diphosphomevalonate decarboxylase

Target id: 642

Nomenclature: diphosphomevalonate decarboxylase

Family: Lanosterol biosynthesis pathway

Annotation status:  image of an orange circle Annotated and awaiting review. Please contact us if you can help with reviewing.  » Email us

   GtoImmuPdb view: OFF :     Currently no data for diphosphomevalonate decarboxylase in GtoImmuPdb

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 400 16q24.3 MVD mevalonate diphosphate decarboxylase
Mouse - 401 8 E1; 8 Mvd mevalonate (diphospho) decarboxylase
Rat - 401 19q12 Mvd mevalonate diphosphate decarboxylase
Previous and Unofficial Names
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
BRENDA
CATH/Gene3D
ChEMBL Target
Ensembl Gene
Entrez Gene
GenitoUrinary Development Molecular Anatomy Project
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Selected 3D Structures
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
EC Number: 4.1.1.33 ATP + (R)-5-diphosphomevalonate -> ADP + isopentenyl diphosphate + CO2 + PO34-
Substrates and Reaction Kinetics
Substrate Sp. Property Value Units Standard property Standard value Assay description Assay conditions Comments Reference
ATP 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 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 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 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 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 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 Rn Km 2x10-5 M pKm 4.7 7
(R)-5-diphosphomevalonate 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 Rn Km 2.6x10-5 M pKm 4.6 in vitro spectrophotometric assay, extracted from rat liver 3
(R)-5-diphosphomevalonate 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 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 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 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 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 Rn Vmax 6.6 µmol/min/mg in vitro spectrophotometric assay, extracted from rat liver 3
Cofactors
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 Affinity Units Reference
diphosphoglycolyl proline 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 Hs Competitive 7.4 pKi 8
pKi 7.4 (Ki 3.7x10-8 M) [8]
6-fluoromevalonate 5-diphosphate 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] Hs Competitive 6.1 pKi 8
pKi 6.1 (Ki 7.5x10-7 M) [8]
2-fluoromevalonate 5-diphosphate 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 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 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 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 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 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 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 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] 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] 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
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. Acta1760 (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]

Contributors

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How to cite this page

Helen E. Benson.
Lanosterol biosynthesis pathway: diphosphomevalonate decarboxylase. Last modified on 25/11/2014. Accessed on 13/12/2017. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=642.