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Information on EC 2.7.4.2 - phosphomevalonate kinase and Organism(s) Homo sapiens and UniProt Accession Q15126

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Homo sapiens
UNIPROT: Q15126 not found.
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Word Map
The taxonomic range for the selected organisms is: Homo sapiens
The enzyme appears in selected viruses and cellular organisms
Synonyms
phosphomevalonate kinase, ccpmk, 5-phosphomevalonate kinase, mevalonate-5-phosphate kinase, mevalonate phosphate kinase, phosphomevalonic kinase, more
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
5-phosphomevalonate kinase
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-
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ATP:5-phosphomevalonate phosphotransferase
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-
-
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kinase, phosphomevalonate (phosphorylating)
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-
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mevalonate phosphate kinase
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mevalonate-5-phosphate kinase
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mevalonic acid phosphate kinase
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-
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phosphomevalonate kinase
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phosphomevalonic kinase
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-
-
-
additional information
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
ATP + (R)-5-phosphomevalonate = ADP + (R)-5-diphosphomevalonate
show the reaction diagram
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
phospho group transfer
SYSTEMATIC NAME
IUBMB Comments
ATP:(R)-5-phosphomevalonate phosphotransferase
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CAS REGISTRY NUMBER
COMMENTARY hide
9026-46-4
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SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
ATP + (R)-5-phosphomevalonate
ADP + (R)-5-diphosphomevalonate
show the reaction diagram
ATP + (R)-mevalonate 5-phosphate
ADP + (R)-mevalonate 5-diphosphate
show the reaction diagram
ATP + 5-phosphomevalonate
ADP + 5-diphosphomevalonate
show the reaction diagram
-
-
?
ADP + (R)-5-diphosphomevalonate
ATP + (R)-5-phosphomevalonate
show the reaction diagram
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-
-
r
ATP + (R)-5-phosphomevalonate
ADP + (R)-5-diphosphomevalonate
show the reaction diagram
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
ATP + (R)-5-phosphomevalonate
ADP + (R)-5-diphosphomevalonate
show the reaction diagram
ATP + (R)-mevalonate 5-phosphate
ADP + (R)-mevalonate 5-diphosphate
show the reaction diagram
the enzyme catalyzes a key step in isoprenoid/sterol biosynthesis
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-
r
ATP + (R)-5-phosphomevalonate
ADP + (R)-5-diphosphomevalonate
show the reaction diagram
COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
ATP
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binding site structure, overview
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Mg2+
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-
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
2,2',2''-(biphenyl-2,4,6-triyltrisulfanediyl)triacetate
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2,2'-[(5,8-dihydroxy-9,10-dioxo-4a,9,9a,10-tetrahydroanthracene-1,4-diyl)diimino]bis(5-methylbenzenesulfonate)
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4-[(E)-(2,4-dihydroxyphenyl)diazenyl]-5-methylnaphthalene-2,7-disulfonate
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mevalonate 5-diphosphate
product inhibition, mutants R111M and R84M show decreased sensitivity compared to the wild-type enzyme
(R)-5-diphosphomevalonate
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.007 - 1.55
(R)-mevalonate 5-diphosphate
0.034 - 2.04
(R)-mevalonate 5-phosphate
0.047 - 5.62
ADP
0.094 - 5.2
ATP
0.007 - 1.55
(R)-5-diphosphomevalonate
0.034 - 2.04
(R)-5-phosphomevalonate
0.047 - 5.62
ADP
0.094 - 5.2
ATP
additional information
additional information
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Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.018 - 1.14
mevalonate 5-diphosphate
0.018 - 1.14
(R)-5-diphosphomevalonate
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
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endogenously expressed human phosphomevalonate kinase and overexpressed human phosphomevalonate kinase
Manually annotated by BRENDA team
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endogenously expressed human phosphomevalonate kinase and overexpressed human phosphomevalonate kinase
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
PMVK mutant Arg138*
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
malfunction
PMVK is a gene involved in the pathogenesis of disseminated superficial porokeratosis (DSP), a rare keratinization disorder of the epidermis, which is characterized by keratotic lesions with an atrophic center encircled by a prominent peripheral ridge. PMVK deficiency or abnormal keratinocyte apoptosis can lead to porokeratosis. The Arg138* genetic variant (nonsense mutation) is involved in the development of DSP in both families. Using HaCaT cells as models, it is revealed that this variant disturbs subcellular localization, expression, and solubility of PMVK, apparent apoptosis in and under the cornoid lamella of PMVK-deficient lesional tissues is observed, with incomplete differentiation of keratinocytes
metabolism
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phosphomevalonate kinase catalyzes the rate-limiting step for biosynthesis of isopentenyl diphosphate from mevalonate
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION?
PMVK_HUMAN
192
0
21995
Swiss-Prot
Mitochondrion (Reliability: 4)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
22000
x * 22000, SDS-PAGE
22900
recombinant His-tagged wild-type enzyme, gel filtration
24200
1 * 24200, sequence calculation
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
?
x * 22000, SDS-PAGE
monomer
1 * 24200, sequence calculation
additional information
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
1.8 A resolution. Molecule exhibits a compact alpha/beta structure and shows a sulfate molecule tightly bound to the P-loop. This sulfate ion forms hydrogen bonds with the amino group of amino acid G21 and with the side chain of R141
NMR-based dynamics and chemical shift experiments of enzyme in complex with MgADP, mevalonate 5-phosphate and the ternary complex. Binding of mevalonate 5-phosphate causes the protein to compress, whereas subsequent binding of MgADP opens the structure. Mevalonate 5-phosphate causes movement around a hinge region to permit domain closure. Amino acids H55 and R93 may act as hinge residues, D163 may be a hinge residue for the lid region. Binding of ATP or ADP causes similar conformational changes. The first nine residues of the N-terminus are highly disordered
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purified recombinant His6-tagged enzyme, mixing of 0.002 ml of 10 mg/mL protein in 100 mM (NH4)2SO4, 20 mM HEPES, pH 7.6, with 0.002 ml reservoir solution containing 15% v/v pentaerythritol ethoxylate, 100 mM HEPES, pH 7.6, 15% v/v MPD, 15°C, 2-3 days, X-ray diffraction structure determination and analysis at 1.76 A resolution, SAD method
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PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
D23N
site-directed mutagenesis, the mutant shows highly reduced activity in both forward and reverse reactions compared to the wild-type enzyme
K17M
site-directed mutagenesis, the mutant shows reduced activity in both forward and reverse reactions compared to the wild-type enzyme
K19M
site-directed mutagenesis, the mutant shows highly reduced activity in both forward and reverse reactions compared to the wild-type enzyme
K22M
site-directed mutagenesis, the mutant shows a 10000fold reduced activity in both forward and reverse reactions compared to the wild-type enzyme, almost inactive mutant
K48M
site-directed mutagenesis, the mutant shows altered kinetics and reduced activity in both forward and reverse reactions compared to the wild-type enzyme
R110M
site-directed mutagenesis, the mutant shows altered kinetics and highly reduced activity in both forward and reverse reactions compared to the wild-type enzyme
R111M
site-directed mutagenesis, the mutant shows altered kinetics and reduced activity in both forward and reverse reactions compared to the wild-type enzyme
R130M
site-directed mutagenesis, the mutant shows altered kinetics and reduced activity in both forward and reverse reactions compared to the wild-type enzyme
R138M
site-directed mutagenesis, the mutant shows altered kinetics and reduced activity in both forward and reverse reactions compared to the wild-type enzyme
R141M
site-directed mutagenesis, the mutant shows altered kinetics and reduced activity in both forward and reverse reactions compared to the wild-type enzyme
R18Q
site-directed mutagenesis, the mutant shows highly reduced activity in both forward and reverse reactions compared to the wild-type enzyme
R73M
site-directed mutagenesis, the mutant shows altered kinetics and reduced activity in both forward and reverse reactions compared to the wild-type enzyme
R84M
site-directed mutagenesis, the mutant shows altered kinetics and reduced activity in both forward and reverse reactions compared to the wild-type enzyme
R93M
site-directed mutagenesis, the mutant shows altered kinetics and reduced activity in both forward and reverse reactions compared to the wild-type enzyme
K48M
mutant exhibits diminished Vmax values in both reaction directions with only slight Km perturbations
K69M
mutant exhibits diminished Vmax values in both reaction directions with only slight Km perturbations
R110M
no catalytic activity
R111M
substantially inflated Km values for mevalonate 5-phosphate and mevalonate 5-diphosphate
R130M
mutant exhibits slight changes in Vmax values in both reaction directions with slight Km perturbations
R138M
mutant exhibits slight changes in Vmax values in both reaction directions with slight Km perturbations
R141M
50fold increase in Km value for ATP, 120fold increase for ADP
R73M
mutant exhibits diminished Vmax values in both reaction directions with only slight Km perturbations
R84M
50- and 33fold increase in Km value for mevalonate 5-phosphate and mevalonate 5-diphosphate, respectively
R93M
mutant exhibits slight changes in Vmax values in both reaction directions with slight Km perturbations
additional information
analysis of the genetic basis of disseminated superficial porokeratosis (DSP) in two five-generation Chinese families with members diagnosed with DSP, whole-exome sequencing and genotyping. Identification of a nonsense variation c.412C > T (p.Arg138*) in the phosphomevalonate kinase gene (PMVK), which encodes a cytoplasmic enzyme catalyzing the conversion of mevalonate 5-phosphate to mevalonate 5-diphosphate in the mevalonate pathway. This genetic variant is involved in the development of DSP in both families. Using HaCaT cells as models, it is revealed that this variant disturbs subcellular localization, expression, and solubility of PMVK, apparent apoptosis in and under the cornoid lamella of PMVK-deficient lesional tissues is observed, with incomplete differentiation of keratinocytes. The R138* mutant shows reduced expression and solubility. Phenotypes, overview
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
Ni-Sepharose column chromatography
recombinant His-tagged wild-type and mutant enzymes from Escherichia coli by nickel affinity chromatography
recombinant His6-tagged enzyme from Escherichia coli strain BL21(DE3) by nickel affinity chromatography and gel filtration
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CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expressed in Escherichia coli BL21 (DE3) Rosetta cells
expression in Escherichia coli
expression of phosphomevalonate kinase-green fluorescence fusion protein in CHO cells and fibroblasts
gene PMVK, DNA and amino acid sequence determination and analysis, functional expression of soluble His-tagged wild-type enzyme and of His-tagged mutants in Escherichia coli strains JM109 and BL21(DE3)
gene PMVK, DNA and amino acid sequence determination and analysis, genotyping
gene PMVK, expression of His-tagged wild-type enzyme and mutants in Escherichia coli strain BL21(DE3)
expressed in CV-1 cells
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expressed in Escherichia coli DH10B cells
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expression in human embryonic kidney (HEK-293) Flp-In and CV1 cells
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expression of the C-terminally His6-tagged enzyme in Escherichia coli strain BL21(DE3)
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REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Olivier, L.M.; Chambliss, K.L.; Gibson, K.M.; Krisans, S.K.
Characterization of phosphomevalonate kinase: chromosomal localization, regulation, and subcellular targeting
J. Lipid Res.
40
672-679
1999
Rattus norvegicus, Homo sapiens (Q15126), Homo sapiens
Manually annotated by BRENDA team
Hogenboom, S.; Tuyp, J.J.; Espeel, M.; Koster, J.; Wanders, R.J.; Waterham, H.R.
Phosphomevalonate kinase is a cytosolic protein in humans
J. Lipid Res.
45
697-705
2004
Homo sapiens
Manually annotated by BRENDA team
Herdendorf, T.J.; Miziorko, H.M.
Phosphomevalonate kinase: functional investigation of the recombinant human enzyme
Biochemistry
45
3235-3242
2006
Homo sapiens (Q15126), Homo sapiens
Manually annotated by BRENDA team
Herdendorf, T.J.; Miziorko, H.M.
Functional evaluation of conserved basic residues in human phosphomevalonate kinase
Biochemistry
46
11780-11788
2007
Homo sapiens, Homo sapiens (Q15126)
Manually annotated by BRENDA team
Olson, A.L.; Yao, H.; Herdendorf, T.J.; Miziorko, H.M.; Hannongbua, S.; Saparpakorn, P.; Cai, S.; Sem, D.S.
Substrate induced structural and dynamics changes in human phosphomevalonate kinase and implications for mechanism
Proteins
75
127-138
2008
Homo sapiens
Manually annotated by BRENDA team
Chang, Q.; Yan, X.; Gu, S.; Liu, J.; Liang, D.
Crystal structure of human phosphomevalonate kinase at 1.8 A resolution
Proteins Struct. Funct. Bioinform.
73
254-258
2008
Homo sapiens (Q15126)
Manually annotated by BRENDA team
Chang, Q.; Yan, X.; Gu, S.; Liu, J.; Liang, D.
Crystal structure of human phosphomevalonate kinase at 1.8 A resolution
Proteins
73
254-258
2008
Homo sapiens
Manually annotated by BRENDA team
Boonsri, P.; Neumann, T.S.; Olson, A.L.; Cai, S.; Herdendorf, T.J.; Miziorko, H.M.; Hannongbua, S.; Sem, D.S.
Molecular docking and NMR binding studies to identify novel inhibitors of human phosphomevalonate kinase
Biochem. Biophys. Res. Commun.
430
313-319
2013
Homo sapiens (Q15126), Homo sapiens
Manually annotated by BRENDA team
Nowroozi, F.F.; Baidoo, E.E.; Ermakov, S.; Redding-Johanson, A.M.; Batth, T.S.; Petzold, C.J.; Keasling, J.D.
Metabolic pathway optimization using ribosome binding site variants and combinatorial gene assembly
Appl. Microbiol. Biotechnol.
98
1567-1581
2014
Homo sapiens
Manually annotated by BRENDA team
Wang, J.; Liu, Y.; Liu, F.; Huang, C.; Han, S.; Lv, Y.; Liu, C.J.; Zhang, S.; Qin, Y.; Ling, L.; Gao, M.; Yu, S.; Li, C.; Huang, M.; Liao, S.; Hu, X.; Lu, Z.; Liu, X.; Jiang, T.; Tang, Z.; Zhang, H.; Guo, A.Y.; Liu, M.
Loss-of-function mutation in PMVK causes autosomal dominant disseminated superficial porokeratosis
Sci. Rep.
6
24226
2016
Homo sapiens (Q15126)
Manually annotated by BRENDA team