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Information on EC 2.7.11.2 - [pyruvate dehydrogenase (acetyl-transferring)] kinase and Organism(s) Mus musculus and UniProt Accession Q9JK42
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EC Tree
2.7.11.2 [pyruvate dehydrogenase (acetyl-transferring)] kinaseIUBMB Comments
The enzyme has no activating compound but is specific for its substrate. It is a mitochondrial enzyme associated with the pyruvate dehydrogenase complex in mammals. Phosphorylation inactivates EC 1.2.4.1, pyruvate dehydrogenase (acetyl-transferring).
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Word Map
- 2.7.11.2
- dichloroacetate
- peroxisome
-
proliferator-activated
- cardiac
- acetyl-coa
- carnitine
- starvation
-
warburg
- agonist
- glycogen
- adipose
- myocardial
-
tricarboxylic
-
high-fat
- triglyceride
-
hypoxia-inducible
- tca
-
gluconeogenesis
- palmitoyltransferase
- hexokinase
- pparalpha
- myotubes
-
forkhead
- pgc-1alpha
- soleus
-
lipoylated
-
insulin-stimulated
-
dihydrolipoyl
- coactivator-1
-
intramitochondrial
-
vastus
-
lateralis
-
dca-induced
-
estrogen-related
- transacetylase
-
alpha-ketoacid
- malonyl-coa
- e1alpha
-
alloxan-diabetes
-
ppardelta
- etomoxir
-
dca-treated
- medicine
- pharmacology
- drug development
The taxonomic range for the selected organisms is: Mus musculus
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Reaction Schemes
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Synonyms
pyruvate dehydrogenase kinase, pyruvate dehydrogenase kinase 4, pdh kinase, pdhk2, pdhk1, pdk-4, pyruvate dehydrogenase kinase-4, pdhk4, pyruvate dehydrogenase kinase 2, pdk-2, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
PDK2
kinase (phosphorylating), pyruvate dehydrogenase
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-
-
-
PDK1
PDK4
pyruvate dehydrogenase kinase
pyruvate dehydrogenase kinase (phosphorylating)
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-
-
-
pyruvate dehydrogenase kinase 4
pyruvate dehydrogenase kinase activator protein
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-
-
-
pyruvate dehydrogenase kinase
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-
-
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
phospho group transfer
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-
-
-
SYSTEMATIC NAME
IUBMB Comments
ATP:[pyruvate dehydrogenase (acetyl-transferring)] phosphotransferase
The enzyme has no activating compound but is specific for its substrate. It is a mitochondrial enzyme associated with the pyruvate dehydrogenase complex in mammals. Phosphorylation inactivates EC 1.2.4.1, pyruvate dehydrogenase (acetyl-transferring).
CAS REGISTRY NUMBER
COMMENTARY
9074-01-5
-
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 + pyruvate dehydrogenase complex
ADP + phosphorylated pyruvate dehydrogenase complex
-
-
-
?
ATP + [pyruvate dehydrogenase (acetyl-transferring)]
ADP + [pyruvate dehydrogenase (acetyl-transferring)] phosphate
ATP + [pyruvate dehydrogenase (acetyl-transferring)]
ADP + [pyruvate dehydrogenase (acetyl-transferring)] phosphate
ATP + [pyruvate dehydrogenase (lipoamide)]
ADP + [pyruvate dehydrogenase (lipoamide)] phosphate
ATP + [pyruvate dehydrogenase (acetyl-transferring)]
ADP + [pyruvate dehydrogenase (acetyl-transferring)] phosphate
-
-
-
?
ATP + [pyruvate dehydrogenase (acetyl-transferring)]
ADP + [pyruvate dehydrogenase (acetyl-transferring)] phosphate
-
-
-
?
ATP + pyruvate dehydrogenase complex
ADP + phosphorylated pyruvate dehydrogenase complex
-
-
-
-
?
ATP + pyruvate dehydrogenase complex
ADP + phosphorylated pyruvate dehydrogenase complex
-
-
-
?
ATP + pyruvate dehydrogenase complex
ADP + phosphorylated pyruvate dehydrogenase complex
-
PDHK4 inhibits the pyruvate dehydrogenase complex by phosphorylation during starvation, regulation mechanism, overview
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-
?
ATP + [pyruvate dehydrogenase (acetyl-transferring)]
ADP + [pyruvate dehydrogenase (acetyl-transferring)] phosphate
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-
-
-
?
ATP + [pyruvate dehydrogenase (acetyl-transferring)]
ADP + [pyruvate dehydrogenase (acetyl-transferring)] phosphate
-
-
-
?
ATP + [pyruvate dehydrogenase (acetyl-transferring)]
ADP + [pyruvate dehydrogenase (acetyl-transferring)] phosphate
-
-
-
?
ATP + [pyruvate dehydrogenase (lipoamide)]
ADP + [pyruvate dehydrogenase (lipoamide)] phosphate
-
-
-
ir
ATP + [pyruvate dehydrogenase (lipoamide)]
ADP + [pyruvate dehydrogenase (lipoamide)] phosphate
-
catalyzes inactivation through phosphorylation of pyruvate dehydrogenase complex EC 1.2.4.1
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ir
additional information
?
-
-
fibrates induction of PDK4 might be coupled to an decrease in serum triglycerides and fatty acid levels which can cause protein degradation in muscles, PDK4 induction is increased in acute rhabdomyolysis
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-
?
additional information
?
-
-
PDK4 is critically important in the starved state because it helps prevent hypoglycemia, the enzyme is part of the pyruvate dehydrogenase complex PDC, complex regulation and the molecular mechanisms
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-
?
additional information
?
-
-
regulation of pyruvate dehydrogenase kinase expression by the farnesoid X receptor, mechanism
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-
?
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 + [pyruvate dehydrogenase (acetyl-transferring)]
ADP + [pyruvate dehydrogenase (acetyl-transferring)] phosphate
ATP + pyruvate dehydrogenase complex
ADP + phosphorylated pyruvate dehydrogenase complex
-
PDHK4 inhibits the pyruvate dehydrogenase complex by phosphorylation during starvation, regulation mechanism, overview
-
-
?
ATP + [pyruvate dehydrogenase (acetyl-transferring)]
ADP + [pyruvate dehydrogenase (acetyl-transferring)] phosphate
ATP + [pyruvate dehydrogenase (lipoamide)]
ADP + [pyruvate dehydrogenase (lipoamide)] phosphate
-
catalyzes inactivation through phosphorylation of pyruvate dehydrogenase complex EC 1.2.4.1
-
ir
ATP + [pyruvate dehydrogenase (acetyl-transferring)]
ADP + [pyruvate dehydrogenase (acetyl-transferring)] phosphate
-
-
-
?
ATP + [pyruvate dehydrogenase (acetyl-transferring)]
ADP + [pyruvate dehydrogenase (acetyl-transferring)] phosphate
-
-
-
?
ATP + [pyruvate dehydrogenase (acetyl-transferring)]
ADP + [pyruvate dehydrogenase (acetyl-transferring)] phosphate
-
-
-
-
?
ATP + [pyruvate dehydrogenase (acetyl-transferring)]
ADP + [pyruvate dehydrogenase (acetyl-transferring)] phosphate
-
-
-
?
ATP + [pyruvate dehydrogenase (acetyl-transferring)]
ADP + [pyruvate dehydrogenase (acetyl-transferring)] phosphate
-
-
-
?
additional information
?
-
-
fibrates induction of PDK4 might be coupled to an decrease in serum triglycerides and fatty acid levels which can cause protein degradation in muscles, PDK4 induction is increased in acute rhabdomyolysis
-
-
?
additional information
?
-
-
PDK4 is critically important in the starved state because it helps prevent hypoglycemia, the enzyme is part of the pyruvate dehydrogenase complex PDC, complex regulation and the molecular mechanisms
-
-
?
additional information
?
-
-
regulation of pyruvate dehydrogenase kinase expression by the farnesoid X receptor, mechanism
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Mg2+
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
oximes of triterpenes
-
with 17beta hydroxyl and abietane derivatives, several, overview
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P53
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negatively regulates transcription of the pyruvate dehydrogenase kinase Pdk2
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
-
farnesoid X receptor agonist GW4064 stimulates PDK4 expression in liver in vivo
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additional information
-
PDK4 mRNA is very rapidly induced by fibrates, e.g. bezafibrate, and statins, e.g. statin, pravastatin, or simvastatin, and anti-bacterial drugs, e.g. quinolon, ofloxacin, and norfloxacin, in a tissue-specific manner, overview
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
isoform PDK2 is predominantly expressed in the arcuate nucleus at high levels but not in other areas of diabetic mouse brain
additional information
-
determination of PDK4 expression level in presence or absence of farnesoid X receptor agonists
additional information
-
tissue-specific induction of PDK4 by statins, fibrates, and anti-bacterial drugs, overview
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
physiological function
malfunction
metabolism
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p53 negatively regulates transcription of the pyruvate dehydrogenase kinase Pdk2, which negatively regulates the pyruvate dehydrogenase complex. Decreased levels of Pdk2 and P-Pdc in turn promote conversion of pyruvate into acetyl-CoA instead of lactate
physiological function
malfunction
isoform PDK2 ablation or inhibition in mouse astrocytes attenuates diabetes-induced hypothalamic inflammation, lactate surge, increased food intake, and hyperglycemia in mice
malfunction
isoform PDK2 deletion or inhibition prevents polarization of macrophages to the M1 phenotype in response to inflammatory stimuli (lipopolysaccharide plus interferon gamma). Global isoform PDK2 deficiency in high fat diet-fed mice reduces insulin resistance and adipose tissue inflammation
physiological function
isoform PDK2 up-regulation in the diabetic dorsal root ganglion plays a critical role in inducing peripheral as well as central sensitizations, eventually causing diabetic neuropathic pain
physiological function
astrocytic isoform PDK2 regulates metabolic and inflammatory pathways that contribute to hypothalamic manifestations of diabetes
physiological function
enzyme isoform PDK2 is a metabolic checkpoint for polarization of macrophages to the M1 phenotype
malfunction
-
pyruvate dehydrogenase activity is 2.5fold higher at rest in PDK4 knockout mouse muscle compared to the wild-type, and about 2fold in activated muscle at low and high intensity contraction
malfunction
-
wild-type mouse primary cortical neurons treated with amyloid beta peptide or cortical tissue extracts from 12-month-old APPswe/PS1dE9 transgenic mice show decreased expression of lactate dehydrogenase A and PDK1 when compared with controls
malfunction
enzyme-deficiency dramatically reduces the expression of genes related to fatty acid uptake, synthesis and gluconeogenesis. Enzyme deficiency ameliorates the hepatic steatosis significantly in nonalcoholic steatohepatitis mice
malfunction
isoform PDK4 deletion or inhibition prevents polarization of macrophages to the M1 phenotype in response to inflammatory stimuli (lipopolysaccharide plus interferon gamma). Global isoform PDK4 deficiency in high fat diet-fed mice reduces insulin resistance and adipose tissue inflammation
physiological function
-
PDK1 phosphorylates and inhibits pyruvate dehydrogenase, an enzyme responsible for the conversion of pyruvate to acetyl-CoA
physiological function
-
Pdk2 is seen as the key control point in conversion of pyruvate to acetyl-CoA reaction because it responds allosterically to rapid local changes in substrate and product: Pdk2-specific activity increases if acetyl-CoA and NADH levels increase, but decreases if pyruvate levels increase
physiological function
-
pyruvate dehydrogenase kinase 4 is one of four PDH kinases regulating the function of the pyruvate dehydrogenase complex, PDH. PDK4 is responsible for reducing PDH activity during low- to moderate-intensity muscle stimulation for contraction of the extensor digitorum muscle
physiological function
isoform PDK4 up-regulation in the diabetic dorsal root ganglion plays a critical role in inducing peripheral as well as central sensitizations, eventually causing diabetic neuropathic pain
physiological function
enzyme isoform PDK4 is a metabolic checkpoint for polarization of macrophages to the M1 phenotype
physiological function
the enzyme potentially contributes to the hepatic steatosis in nonalcoholic steatohepatitis via regulating several signaling pathway
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). PDK2_MOUSE
407
0
46041
Swiss-Prot
Mitochondrion (Reliability: 3)
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
-
enzyme-deficient PDHK4-/- mice show lower blood glucose levels and increased pyruvate dehydrogenase complex activity in kidney, gastrocnemius muscle, diaphragm and heart, but not in the liver, compared to the wild-type mice, the mutant mice accumulate less lactate and pyruvate because of a faster rate of pyruvate oxidation and a reduced rate of glycolysis, phenotype, overview, heterozygous mutant mice show about 50% reduced enzyme activity in skeletal muscle, genotype distribution, overview
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
overexpression of either PDK1 in rat CNS cell line B12 confers resistance to amyloid-beta peptide and other neurotoxins
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the gene encoding PDK4 is located on chromosome 6, DNA sequence analysis, genomic organization, possible regulatory important elements are Sp1 and CBF sites
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EXPRESSION
ORGANISM
UNIPROT
LITERATURE
hepatic enzyme levels are highly induced in methionine and choline deficient diet fed mice
the amount of Pdk2 mRNA in both colon and spleen decreases upon irradiation of wild-type mice but not upon irradiation of p53 knockout mice, p53 decreases Pdk2 transcription in vivo
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REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Aicher, T.D.; Damon, R.E.; Koletar, J.; Vinluan, C.C.; Brand, L.J.; Gao, J.; Shetty, S.S.; Kaplan, E.L.; Mann, W.R.
Triterpene and diterpene inhibitors of pyruvate dehydrogenase kinase (PDK)
Bioorg. Med. Chem. Lett.
9
2223-2228
1999
Mus musculus, Rattus norvegicus
Kwon, H.S.; Harris, R.A.
Mechanisms responsible for regulation of pyruvate dehydrogenase kinase 4 gene expression
Adv. Enzyme Regul.
44
109-121
2004
Homo sapiens, Mus musculus, Rattus norvegicus
Savkur, R.S.; Bramlett, K.S.; Michael, L.F.; Burris, T.P.
Regulation of pyruvate dehydrogenase kinase expression by the farnesoid X receptor
Biochem. Biophys. Res. Commun.
329
391-396
2005
Homo sapiens, Mus musculus, Mus musculus C57BL/6, Rattus norvegicus
Motojima, K.; Seto, K.
Fibrates and statins rapidly and synergistically induce pyruvate dehydrogenase kinase 4 mRNA in the liver and muscles of mice
Biol. Pharm. Bull.
26
954-958
2003
Mus musculus
Jeoung, N.H.; Wu, P.; Joshi, M.A.; Jaskiewicz, J.; Bock, C.B.; Depaoli-Roach, A.A.; Harris, R.A.
Role of pyruvate dehydrogenase kinase isoenzyme 4 (PDHK4) in glucose homoeostasis during starvation
Biochem. J.
397
417-425
2006
Mus musculus
Herbst, E.A.; Dunford, E.C.; Harris, R.A.; Vandenboom, R.; Leblanc, P.J.; Roy, B.D.; Jeoung, N.H.; Peters, S.J.
Role of pyruvate dehydrogenase kinase 4 in regulating PDH activation during acute muscle contraction
Appl. Physiol. Nutr. Metab.
37
48-52
2012
Mus musculus
Contractor, T.; Harris, C.R.
p53 negatively regulates transcription of the pyruvate dehydrogenase kinase Pdk2
Cancer Res.
72
560-567
2012
Homo sapiens, Mus musculus
Newington, J.T.; Rappon, T.; Albers, S.; Wong, D.Y.; Rylett, R.J.; Cumming, R.C.
Overexpression of pyruvate dehydrogenase kinase 1 and lactate dehydrogenase A in nerve cells confers resistance to amyloid beta and other toxins by decreasing mitochondrial respiration and reactive oxygen species production
J. Biol. Chem.
287
37245-37258
2012
Homo sapiens, Mus musculus, Rattus norvegicus
Rahman, M.H.; Jha, M.K.; Kim, J.H.; Nam, Y.; Lee, M.G.; Go, Y.; Harris, R.A.; Park, D.H.; Kook, H.; Lee, I.K.; Suk, K.
Pyruvate dehydrogenase kinase-mediated glycolytic metabolic shift in the dorsal root ganglion drives painful diabetic neuropathy
J. Biol. Chem.
291
6011-6025
2016
Mus musculus (O70571), Mus musculus (Q9JK42)
Klyuyeva, A.; Tuganova, A.; Kedishvili, N.; Popov, K.M.
Tissue-specific kinase expression and activity regulate flux through the pyruvate dehydrogenase complex
J. Biol. Chem.
294
838-851
2019
Mus musculus (O70571), Mus musculus (Q8BFP9), Mus musculus (Q922H2), Mus musculus (Q9JK42), Mus musculus
Zhang, M.; Zhao, Y.; Li, Z.; Wang, C.
Pyruvate dehydrogenase kinase 4 mediates lipogenesis and contributes to the pathogenesis of nonalcoholic steatohepatitis
Biochem. Biophys. Res. Commun.
495
582-586
2018
Homo sapiens, Mus musculus (Q16654)
Min, B.; Park, S.; Kang, H.; Kim, D.; Ham, H.; Ha, C.; Choi, B.; Lee, J.; Oh, C.; Yoo, E.; Kim, H.; Kim, B.; Jeon, J.; Hyeon, D.; Hwang, D.; Kim, Y.; Lee, C.; Lee, T.; Jungwhan, K.; Choi, Y.; Park, K.; Chawla, A.; Lee, J.; Harris, R.; Lee, I.
Pyruvate dehydrogenase kinase is a metabolic checkpoint for polarization of macrophages to the M1 phenotype
Front. Immunol.
10
944
2019
Mus musculus (O70571), Mus musculus (Q9JK42)
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