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Enzyme Nomenclature
Information on EC 2.7.6.2 - thiamine diphosphokinase
Word Map on EC 2.7.6.2
- 2.7.6.2
- pyrophosphate
- tpp
- transketolase
- dihydropteroate
-
ribosephosphate
-
pyrophosphorylated
- pyrithiamine
-
hydroxymethyldihydropterin
- 6-hydroxymethyl-7,8-dihydropterin
- dihydroneopterin
- oxythiamine
-
thiamine-responsive
-
megaloblastic
-
beriberi
- medicine
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The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
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EC NUMBER 
COMMENTARY 
2.7.6.2
-
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RECOMMENDED NAME
GeneOntology No.
thiamine diphosphokinase
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
ATP + thiamine = AMP + thiamine diphosphate
-
-
-
-
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
diphosphate transfer
-
-
-
-
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PATHWAY
BRENDA Link
KEGG Link
MetaCyc Link
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SYSTEMATIC NAME
IUBMB Comments
ATP:thiamine diphosphotransferase
-
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CAS REGISTRY NUMBER
COMMENTARY
9026-24-8
-
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
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GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
TPK1 mutations cause thiamine pyrophosphokinase deficiency, a treatable neurological disorder. Diagnosis of TPK deficiency in a clinical setting, overview. TPK1 mutations result in episodic encephalopathy type thiamine metabolism dysfunction is the most recently described disorder of this group
physiological function
thiamine diphosphate is a cofactor for enzymes important in a range of fundamental processes such as cellular respiration (pyruvate dehydrogenase and 2-ketoglutarate dehydrogenase) and in providing substrates for synthesis of nucleic acids, nucleotides, fatty acids and steroids (transketolase in the pentose phosphate pathway). It is needed for the catabolism of amino acids (branched-chain ?-keto acid dehydrogenase), phytanic acid and 2-hydroxy straight chain fatty acids (2-hydroxyphytanoyl-CoA lyase)
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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 + thiamine
AMP + thiamine diphosphate
thiamine pyrophosphokinase is required for thiamine cofactor activation in Arabidopsis
-
-
?
ATP + thiamine
AMP + thiamine diphosphate
no TMP kinase activity is shown by either isozymes TPK1 or TPK2
-
-
?
ATP + thiamine
AMP + thiamine diphosphate
the tpk-1 gene functions cell nonautonomously, as the expression of wild-type tpk-1 in one tissue can residue the function of other tissues that express only mutant tpk-1. Thiamine diphosphate can be transported across the cell membrane
-
-
?
ATP + thiamine
AMP + thiamine diphosphate
Q59N99
importance of TPP/thiamine in the alpha-oxidation pathway. Most TPP is tightly bound to peroxisomal proteins, most likely to 2-hydroxyacyl-CoA lyase 1, HACL1, or membranes
-
-
?
ATP + thiamine
AMP + thiamine diphosphate
-
importance of TPP/thiamine in the alpha-oxidation pathway. Most TPP is tightly bound to peroxisomal proteins, most likely to 2-hydroxyacyl-CoA lyase 1, HACL1, or membranes
-
-
?
ATP + thiamine
AMP + thiamine diphosphate
-
the enzyme is important for the formation of the coenzyme thiamine diphosphate
-
-
?
ATP + thiamine
AMP + thiamine diphosphate
-
enzyme is involved in biosynthesis of thiamine diphosphate
-
-
?
ATP + thiamine
AMP + thiamine diphosphate
the enzyme is a regulator of thiamine metabolism, phosphate metabolism, mating, and growth
-
-
?
CTP + thiamine
CMP + thiamine diphosphate
31.4% of the activity with ATP
-
-
?
GTP + thiamine
GMP + thiamine diphosphate
-
GTP is the preferred nucleotide
-
-
-
GTP + thiamine
GMP + thiamine diphosphate
18.3% of the activity with ATP
-
-
?
pyrithiamine + ATP
pyrithiamine diphosphate + AMP
-
inhibits the substrate thiamine
-
-
?
pyrithiamine + ATP
pyrithiamine diphosphate + AMP
-
its specific activity is 30% lower in comparison to its natural substrate thiamine
-
-
?
thiamine + ATP
thiamine diphosphate + AMP
-
TPP plays a critical role in the carbohydrate and energy metabolism. It functions as a prosthetic group for the mitochondrial enzyme complexes like pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase and branched chain alpha-keto acid dehydrogenase. In addition, TPP is involved in the cytosolic pentose pathway functioning as coenzyme for transketolase.
-
-
?
UTP + thiamine
UMP + thiamine diphosphate
207% of the activity with ATP
-
-
?
additional information
?
-
-
thiamine binding site structure, overview
-
-
-
additional information
?
-
-
three common intronic variants in the maternal and fetal thiamine pyrophosphokinase gene (TPK1) are associated with birth weight, overview
-
-
-
additional information
?
-
-
the YcfN protein acts as a nonspecific adenosylcobinamide kinase enzyme, which is not associated with adenosylcobalamine biosynthesis, but it allows a CobU-deficient strain of serovar Typhimurium to synthesize enough adenosylcobalamine from cobinamide so that the cell can grow. YcfN is required for the phosphorylation of thiamine in the thiamine salvaging pathway of Escherichia coli
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-
-
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NATURAL SUBSTRATES
NATURAL PRODUCTS
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 + thiamine
AMP + thiamine diphosphate
F4IV16
thiamine pyrophosphokinase is required for thiamine cofactor activation in Arabidopsis
-
-
?
ATP + thiamine
AMP + thiamine diphosphate
P30636
the tpk-1 gene functions cell nonautonomously, as the expression of wild-type tpk-1 in one tissue can residue the function of other tissues that express only mutant tpk-1. Thiamine diphosphate can be transported across the cell membrane
-
-
?
ATP + thiamine
AMP + thiamine diphosphate
Q59N99
importance of TPP/thiamine in the alpha-oxidation pathway. Most TPP is tightly bound to peroxisomal proteins, most likely to 2-hydroxyacyl-CoA lyase 1, HACL1, or membranes
-
-
?
ATP + thiamine
AMP + thiamine diphosphate
-
importance of TPP/thiamine in the alpha-oxidation pathway. Most TPP is tightly bound to peroxisomal proteins, most likely to 2-hydroxyacyl-CoA lyase 1, HACL1, or membranes
-
-
?
ATP + thiamine
AMP + thiamine diphosphate
-
the enzyme is important for the formation of the coenzyme thiamine diphosphate
-
-
?
ATP + thiamine
AMP + thiamine diphosphate
P41888
the enzyme is a regulator of thiamine metabolism, phosphate metabolism, mating, and growth
-
-
?
thiamine + ATP
thiamine diphosphate + AMP
-
TPP plays a critical role in the carbohydrate and energy metabolism. It functions as a prosthetic group for the mitochondrial enzyme complexes like pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase and branched chain alpha-keto acid dehydrogenase. In addition, TPP is involved in the cytosolic pentose pathway functioning as coenzyme for transketolase.
-
-
?
additional information
?
-
-
three common intronic variants in the maternal and fetal thiamine pyrophosphokinase gene (TPK1) are associated with birth weight, overview
-
-
-
additional information
?
-
-
the YcfN protein acts as a nonspecific adenosylcobinamide kinase enzyme, which is not associated with adenosylcobalamine biosynthesis, but it allows a CobU-deficient strain of serovar Typhimurium to synthesize enough adenosylcobalamine from cobinamide so that the cell can grow. YcfN is required for the phosphorylation of thiamine in the thiamine salvaging pathway of Escherichia coli
-
-
-
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COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Co2+
Mg2+
Mn2+
Zn2+
Co2+
-
absolute requirement for a divalent cation such as Mg2+, Mn2+ or Co2+. In presence of 2 mM ATP maximal activity occurs with 1 mM Co2+
Mg2+
-
ligands electronic density map and Mg2+ coordination structure, the delta-oxygen from D113 and D115 and one oxygen atom from each phosphate group of the thiamine-PNP. The last coordination of this Mg2+ involves an oxygen atom from the free inorganic phosphate, overview
Mg2+
-
absolute requirement for a divalent cation such as Mg2+, Mn2+ or Co2+. In presence of 2 mM ATP maximal activity occurs with above 3 mM Mg2+
Mg2+
-
for optimal activity the ratio of magnesium to ATP must be fixed at 0.6. The Mg(ATP)26- species might by the actual diphosphoryl donor
Mn2+
-
absolute requirement for a divalent cation such as Mg2+, Mn2+ or Co2+. In presence of 2 mM ATP maximal activity occurs with 0.5 mM Mn2+
Mn2+
-
Substitution of magnesium by Mn2+ decreases the enzyme activity by 42%.
Zn2+
-
Substitution of magnesium by Zn2+ decreases the enzyme activity by 85%.
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INHIBITORS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
ALT-711
-
low-affinity inhibitor, mixed-mode inhibition with a major role for competitive inhibition
iodoacetamide
-
3.3 mM, 23.3% inhibition, activity is recovered to approximately 90% on incubation with a 10fold excess of dithiothreitol
PCMB
-
1 mM, 55.1% inhibition, activity is recovered to approximately 90% on incubation with a 10fold excess of dithiothreitol
PCMB
-
0.1 mM, complete inhibition, completely restored by 10 mM dithiothreitol
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
0.017
-
PfTPK2, with 4 mM magnesium ions in the enzyme assay; substrate: pyrithiamine, PfTPK
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pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
8 - 9
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pH RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
6.4 - 8
-
pH 6.4: about 40% of maximal activity, pH 8.0: about 50% of maximal activity
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TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
37
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TEMPERATURE RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
37 - 50
37°C: optimal activity of TPK2, 50°C: TPK2 is completely inactive
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pI VALUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
additional information
additional information
-
isozymes TPK1 and TPK2 are biochemically redundant cytosolic proteins that are similarly expressed throughout different plant tissues
additional information
isozymes TPK1 and TPK2 are biochemically redundant cytosolic proteins that are similarly expressed throughout different plant tissues
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LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
-
Peroxisomes are devoid of thiamine pyrophosphokinase activity.
additional information
additional information
Q59N99
no enzyme localization in the peroxisome, subcellular localization analysis, overview
-
additional information
-
no enzyme localization in the peroxisome, subcellular localization analysis, overview
-
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PDB
SCOP
CATH
ORGANISM
UNIPROT
Bacteroides thetaiotaomicron (strain ATCC 29148 / DSM 2079 / NCTC 10582 / E50 / VPI-5482)
Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
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MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
30000
96000
-
aggregate of the functional dimer, equilibrium sedimentation
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SUBUNITS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
dimer
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Crystallization/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
purified recombinant enzyme in complex with ATP analogue AMP-PNP and thiamine, hanging drop vapor diffusion method, mixing of 500 nl of protein solution with 500 nl of reservoir solution containing 17.5-20% PEG 4000, 0.2 M MgCl2 , 0.1 M Tris, and 20% glycerol, pH 7.0-pH 7.5, and equilibration against 1 ml or reservoir solution, X-ray diffraction structure determination and analysis at 1.96-2.1 A resolution
-
complexed with thiamin diphosphate-Mg2+ or thiamin-Mg2+, hanging drop vapor diffusion method, using 1.15-1.3 M sodium citrate, 0.1 M Na-HEPES, pH 8.6, at 22°C
-
Crystallization experiments were set up by incubating mouse TPK with pyrithiamine and MgATP2- prior to adding the equilibrium mixture of enzyme, substrate, and products to the previously determined crystallization conditions.
-
hanging-drop vapor diffusion method, crystals of the complex of native recombinant enzyme with thiamine
-
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TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
the enzyme becomes increasingly unstable with progressive purification
-
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Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
partial
recombinant His-tagged wild-type and mutant enzymes from Escherichia coli strain BL21(DE3)pLysS by cobalt affinity chromatography
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Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
Escherichia coli strain KL21 (DE3)pLysS is transformed with the expression vector coding for a histidine-tagged wild-type or mutant hTPK1
-
gene TPK1, TPK1 Sanger sequencing analysis, recombinant expression of His-tagged wild-type and mutant enzymes in Escherichia coli strain BL21(DE3)pLysS
isozymes TPK1 and TPK2, DNA and amino acid sequence determination and analysis, phylogenetic analysis, expression in Escherichia coli strain BL21, expression of fluorescent tagged isozymes in cytosol of mesophyll protoplasts
TPK1 gene, located in 7q34-36, genotyping in 964 individuals from 220 families of European ancestry revealing an association between maternal rs228584 genotype and offspring birth weight
-
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EXPRESSION
ORGANISM
UNIPROT
LITERATURE
during embryogenesis, total thiamin diphosphokinase transcripts increase abruptly in early development, and decrease to about half of the peak shortly after hatching
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ENGINEERING
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
D133N
-
mutation causes a selective decrease in the ratio of turnover-number to Km-value for thiamine
D222H
naturally occurring homozygous TPK1 mutation in a patient with enzyme deficiency suffering neurological disorder
Q96E
-
mutation causes an 2.5fold increase in the ratio of turnover-number to Km-value for thiamine compared to the wild-type
S160L
naturally occurring homozygous TPK1 mutation in a patient with enzyme deficiency suffering neurological disorder. Early thiamine supplementation prevents encephalopathic episodes and improved developmental progression of Patient 1, emphasizing the importance of early diagnosis and treatment of TPK deficiency. The p.Ser160Leu mutation is predicted to interferewith TPK dimerization, which may be another mechanism for the disease
S74A
-
mutation causes a 1.4fold increase in turnover number, the Km-value for ATP is 2fold that of the wild-type enzyme
additional information
additional information
-
construction of a double knockout mutant lacking isozymes TPK1 and TPK2, the mutant shows severely depressed levels of TPP and elevated levels of free thiamine compared to the wild-type enzyme
additional information
construction of a double knockout mutant lacking isozymes TPK1 and TPK2, the mutant shows severely depressed levels of TPP and elevated levels of free thiamine compared to the wild-type enzyme
additional information
-
three common intronic variants in the maternal and fetal thiamine pyrophosphokinase gene (TPK1) are associated with birth weight, overview
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
-
Malaria is a devastating and quite often deadly parasitic disease, resulting in significant public health problems in the tropics. The inevitable emergence of drug-resistant forms requires the continuous discovery and development of new antimalarials. These drugs should only target the parasite, with only harmless or no effects on the human host. Thus, ideal drug targets would be peculiarities in the parasite metabolism, such as vitamin B1 and B6 biosyntheses that are absent in its host.
additional information
-
Administration of oxythiamine to animals produces primarily metabolic aberrations such as lethargy and anorexia while the administration of pyrithiamine to animals produces neurological problems similar to Wernicke-Korsakoff Syndrome.
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LINKS TO OTHER DATABASES (specific for EC-Number 2.7.6.2)
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