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mevalonate kinase

Family: Lanosterol biosynthesis pathway

Contents:
Gene and Protein Information
Previous and Unofficial Names
Database Links
Selected 3D Structures
Enzyme Reaction
Substrates and Reaction Kinetics
Cofactors
Inhibitors
Clinically-Relevant Mutations and Pathophysiology
General Comments
References
Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 396 12q24 MVK mevalonate kinase
Mouse - 395 5 F; 5 64.0 cM Mvk mevalonate kinase
Rat - 395 12 Mvk mevalonate kinase
Previous and Unofficial Names
MVK
ATP:mevalonate 5-phosphotransferase
kinase, mevalonate (phosphorylating)
mevalonate 5-phosphotransferase
mevalonate phosphokinase
mevalonic acid kinase
mevalonic kinase
MVA kinase
LRBP
MK
mevalonate kinase (mevalonic aciduria)
LH receptor mRNA-binding protein
mevalonic aciduria
Database Links
BRENDA 2.7.1.36
ChEMBL Target CHEMBL4274 (Rn)
Ensembl ENSG00000110921 (Hs), ENSMUSG00000041939 (Mm)
Entrez Gene 4598 (Hs), 17855 (Mm), 81727 (Rn)
ExplorEnz 2.7.1.36
GeneCards MVK (Hs)
GenitoUrinary Development Molecular Anatomy Project Mvk (Mm)
Human Protein Reference Database 02015 (Hs)
InterPro Q03426 (Hs), Q9R008 (Mm), P17256 (Rn)
KEGG BRITE Hierarchy 2.7.1.36
KEGG Gene hsa:4598 (Hs), mmu:17855 (Mm), rno:81727 (Rn)
OMIM 251170 (Hs)
PharmGKB Gene PA31331 (Hs)
PhosphoSitePlus Q03426 (Hs), Q9R008 (Mm)
RefSeq Nucleotide NM_001114185 (Hs), NM_000431 (Hs), NM_023556 (Mm), NM_031063 (Rn)
RefSeq Protein NP_001107657 (Hs), NP_000422 (Hs), NP_076045 (Mm), NP_112325 (Rn)
TreeFam ENSG00000110921 (Hs), ENSMUSG00000041939 (Mm)
UniGene Hs. 130607 (Hs)
UniProt Q03426 (Hs), Q9R008 (Mm), P17256 (Rn)
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of rat mevalonate kinase in complex with feedback inhibitor farnesyl diphosphate
PDB Id:  2R42
Ligand:  farnesyl diphosphate   This ligand is endogenous
Resolution:  2.4Å
Species:  Rat
References:  4
Search for other structures on the PDB
Search by keyword: Lanosterol biosynthesis pathway mevalonate kinase Search by accession number: Q03426, Q9R008, P17256
Enzyme Reaction
EC Number: 2.7.1.36 ATP + (R)-mevalonate -> ADP + (R)-5-phosphomevalonate
Substrates and Reaction Kinetics
Substrate Sp. Property Value Units Assay description Assay conditions Comments Reference
ATP Rn Kcat 21.9 s-1 wild type purified enzyme; in vitro assay pH 7.5, 34°C 3
(R)-mevalonate Rn Kcat 21.9 s-1 purified wild type enzyme; in vitro assay pH 7.5, 25°C 1
ATP Hs Km 74.0 µM wild type enzyme, in vitro assay pH 7.0, 30°C 7
ATP Hs Km 178.0 µM recombinant human MVK expressed in E coli; spectrophotometric assay 4
ATP Hs Km 178.4 µM recombinant human MVK expressed in E coli; spectrophotometric assay 30°C, pH 7.5 4
ATP Hs Km 440.0 µM recombinant enzyme expressed in E coli, purified by affinity chromatography; in vitro assay- spectrophotometric assay pH 7.0 5
ATP Rn Km 950.0 µM wild type purified enzyme; in vitro assay pH 7.5, 34°C 3
ATP Rn Km 953.0 µM wild type purified enzyme; in vitro assay pH 7.5, 25°C 1
ATP Rn Km 953.0 µM recombinant overexpression in E coli and purification, in vitro assay pH 7.5, 25°C 2
ATP Rn Km 1240.0 µM recombinant enzyme, expression and purification in E coli; in vitro assay pH 7.0, 30°C 8
ATP Rn Km 1750.0 µM wild type purified enzyme, in vitro assay pH 7.0, 25°C 10
(R)-mevalonate Rn Km 35.0 µM purified wild type enzyme; in vitro assay pH 7.5, 25°C 1
(R)-mevalonate Rn Km 35.0 µM purified wild type enzyme; in vitro assay pH 7.5, 34°C 3
(RS)-mevalonate Hs Km 24.0 µM recombinant enzyme, in vitro assay pH 7.0, 30°C 7
(RS)-mevalonate Rn Km 35.0 µM recombinant enzyme, overexpression in E coli and purification, in vitro assay pH 7.0, 25°C 2
(RS)-mevalonate Hs Km 40.8 µM recombinant human MVK expressed in E coli; spectrophotometric assay 30°C, pH 7.5 4
(RS)-mevalonate Hs Km 150.0 µM recombinant enzyme expressed in E coli, purified by affinity chromatography; in vitro assay- spectrophotometric assay pH 7.0 5
(RS)-mevalonate Rn Km 271.0 µM wild type partially purified, in vitro assay pH 7.0, 25°C 10
(RS)-mevalonate Rn Km 271.0 µM wild type purified enzyme, in vitro assay pH 7.0, 25°C 10
(RS)-mevalonate Rn Km 288.0 µM recombinant expression and purification in E coli; in vitro assay pH 7.0, 30°C 8
ATP Hs Vmax 37.0 µmol/min/mg wild type enzyme, in vitro assay pH 7.0, 30°C 7
ATP Rn Vmax 38.7 µmol/min/mg wild type purified enzyme; in vitro assay pH 7.5, 34°C 3
(R)-mevalonate Rn Vmax 38.7 µmol/min/mg purified wild type enzyme; in vitro assay pH 7.5, 34°C 3
(R)-mevalonate Rn Vmax 38.7 µmol/min/mg purified wild type enzyme; in vitro assay pH 7.5, 25°C 1
(RS)-mevalonate Hs Vmax 13.6 µmol/min/mg recombinant ennzyme, partially purified, in vitro assay pH 7.0 5
(RS)-mevalonate Hs Vmax 28.0 µmol/min/mg recombinant human MVK expressed in E coli; spectrophotometric assay 30°C, pH 7.5 4
(RS)-mevalonate Rn Vmax 29.4 µmol/min/mg wild type partially purified, in vitro assay pH 7.0, 25°C 10
(RS)-mevalonate Rn Vmax 30.2 µmol/min/mg recombinant expression and purification in E coli; in vitro assay pH 7.0, 30°C 8
(RS)-mevalonate Hs Vmax 37.0 µmol/min/mg recombinant enzyme, in vitro assay pH 7.0, 30°C 7
(RS)-mevalonate Rn Vmax 38.7 µmol/min/mg recombinant enzyme, overexpression in E coli and purification, in vitro assay pH 7.0, 25°C 2
Cofactors
Cofactor Species Comments Reference
Mg2+ Human The reaction catalysed by mevalonate kinase requires a divalent cation. Use of magnesium as a cofactor has also been characterised in rats. 4,6,9
Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
farnesyl thiodiphosphate Hs Inhibition 7.54 pKi 12
trans,trans-farnesyl diphosphate Hs Feedback inhibition 7.0 – 7.47 pKi 4-5
geranylgeranyl diphosphate Hs Feedback inhibition 7.23 pKi 5
geranyl diphosphate Hs Feedback inhibition 6.94 pKi 5
farnesyl thiodiphosphate Rn Inhibition 6.33 pKi 12
trans,trans-farnesyl diphosphate Rn Feedback inhibition 5.6 – 6.46 pKi 10,12
isopentenyl diphosphate Hs Feedback inhibition 4.8 pKi 5
dimethylallyl diphosphate Hs Inhibition 4.7 pKi 5
farnesol Hs Inhibition 4.14 pKi 5
dolichol phosphate Hs Inhibition 4.08 pKi 5
geranyl diphosphate Rn Feedback inhibition 5.3 pIC50 9
(RS)-5-diphosphomevalonate Rn Feedback inhibition 3.74 pIC50 9
View species-specific inhibitor tables
Clinically-Relevant Mutations and Pathophysiology
Disease:  Mevalonic aciduria
OMIM:  610377
References: 
Mutations not determined
Disease:  Hyper-IgD syndrome
OMIM:  260920
References: 
Mutations not determined
General Comments
Deficiency in mevalonate kinase causes metabolic inflammatory disease [11].

REFERENCES

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1. Chu, X; Li, D. (2003) Expression, purification, and characterization of His20 mutants of rat mevalonate kinase. Protein Expr. Purif., 32 (1): 75-82. [PMID:14680942]

2. Chu, X; Li, D. (2003) Cloning, expression, and purification of His-tagged rat mevalonate kinase. Protein Expr. Purif., 27 (1): 165-70. [PMID:12509999]

3. Chu, X; Yu, W; Wu, L; Liu, X; Li, N; Li, D. (2007) Effect of a disulfide bond on mevalonate kinase. Biochim. Biophys. Acta, 1774 (12): 1571-81. [PMID:17964869]

4. Fu, Z; Voynova, NE; Herdendorf, TJ; Miziorko, HM; Kim, JJ. (2008) Biochemical and structural basis for feedback inhibition of mevalonate kinase and isoprenoid metabolism. Biochemistry, 47 (12): 3715-24. [PMID:18302342]

5. Hinson, DD; Chambliss, KL; Toth, MJ; Tanaka, RD; Gibson, KM. (1997) Post-translational regulation of mevalonate kinase by intermediates of the cholesterol and nonsterol isoprene biosynthetic pathways. J. Lipid Res., 38 (11): 2216-23. [PMID:9392419]

6. Hoffmann, F; Lohse, P; Stojanov, S; Shin, YS; Renner, ED; Kéry, A; Zellerer, S; Belohradsky, BH. (2005) Identification of a novel mevalonate kinase gene mutation in combination with the common MVK V377I substitution and the low-penetrance TNFRSF1A R92Q mutation. Eur. J. Hum. Genet., 13 (4): 510-2. [PMID:15657603]

7. Potter, D; Miziorko, HM. (1997) Identification of catalytic residues in human mevalonate kinase. J. Biol. Chem., 272 (41): 25449-54. [PMID:9325256]

8. Potter, D; Wojnar, JM; Narasimhan, C; Miziorko, HM. (1997) Identification and functional characterization of an active-site lysine in mevalonate kinase. J. Biol. Chem., 272 (9): 5741-6. [PMID:9038186]

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

10. Tanaka, RD; Schafer, BL; Lee, LY; Freudenberger, JS; Mosley, ST. (1990) Purification and regulation of mevalonate kinase from rat liver. J. Biol. Chem., 265 (4): 2391-8. [PMID:2153681]

11. van der Burgh, R; Ter Haar, NM; Boes, ML; Frenkel, J. (2012) Mevalonate kinase deficiency, a metabolic autoinflammatory disease. Clin. Immunol.,  [Epub ahead of print]. [PMID:23110805]

12. Voynova, NE; Rios, SE; Miziorko, HM. (2004) Staphylococcus aureus mevalonate kinase: isolation and characterization of an enzyme of the isoprenoid biosynthetic pathway. J. Bacteriol., 186 (1): 61-7. [PMID:14679225]

To cite this database page, please use the following:

Helen E. Benson.
Lanosterol biosynthesis pathway: mevalonate kinase. Last modified on 13/11/2012. Accessed on 25/05/2013. IUPHAR database (IUPHAR-DB), http://iuphar-db.org/DATABASE/ObjectDisplayForward?04objectId=640.


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