Information on EC 2.7.11.2 - [pyruvate dehydrogenase (acetyl-transferring)] kinase

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The expected taxonomic range for this enzyme is: Eukaryota

EC NUMBER
COMMENTARY hide
2.7.11.2
-
RECOMMENDED NAME
GeneOntology No.
[pyruvate dehydrogenase (acetyl-transferring)] kinase
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
ATP + [pyruvate dehydrogenase (acetyl-transferring)] = ADP + [pyruvate dehydrogenase (acetyl-transferring)] phosphate
show the reaction diagram
ATP + [pyruvate dehydrogenase (acetyl-transferring)] = ADP + [pyruvate dehydrogenase (acetyl-transferring)]phosphate
show the reaction diagram
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
phopho group transfer
phospho group transfer
-
-
-
-
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 hide
9074-01-5
-
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
-
SwissProt
Manually annotated by BRENDA team
multi-copy gene BnPDK1
UniProt
Manually annotated by BRENDA team
at least 4 different isozymes: PDK1, PDK2, PDK3, PDK4
-
-
Manually annotated by BRENDA team
Mus musculus C75BL/6
C75BL/6 mice
-
-
Manually annotated by BRENDA team
var. Alaskan Marvel
-
-
Manually annotated by BRENDA team
Rattus norvegicus Fawn-Hooded
-
-
-
Manually annotated by BRENDA team
mitochondrial precursor; isozyme PDK4
SwissProt
Manually annotated by BRENDA team
strain BY4741, gene YIL042c
-
-
Manually annotated by BRENDA team
strain BY4741, gene YIL042c
-
-
Manually annotated by BRENDA team
Xenopus (Silurana) tropicalis
female frogs
-
-
Manually annotated by BRENDA team
at least 2 isozymes
-
-
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
malfunction
metabolism
physiological function
additional information
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
ADP + pyruvate dehydrogenase
ADP + phosphorylated pyruvate dehydrogenase
show the reaction diagram
-
phosphorylation of serine residues of the E1 PDC component
-
-
ir
ATP + Ac-YHGHSMSDPGVSYR
ADP + [Ac-YHGHSMSDPGVSYR]phosphate
show the reaction diagram
ATP + casein
ADP + casein phosphate
show the reaction diagram
-
kidney enzyme, low activity
-
?
ATP + Pda1p subunit
ADP + phosphorylated Pda1p subunit
show the reaction diagram
ATP + PDHA1
ADP + phosphorylated PDHA1
show the reaction diagram
-
-
-
-
?
ATP + pyruvate dehydrogenase
ADP + phosphorylated pyruvate dehydrogenase
show the reaction diagram
ATP + pyruvate dehydrogenase complex
ADP + phosphorylated pyruvate dehydrogenase complex
show the reaction diagram
ATP + YHGHSMSDPGVSYR
ADP + ?
show the reaction diagram
-
-
-
?
ATP + [pyruvate dehydrogenase (acetyl-transferring)]
ADP + [pyruvate dehydrogenase (acetyl-transferring)] phosphate
show the reaction diagram
ATP + [pyruvate dehydrogenase (lipoamide)]
ADP + [pyruvate dehydrogenase (lipoamide)] phosphate
show the reaction diagram
additional information
?
-
NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
ATP + Pda1p subunit
ADP + phosphorylated Pda1p subunit
show the reaction diagram
ATP + pyruvate dehydrogenase
ADP + phosphorylated pyruvate dehydrogenase
show the reaction diagram
ATP + pyruvate dehydrogenase complex
ADP + phosphorylated pyruvate dehydrogenase complex
show the reaction diagram
ATP + [pyruvate dehydrogenase (acetyl-transferring)]
ADP + [pyruvate dehydrogenase (acetyl-transferring)] phosphate
show the reaction diagram
ATP + [pyruvate dehydrogenase (lipoamide)]
ADP + [pyruvate dehydrogenase (lipoamide)] phosphate
show the reaction diagram
additional information
?
-
COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
ATPgammaS
-
dissociation constants as ATP in binding to PDK3
additional information
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Divalent cations
-
requirement
Mn2+
-
can replace Mg2+ to some extent; requirement
Na+
-
hinders interaction between PDK2 and the inner lipoyl domain L2
NH4+
-
activation in the absence of ADP, inhibits in presence of ADP
phosphate
additional information
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
(R)-3,3,3-trifluoro-2-hydroxy-2-methylpropioamide
-
strong inhibition, isozymes PDK1 and PDK2, inhibition mechanism
2-Chloroisohexanoate
-
weak
2-oxobutyrate
-
-
4-[4-(4-methoxyphenyl)-5-methyl-1H-pyrazol-3-yl]benzene-1,3-diol
inhibitor M77976 binds to the ATP-binding pocket of PDK4 and causes local conformational changes with complete disordering of the ATP lid. M77976 binding also leads to a large domain rearrangement that further expands the active-site cleft of PDK4 compared with the ADP- and AMPPNP-bound forms
adenosine 5'-[beta,gamma,imido]triphosphate
-
isozymes PDK1 and PDK2, inhibition mechanism
adenosine 5'-[beta,gamma-imido]triphosphate
-
-
ATP
-
above 0.5 mM, substrate inhibition, only in the presence of K+, Mg2+ does not protect
AZ12
-
i.e. N-[4-([ethylanilino]sulfonyl)2-methylphenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide, binding structure, requires K+ for inhibition
AZD7545
Butyryl-CoA
-
at high concentrations
Chymotrypsin
-
proteolysis of kinase alpha-, not beta-subunit, no inactivation by trypsin-mediated proteolysis of beta-subunit
-
Cl-
-
40% inhibition at 80 mM, K+-independent inhibition
CoA
-
-
compound K
decanoyl-CoA
-
-
Dichloroacetate
dichloroacetophenone
-
isozymes PDK1 and PDK2, inhibition mechanism
Dihydrolipoic acid
Disulfides
-
thiols reverse
H2O2
-
PDHK2 activity is inhibited by low levels of hydrogen peroxide generated by the respiratory chain via reversible oxidation of Cys45 and Cys392 on PDHK2
Hexanoyl-CoA
-
-
HPO42-
Insulin
lactone derivative of dichloroacetophenone
-
isozymes PDK1 and PDK2, inhibition mechanism
Linolenoyl-CoA
-
-
linoleoyl-CoA
-
-
menadione
-
PDHK2 activity is inhibited via reversible oxidation of Cys45 and Cys392 on PDHK2
MnCl2
-
-
myristoyl-CoA
-
-
Na+
-
above 50 mM, alone and synergism with ADP
NAD+
-
-
oleoyl-CoA
-
-
oximes of triterpenes
Pfz3
-
i.e. N-(2-aminoethyl)-2-(3-chloro-4-[(4-isopropylbenzyl)oxy]phenyl)acetamide, binding site structure, involves e.g. the R domain, allosteric inhibition mechanism, overview
phosphate
Pyruvamide
-
inhibition of isozymes PDK1, PDK2, and PDK4
pyruvate
R-lipoic acid
radicicol
Rapamycin
-
inhibits PDK2 and PDK4, has no effect on insulin-caused downregulation of the isozymes
S-lipoic acid
SO42-
-
with the same effect as HPO42-
stearoyl-CoA
-
-
thiamine diphosphate
triterpenes
-
isozymes PDK1 and PDK2, inhibition mechanism
-
Trypsin
additional information
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
2-oxoisopentanoate
acetoacetyl-CoA
-
slight activation
acetyl-CoA
AZD7545
-
structural mechanisms for inhibition of pyruvate dehydrogenase kinase isozymes, binding structure analysis, overview, when the E2p/E3BP core is absent, AZD7545 stimulates scaffold-free basal PDK1 and PDK3 activities to 1.3fold and 10fold, respectively
-
benzoyl-CoA
-
slight activation
dibutyryl cAMP
-
in muscle, reversed by insulin
Dihydrolipoyl transacetylase
free fatty acids
-
leads to overexpression of isozyme PDK4 via mechanism involving peroxisome proliferator-activated receptor-alpha
-
glucocorticoids
inner lipoyl-bearing domain 2
-
i.e. L2, binding to the inner lipoyl domain L2 of E2 component of the PDC enzyme complex activates and regulates the enzyme by conformational changes and disrupting the ATP lid and eliminating product inhibition by ADP, mechanism, L2 binding strongly decreases PDHK2 affinity for ATP, strongest activation occurrs in presence of E1, E1-binding domain, and E2, overview
-
L-methylmalonyl-CoA
-
slight activation
L2 domain
-
inner lipoyl domain of the E2 component of PDC, activates PDK2
-
L2 domain of pyruvate dehydrogenase complex
-
binding to the inner lipoyl domains L2 of E2 component activate the enzyme by conformational changes and disrupting the ATP lid and eliminating product inhibition by ADP, binding structure, overview, L2 binding increases affinities for both ADP and ATP
-
lipoyl domain L2
-
L2 of the PDK3-containing pyruvate dehydrogenase complex induces a cross-tail conformation in PDK3, resulting in an opening of the active site cleft and the stimulation of kinase activity
-
malonyl-CoA
-
-
Octanoate
-
in muscle, reversed by insulin
oleate
-
activates PDK2 and PDK4 nearly 2fold at 0.1 mM, not synergistic with palmitate, stimulation is completely inhibited by insulin at 0.001 mM
palmitate
-
activates PDK2 and PDK4 nearly 2fold at 0.1 mM, not synergistic with oleate, stimulation is completely inhibited by insulin at 0.001 mmM
peroxisome proliferator-activated receptor-alpha
-
involved in mechanism to enhance expression of isozyme PDK4, but not isozyme PDK2, during starvation
-
phosphate
-
isozyme PDK43, direct inhibition and elevation of the Km for ATP
propionyl-CoA
-
slight activation at low concentrations, synergism with NADH plus NAD+
pyruvate
Thyroid hormones
-
selective increase in amount of isozyme PDHK4 protein in both hyperthyroidism and high-fat feeding
-
WY-14,643
additional information
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.006 - 1.5
ATP
0.02
Mg2+
0.0006 - 3.5
Pyruvate dehydrogenase
additional information
additional information
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.12 - 4.7
ATP
0.0004 - 0.55
Pyruvate dehydrogenase
0.0383 - 0.277
[Pyruvate dehydrogenase (lipoamide)]
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0031
adenosine 5'-[beta,gamma-imido]triphosphate
-
pH 7.4, 30C, versus ATP
0.1 - 1.6
ADP
0.2 - 1
Dichloroacetate
10
HPO42-
-
pH 7.8, 30C
0.27 - 0.325
pyruvate
additional information
additional information
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.648
4-[4-(4-methoxyphenyl)-5-methyl-1H-pyrazol-3-yl]benzene-1,3-diol
Homo sapiens
Q16654
pH 8.0, temperature not specified in the publication
0.087 - 0.6
AZD7545
0.013 - 108
Dichloroacetate
0.23 - 1.079
radicicol
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
0.006
-
PDK3 activity with E1
0.008
purified recombinant enzyme
0.018
-
purified dihydrolipoyl transacetylase-protein X-pyruvate dehydrogenase kinase subcomplex
0.02
-
about, with E2 bound to E1, 0.2 mM ATP
0.027
-
PDK2 activity with E1
0.03
-
about, with E2 bound to E1 in presence of NADH/NAD+ and acetyl-CoA, 0.2 mM ATP
0.031
-
PDK1 activity with E1
0.032
-
PDK4 activity with E1
0.037
-
about, with free E2, 0.2 mM ATP
0.038
-
PDK4 activity with reconstituted PDC
0.045
PDHK2 mutant T302A
0.056
-
PDK1 activity with reconstituted PDC
0.064
-
PDK3 activity with reconstituted PDC
0.066
-
about, with free E2 in presence of NADH/NAD+ and acetyl-CoA, 0.2 mM ATP
0.087
-
PDK2 activity with reconstituted PDC
0.17
PDHK2 mutant R250A
0.276
-
fed rat, purified enzyme
0.332
-
purified enzyme, in presence of dihydrolipoyl transacetylase
0.44
-
isozyme PDK3, pH 7.3, 30C
0.46
PDHK2 mutant Y320F
0.53
wild type PDHK2
0.69
-
isozyme PDK2, pH 7.3, 30C
0.74
-
purified recombinant enzyme, in presence of NADH and acetyl-CoA
0.92
-
purified recombinant enzyme, in presence of NADH and acetyl-CoA
1.1
-
purified isozyme PDK2
1.24
-
starved rat, purified enzyme
1.9 - 2.7
-
purified enzyme, in presence of dihydrolipoyl transacetylase, reconstituted enzyme complex
additional information
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
7 - 7.2
-
in presence of Mg2+ or Mn2+
7 - 7.4
-
assay at
7
-
assay at
7 - 7.4
-
assay at
7.2
-
assay at
7.2 - 8
-
broad, at 0.15 M buffer concentration
additional information