, 4ºC 45000 MW enzyme form 3
ATP Substrate is endogenous in the given species Rn Km 5.3x10-4 M pKm 3.3 purified from rat liver , in vitro assay pH 7.0, 30ºc Concentration of substrates & reagents: 0.16mM NADH, 5mM MgCl2, 4mM ATP, 36µM mevalonate-5-diphosphate 5
ATP Substrate is endogenous in the given species Hs Km 6.9x10-4 M pKm 3.2 enzyme expressed in E coli, extracted, purified, in vitro spectrophotometric assay pH 7.0, 30°C Concentration of substrates and reagents: 10mM MgCl2 0.2mM NADH, 8mM ATP, 0.4mM mevalonate diphosphate 9
ATP Substrate is endogenous in the given species Rn Km 7.1x10-4 M pKm 3.1 purified enzyme from rat liver, in vitro assay, spectrophotometric assay pH 7.0 Substrate concentrations (1mM final volume): 5mM ATP, 0.24mM NADH, 250 nmol (R)-5-diphosphomevalonate 2
ATP Substrate is endogenous in the given species Rn Km 8x10-4 M pKm 3.1 purified enzyme from rat liver, in vitro assay, spectrophotometric assay pH 7.0 Substrate concentrations (1mM final volume): 5mM ATP, 0.24mM NADH, 250 nmol (R)-5-diphosphomevalonate 2
(R)-5-diphosphomevalonate Substrate is endogenous in the given species Rn Km 2x10-5 M pKm 4.7 purified enzyme from rat liver, in vitro assay, spectrophotometric assay pH 7.0 Substrate concentrations (1mM final volume): 5mM ATP, 0.24mM NADH, 250 nmol (R)-5-diphosphomevalonate. 37000 MW enzyme form, induced by statin diet 2
(R)-5-diphosphomevalonate Substrate is endogenous in the given species Rn Km 2x10-5 M pKm 4.7 7
(R)-5-diphosphomevalonate Substrate is endogenous in the given species Rn Km 2.27x10-5 M pKm 4.6 purified enzyme from rat liver, in vitro assay, spectrophotometric assay pH 7.0 Substrate concentrations (1mM final volume): 5mM ATP, 0.24mM NADH, 250 nmol (R)-5-diphosphomevalonate. 45000 MW enzyme form 2
(R)-5-diphosphomevalonate Substrate is endogenous in the given species Rn Km 2.6x10-5 M pKm 4.6 in vitro spectrophotometric assay, extracted from rat liver 3
(R)-5-diphosphomevalonate Substrate is endogenous in the given species Hs Km 2.89x10-5 M pKm 4.5 enzyme expressed in E coli, extracted, purified, in vitro spectrophotometric assay pH 7.0, 30ºc Concentration of substrates and reagents: 10mM MgCl2 0.2mM NADH, 8mM ATP, 0.4mM mevalonate diphosphate 9
(R)-5-diphosphomevalonate Substrate is endogenous in the given species Rn Km 3.6x10-5 M pKm 4.4 purified from rat liver, in vitro assay pH 7.5, 25ºc Concentration of substrates & reagents: 0.16mM NADH, 5mM MgCl2, 4mM ATP, 36µM mevalonate-5-diphosphate 5
(RS)-5-diphosphomevalonate Substrate is endogenous in the given species Mm Km 1x10-5 M pKm 5.0 purified from mouse liver, in vitro assay pH 7.2 Concentrations of substrates and reagents: 5mM ATP, 5mM MgCl2, 250 nmol (RS)-5-diphosphomevalonate 1
(R)-5-diphosphomevalonate Substrate is endogenous in the given species Hs Vmax 6.1 µmol/min/mg enzyme expressed in E coli, extracted, purified, in vitro spectrophotometric assay pH 7.0, 30ºc Concentration of substrates and reagents: 10mM MgCl2 0.2mM NADH, 8mM ATP, 0.4mM mevalonate diphosphate 9
(R)-5-diphosphomevalonate Substrate is endogenous in the given species Rn Vmax 6.6 µmol/min/mg purified from rat liver, in vitro assay. 10µg of enzyme used pH 7.5, 25ºc Concentration of substrates & reagents: 0.16mM NADH, 5mM MgCl2, 4mM ATP, 36µM mevalonate-5-diphosphate 5
(R)-5-diphosphomevalonate Substrate is endogenous in the given species Rn Vmax 6.6 µmol/min/mg in vitro spectrophotometric assay, extracted from rat liver 3
Cofactors Click here for help
Cofactor Species Comments Reference
Mg2+ Human Also characterised in mice. It has been shown that Mg2+ can be substituted by other divalent cations Mn2+ and Co2+ 1,9
ATP Human ATP is required as a phosphate acceptor. This has also been characterised in rats and mice 1-2

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Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
diphosphoglycolyl proline Small molecule or natural product Hs Competitive 8.6 pKi 9
⤷ pKi 8.6 (Ki 2.3x10-9 M) [9]
Description: recombinant enzyme expressed in E coli, purified, in vitro spectrophotometric assay
Conditions: The concentration of mevalonate 5-diphosphate varied between 86- 285µM. ATP concentration constant at ~8mM. pH 7.0, 30ºC
6-fluoromevalonate pyrophosphate Small molecule or natural product Ligand has a PDB structure Hs Competitive 7.4 pKi 8
⤷ pKi 7.4 (Ki 3.7x10-8 M) [8]
6-fluoromevalonate 5-diphosphate Small molecule or natural product Hs Competitive 7.2 pKi 9
⤷ pKi 7.2 (Ki 6.2x10-8 M) [9]
Description: recombinant enzyme expressed in E coli, purified, in vitro spectrophotometric assay
Conditions: Concentration of mevalonate 5-diphosphate varied between 33-657µM; ATP concentration 8mM. pH 7.0, 30ºC
analog 3 [Vlattas et al., 1996] Small molecule or natural product Hs Competitive 6.1 pKi 8
⤷ pKi 6.1 (Ki 7.5x10-7 M) [8]
2-fluoromevalonate 5-diphosphate Small molecule or natural product Rn Irreversible inhibition 5.5 pKi 5
⤷ pKi 5.5 (Ki 3.02x10-6 M) [5]
Description: expression of rat enzyme in E coli, purification, in vitro spectrophotometric assay
Conditions: Concentration of substrates: 0.16mM NADH, 4mM ATP, 36µM mevalonate 5-diphosphate. pH 7.5, 25 ºC
P'-geranyl 2-fluoromevalonate 5-diphosphate Small molecule or natural product Hs Competitive 5.4 pKi 9
⤷ pKi 5.4 (Ki 4.15x10-6 M) [9]
Description: expression of rat enzyme in E coli, purification, in vitro spectrophotometric assay
Conditions: pH 7.5, 25 ºC
P'-geranyl 3,5,9-trihydroxy-3-methylnonanate 9-diphosphate Small molecule or natural product Rn Competitive 5.2 pKi 4
⤷ pKi 5.2 (Ki 6.5x10-6 M) [4]
Description: enzyme expressed in E coli, purified, in vitro assay, spectrophotometric assay
Conditions: Concentration of substrates: 0.16mM NADH, 4mM ATP, 36µM mevalonate 5-diphosphate. pH 8, 25ºC
P'-geranyl 3,5,8-trihydroxy-3-methyloctanate 8-diphosphate Small molecule or natural product Rn Competitive 5.7 pIC50 4
⤷ pIC50 5.7 (IC50 2x10-6 M) [4]
Description: enzyme expressed in E coli, purified, in vitro assay, spectrophotometric assay
Conditions: Concentration of substrates: 0.16mM NADH, 4mM ATP, 36µM mevalonate 5-diphosphate. pH 8, 25ºC
P'-geranyl 3,5,7-trihydroxy-3-methylheptanate 7-diphosphate Small molecule or natural product Rn Competitive 5.6 pIC50 4
⤷ pIC50 5.6 (IC50 2.6x10-6 M) [4]
Description: enzyme expressed in E coli, purified, in vitro assay, spectrophotometric assay
Conditions: Concentration of substrates: 0.16mM NADH, 4mM ATP, 36µM mevalonate 5-diphosphate. pH 8, 25ºC
P'-geranyl 2-fluoromevalonate 5-diphosphate Small molecule or natural product Rn Competitive 5.3 pIC50 3
⤷ pIC50 5.3 (IC50 4.6x10-6 M) [3]
Description: expression of rat enzyme in E coli, purification, in vitro spectrophotometric assay
Conditions: pH 7.5, 25 ºC
2,2-difluoromevalonate 5-diphosphate Small molecule or natural product Rn Competitive 5.1 pIC50 3
⤷ pIC50 5.1 (IC50 7.5x10-6 M) [3]
Description: expression of rat enzyme in E coli, purification, in vitro spectrophotometric assay
Conditions: pH 7.5, 25 ºC
geranyl diphosphate Small molecule or natural product Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Rn Feedback inhibition 4.2 – 5.3 pIC50 4-5
⤷ pIC50 4.2 – 5.3 (IC50 6.5x10-5 – 5x10-6 M) [4-5]
Description: expression of rat enzyme in E coli, purification, in vitro spectrophotometric assay
Conditions: Concentration of substrates: 0.16mM NADH, 4mM ATP, 36µM mevalonate 5-diphosphate. pH 7.5, 25 ºC
compound 18 [PMID: 17888661] Small molecule or natural product Rn Competitive 4.1 pIC50 3
⤷ pIC50 4.1 (IC50 8x10-5 M) [3]
Description: expression of rat enzyme in E coli, purification, in vitro spectrophotometric assay
Conditions: pH 7.5, 25 ºC
compound 19 [PMID: 17888661] Small molecule or natural product Rn Competitive 3.9 pIC50 3
⤷ pIC50 3.9 (IC50 1.2x10-4 M) [3]
Description: expression of rat enzyme in E coli, purification, in vitro spectrophotometric assay
Conditions: pH 7.5, 25 ºC
View species-specific inhibitor tables
Tissue Distribution Click here for help
Liver, skeletal muscle, heart, brain, placenta, lung, kidney, and pancreatic tissues
Species:  Human
Technique:  Northern blot
References:  6

References

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1. Michihara A, Akasaki K, Yamori Y, Tsuji H. (2002) Purification and characterization of mouse mevalonate pyrophosphate decarboxylase. Biol Pharm Bull, 25 (3): 302-6. [PMID:11913522]

2. Michihara A, Sawamura M, Nara Y, Ikeda K, Yamori Y. (1997) Purification and characterization of two mevalonate pyrophosphate decarboxylases from rat liver: a novel molecular species of 37 kDa. J Biochem, 122 (3): 647-54. [PMID:9348097]

3. Qiu Y, Gao J, Guo F, Qiao Y, Li D. (2007) Mutation and inhibition studies of mevalonate 5-diphosphate decarboxylase. Bioorg Med Chem Lett, 17 (22): 6164-8. [PMID:17888661]

4. Qiu Y, Li D. (2006) Bifunctional inhibitors of mevalonate kinase and mevalonate 5-diphosphate decarboxylase. Org Lett, 8 (6): 1013-6. [PMID:16524256]

5. Qiu Y, Li D. (2006) Inhibition of mevalonate 5-diphosphate decarboxylase by fluorinated substrate analogs. Biochim Biophys Acta, 1760 (7): 1080-7. [PMID:16626865]

6. Toth MJ, Huwyler L. (1996) Molecular cloning and expression of the cDNAs encoding human and yeast mevalonate pyrophosphate decarboxylase. J Biol Chem, 271 (14): 7895-8. [PMID:8626466]

7. Toth MJ, Huwyler L, Park J. (1996) Purification of rat liver mevalonate pyrophosphate decarboxylase. Prep Biochem Biotechnol, 26 (1): 47-51. [PMID:8744421]

8. Vlattas I, Dellureficio J, Ku E, Bohacek R, Zhang X. (1996) Inhibition of mevalonate 5-pyrophosphate decarboxylase by a proline-containing transition state analog. Bioorg Med Chem Lett, 6 (17): 2091-2096.

9. Voynova NE, Fu Z, Battaile KP, Herdendorf TJ, Kim JJ, Miziorko HM. (2008) Human mevalonate diphosphate decarboxylase: characterization, investigation of the mevalonate diphosphate binding site, and crystal structure. Arch Biochem Biophys, 480 (1): 58-67. [PMID:18823933]

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