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Information on EC 2.7.1.185 - mevalonate 3-kinase and Organism(s) Thermoplasma acidophilum and UniProt Accession Q9HIN1
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2.7.1.185 mevalonate 3-kinaseIUBMB Comments
Mevalonate 3-kinase and mevalonate-3-phosphate-5-kinase (EC 2.7.1.186) act sequentially in an alternate mevalonate pathway in the archaeon Thermoplasma acidophilum. Mevalonate 3-kinase is different from mevalonate kinase, EC 2.7.1.36, which transfers phosphate to position 5 of (R)-mevalonate and is part of the classical mevalonate pathway in eukaryotes and archaea.
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Word Map
- 2.7.1.185
- acidophilum
-
thermoplasma
-
isopentenyl
-
isoprenoids
- pyrophosphate
- decarboxylases
-
picrophilus
- archaea
- torridus
- cholesterol
- synthesis
The taxonomic range for the selected organisms is: Thermoplasma acidophilum
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Synonyms
mevalonate 3-kinase, mevalonate-3-kinase, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
Ta1305
SYSTEMATIC NAME
IUBMB Comments
ATP:(R)-mevalonate 3-phosphotransferase
Mevalonate 3-kinase and mevalonate-3-phosphate-5-kinase (EC 2.7.1.186) act sequentially in an alternate mevalonate pathway in the archaeon Thermoplasma acidophilum. Mevalonate 3-kinase is different from mevalonate kinase, EC 2.7.1.36, which transfers phosphate to position 5 of (R)-mevalonate and is part of the classical mevalonate pathway in eukaryotes and archaea.
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
ATP + (R)-mevalonate
ADP + (R)-3-phosphomevalonate
-
-
-
?
ATP + (R)-mevalonate
ADP + (R)-3-phosphomevalonate
mevalonate-3-kinase and mevalonate-3-phosphate-5-kinase act sequentially in a putative alternate mevalonate pathway in Thermoplasma acidophilum
-
-
?
ATP + (R)-mevalonate
ADP + (R)-3-phosphomevalonate
the enzyme is part of a putative alternate mevalonate pathway in Thermoplasma acidophilum
-
-
?
additional information
?
-
substrate specificity, overview
-
-
-
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
ATP + (R)-mevalonate
ADP + (R)-3-phosphomevalonate
-
-
-
?
ATP + (R)-mevalonate
ADP + (R)-3-phosphomevalonate
mevalonate-3-kinase and mevalonate-3-phosphate-5-kinase act sequentially in a putative alternate mevalonate pathway in Thermoplasma acidophilum
-
-
?
ATP + (R)-mevalonate
ADP + (R)-3-phosphomevalonate
the enzyme is part of a putative alternate mevalonate pathway in Thermoplasma acidophilum
-
-
?
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
8.5
8.5
the monomeric and dimeric forms have equal activity under optimal conditions
pH RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
7 - 9.5
pH 7.0: about 75% of maximal activity, pH 9.5: about 85% of maximal activity
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
55
55
the monomeric and dimeric forms have equal activity under optimal conditions
TEMPERATURE RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
40 - 60
40°C: about 55% of maximal activity, 60°C: about 95% of maximal activity
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
mevalonate 3-kinase is an enzyme involved in the modified mevalonate pathway specific to limited species of thermophilic archaea
metabolism
mevalonate 3-kinase plays a key role in a recently discovered modified mevalonate pathway specific to thermophilic archaea of the order Thermoplasmatales, pathway overview. In the pathway called modified MVA pathway II, mevalonate (MVA) is phosphorylated at the 3-hydroxyl group to yield 3-phosphomevalonate (MVA-3-P) by the action of mevalonate 3-kinase (M3K) rather than at the 5-hydroxyl group as in the reaction of MVK (EC 2.7.4.2). M3K is also homologous to diphosphomevalonate decarboxylase (DMD, EC 4.1.1.33). After the formation of MVA-3-P, another kinase, MVA-3-P 5-kinase (M3P5K), catalyzes its 5-phosphorylation, and a subsequent decarboxylation is catalyzed by another DMD homologue, 3,5-bisphosphomevalonate decarboxylase (BMD), to give isopentenyl phosphate (IP). IP is then phosphorylated by isopentenyl phosphate kinase (IPK) to yield isopentenyl diphosphate (IPP). The M3K enzyme is homologous to diphosphomevalonate decarboxylase, which is involved in the widely distributed classical mevalonate pathway, and to phosphomevalonate decarboxylase, which is possessed by halophilic archaea and some Chloroflexi bacteria. Neither wild-type TacM3K nor any mutants show reactivity toward MVA 5-diphosphate
physiological function
additional information
physiological function
mevalonate-3-kinase and mevalonate-3-phosphate-5-kinase act sequentially in a putative alternate mevalonate pathway in Thermoplasma acidophilum
physiological function
the enzyme is part of a putative alternate mevalonate pathway in Thermoplasma acidophilum
physiological function
mevalonate 3-kinase catalyzes the ATP-dependent 3-phosphorylation of mevalonate but does not catalyze the subsequent decarboxylation as related decarboxylases do
additional information
comparison between the substrate-complex crystal structure of TacM3K (PDB ID 4RKS) and that of Sulfolobus solfataricus DMD (SsoDMD, PDB ID 5GMD) revealing interesting differences in the structures of the active sites. The steric hindrance introduced by Glu140 seems responsible for excluding larger substrates, such as MVA 5-phosphate and MVA 5-diphosphate, from the active site of TacM3K
additional information
-
comparison between the substrate-complex crystal structure of TacM3K (PDB ID 4RKS) and that of Sulfolobus solfataricus DMD (SsoDMD, PDB ID 5GMD) revealing interesting differences in the structures of the active sites. The steric hindrance introduced by Glu140 seems responsible for excluding larger substrates, such as MVA 5-phosphate and MVA 5-diphosphate, from the active site of TacM3K
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
dimer
the monomeric and dimeric forms have equal activity under optimal conditions
monomer
the monomeric and dimeric forms have equal activity under optimal conditions
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
analysis of the substrate-complex crystal structure of TacM3K (PDB ID 4RKS)
hanging drop method, crystal structure of mevalonate-3-kinase in the apo form, and with bound substrates is determined and compared to mevalonate diphosphate decarboxylase structures. The crystal structure of mevalonate-3-kinase provides insight into the mechanism of mevalonate diphosphate decarboxylase. Despite sharing nearly identical overall folds, important active site differences are identified. Glu140 in the center of the mevalonate-3-kinase active site is responsible for binding mevalonate while excluding mevalonate 5-diphosphate, Arg185/Ser105 catalyze phosphate transfer, and an invariant Asp/Lys pair previously thought to be responsible for phosphorylation in mevalonate diphosphate decarboxylase, is missing in mevalonate-3-kinase and replaced by non-essential Thr275/Leu18. A model is proposed in which mevalonate-3-kinase and mevalonate diphosphate decarboxylase both phosphorylate by stabilizing a phosphotransfer transition state (mevalonate-3-kinase via Arg185/Ser105, mevalonate diphosphate decarboxylase via Lys188), suggesting the invariant Asp/Lys pair unique to mevalonate diphosphate decarboxylase may be critical for the decarboxylation step rather than phosphorylation
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
E140G
site-directed mutagenesis, the mutation results in the conversion of mevalonate 3-kinase into 5-phosphomevalonate 3-kinase, which can synthesize 3,5-bisphosphomevalonate from 5-phosphomevalonate
E140S
site-directed mutagenesis, the mutation results in the conversion of mevalonate 3-kinase into 5-phosphomevalonate 3-kinase, which can synthesize 3,5-bisphosphomevalonate from 5-phosphomevalonate
L18A
kcat/KM for (R)-mevalonate is 4.4% compared to the wild-type value
R185K
kcat/KM for (R)-mevalonate is 0.5% compared to the wild-type value
S105A
kcat/KM for (R)-mevalonate is 10.3% compared to the wild-type value
T275A
kcat/KM for (R)-mevalonate is 25.6% compared to the wild-type value
additional information
additional information
substrate-interacting glutamate residue E140 of Thermoplasma acidophilum mevalonate 3-kinase is replaced by smaller amino acids, including its counterparts in diphosphomevalonate decarboxylase and phosphomevalonate decarboxylase, with the aim of altering substrate specificity. These single amino acid mutations results in the conversion of mevalonate 3-kinase into 5-phosphomevalonate 3-kinase, which can synthesize 3,5-bisphosphomevalonate from 5-phosphomevalonate. The mutants catalyzing the hitherto undiscovered reaction enables the construction of an artificial mevalonate pathway in Escherichia coli cells, as is demonstrated by the accumulation of lycopene, a red carotenoid pigment. Neither wild-type TacM3K nor any mutants show reactivity toward MVA 5-diphosphate. Alternative MVA pathway II overview. Constructed plasmids and strains, overview
additional information
-
substrate-interacting glutamate residue E140 of Thermoplasma acidophilum mevalonate 3-kinase is replaced by smaller amino acids, including its counterparts in diphosphomevalonate decarboxylase and phosphomevalonate decarboxylase, with the aim of altering substrate specificity. These single amino acid mutations results in the conversion of mevalonate 3-kinase into 5-phosphomevalonate 3-kinase, which can synthesize 3,5-bisphosphomevalonate from 5-phosphomevalonate. The mutants catalyzing the hitherto undiscovered reaction enables the construction of an artificial mevalonate pathway in Escherichia coli cells, as is demonstrated by the accumulation of lycopene, a red carotenoid pigment. Neither wild-type TacM3K nor any mutants show reactivity toward MVA 5-diphosphate. Alternative MVA pathway II overview. Constructed plasmids and strains, overview
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant His-tagged enzyme from Escherichia coli strain BL21 by nickel affinity chromatography
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expression in Escherichia coli
gene Ta1305, the pBAD-TacM plasmid series contains the genes of M3K, M3P5K, BMD, and IPK for the expression of part of modified MVA pathway II. Although the M3K, M3P5K, and IPK genes are derived from Thermoplasma acidophilum, various BMD genes have been utilized for plasmid construction. Recombinant expression of His-tagged enzyme in Escherichia coli strain BL21
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Vinokur, J.M.; Korman, T.P.; Cao, Z.; Bowie, J.U.
Evidence of a novel mevalonate pathway in archaea
Biochemistry
53
4161-4168
2014
Thermoplasma acidophilum (Q9HIN1), Thermoplasma acidophilum
Azami, Y.; Hattori, A.; Nishimura, H.; Kawaide, H.; Yoshimura, T.; Hemmi, H.
(R)-Mevalonate 3-phosphate is an intermediate of the mevalonate pathway in Thermoplasma acidophilum
J. Biol. Chem.
289
15957-15967
2014
Thermoplasma acidophilum (Q9HIN1)
Vinokur, J.M.; Korman, T.P.; Sawaya, M.R.; Collazo, M.; Cascio, D.; Bowie, J.U.
Structural analysis of mevalonate-3-kinase provides insight into the mechanisms of isoprenoid pathway decarboxylases
Protein Sci.
24
212-220
2015
Thermoplasma acidophilum (Q9HIN1), Thermoplasma acidophilum
Motoyama, K.; Sobue, F.; Kawaide, H.; Yoshimura, T.; Hemmi, H.
Conversion of mevalonate 3-kinase into 5-phosphomevalonate 3-kinase by single amino acid mutations
Appl. Environ. Microbiol.
85
e00256-19
2019
Thermoplasma acidophilum (Q9HIN1), Thermoplasma acidophilum, Thermoplasma acidophilum AMRC-C165 (Q9HIN1), Thermoplasma acidophilum ATCC 25905 (Q9HIN1), Thermoplasma acidophilum JCM 9062 (Q9HIN1), Thermoplasma acidophilum NBRC 15155 (Q9HIN1)
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