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Information on EC 1.2.4.1 - pyruvate dehydrogenase (acetyl-transferring) and Organism(s) Homo sapiens and UniProt Accession P08559

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IUBMB Comments
Contains thiamine diphosphate. It is a component (in multiple copies) of the multienzyme pyruvate dehydrogenase complex, EC 1.2.1.104, in which it is bound to a core of molecules of EC 2.3.1.12, dihydrolipoyllysine-residue acetyltransferase, which also binds multiple copies of EC 1.8.1.4, dihydrolipoyl dehydrogenase. It does not act on free lipoamide or lipoyllysine, but only on the lipoyllysine residue in EC 2.3.1.12.
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Homo sapiens
UNIPROT: P08559
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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
pdh, pdha1, mitochondrial pyruvate dehydrogenase, e1alpha, pyruvate dehydrogenase multienzyme complex, pyruvate dehydrogenase e1, pdhc-e1, mtpdc, pdhc e1, pyruvate dehydrogenase e1 component, more
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
PDHE1alpha
E1 alpha subunit of pyruvate dehydrogenase
pyruvate dehydrogenase multienzyme complex
-
thiamin-dependent pyruvate dehydrogenase
part of the pyruvate dehydrogenase multienzyme complex PDHc as component E1
dehydrogenase, pyruvate
-
-
-
-
mitochondrial pyruvate dehydrogenase
-
-
MtPDC
-
-
-
-
PDHa
-
subunit alpha of pyruvate dehydrogenase E1
PDHC
-
-
pyruvate decarboxylase
-
-
-
-
pyruvate dehydrogenase
-
-
-
-
pyruvate dehydrogenase complex
pyruvate dehydrogenase E1
-
bound to the E1-binding domain of dihydrolipoamide acetyltransferase (E2) in pyruvate dehydrogenase complex (PDC)
pyruvate dehydrogenase E1 alpha subunit
-
-
pyruvic acid dehydrogenase
-
-
-
-
pyruvic dehydrogenase
-
-
-
-
VEG220
-
-
-
-
Vegetative protein 220
-
-
-
-
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
pyruvate + [dihydrolipoyllysine-residue acetyltransferase] lipoyllysine = [dihydrolipoyllysine-residue acetyltransferase] S-acetyldihydrolipoyllysine + CO2
show the reaction diagram
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
redox reaction
-
-
-
-
oxidation
-
-
-
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reduction
-
-
-
-
SYSTEMATIC NAME
IUBMB Comments
pyruvate:[dihydrolipoyllysine-residue acetyltransferase]-lipoyllysine 2-oxidoreductase (decarboxylating, acceptor-acetylating)
Contains thiamine diphosphate. It is a component (in multiple copies) of the multienzyme pyruvate dehydrogenase complex, EC 1.2.1.104, in which it is bound to a core of molecules of EC 2.3.1.12, dihydrolipoyllysine-residue acetyltransferase, which also binds multiple copies of EC 1.8.1.4, dihydrolipoyl dehydrogenase. It does not act on free lipoamide or lipoyllysine, but only on the lipoyllysine residue in EC 2.3.1.12.
CAS REGISTRY NUMBER
COMMENTARY hide
9014-20-4
-
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
pyruvate + CoA + NAD+
acetyl-CoA + CO2 + NADH
show the reaction diagram
2-hydroxyethylidene-thiamine diphosphate + 2,6-dichlorophenolindophenol
S-acetyldihydrolipoamide + reduced 2,6-dichlorophenolindophenol
show the reaction diagram
-
-
-
?
acetaldehyde + benzaldehyde
(R)-phenylacetylcarbinol
show the reaction diagram
-
-
-
-
?
pyruvate + CoA + NAD+
acetyl-CoA + CO2 + NADH
show the reaction diagram
-
-
-
-
?
pyruvate + CoA + oxidized 2,6-dichlorophenolindophenol
acetyl-CoA + CO2 + reduced 2,6-dichlorophenolindophenol
show the reaction diagram
pyruvate + lipoamide
S-acetyldihydrolipoamide + CO2
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
pyruvate + CoA + NAD+
acetyl-CoA + CO2 + NADH
show the reaction diagram
-
-
-
?
pyruvate + CoA + NAD+
acetyl-CoA + CO2 + NADH
show the reaction diagram
-
-
-
-
?
pyruvate + lipoamide
S-acetyldihydrolipoamide + CO2
show the reaction diagram
-
-
-
ir
COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
thiamine diphosphate
thiamine diphosphate
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
3-deazathiamine diphosphate
-
competitive inhibitor, compound added to the culture medium for HeLa cells does not hamper the rate of cell growth and shows not significant impact on the viability of the cells
methyl acetylphosphonate
-
phosphonate analogue of pyruvate, leading to formation of a stable 1’,4’-imino-2-alpha-phosphonolactyl-thiamindiphosphate
Oxythiamine diphosphate
-
competitive inhibitor, shows a significant cytostatic effect on HeLa cell culture
phosphorylation
-
phosphorylation inactivates recombinant alpha2,beta2 tetramer in about 10 min
-
pyruvate dehydrogenase kinase
-
phosphorylation of E1p by pyruvate dehydrogenase kinase isoforms inactivates the pyruvate dehydrogenase complex
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thiamine 2-thiothiazolone diphosphate
-
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
pyruvate dehydrogenase kinase
-
dephosphorylation by pyruvatedehydrogenase phosphatase isoforms restores pyruvate dehydrogenase complex activity
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.01 - 0.026
pyruvate
0.0015
thiamine diphosphate
-
recombinant enzyme
additional information
additional information
-
detailed kinetic and thermodynamic analysis
-
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.077
pyruvate
-
pH 7.6, 30°C, presence of 0.3 M KCl
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0000737
thiamine 2-thiothiazolone diphosphate
-
-
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
0.0162
-
recombinant His-tagged-alpha2,beta2 tetramer, assay with 2-hydroxyethylidene-thiamine diphosphate and 2,6-dichlorphenolindophenol
0.0269
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recombinant His-tagged-alpha2,beta2 tetramer, assay with pyruvate and 2,6-dichlorphenolindophenol
0.13
-
recombinant alpha2beta2 tetramer
0.145
-
recombinant alpha2,His-tagged-beta2 tetramer, K3Fe(CN)6 as artificial electron acceptor
0.18
-
recombinant alpha2,beta2 tetramer with six histidine residues attached to the N-terminus
0.187
-
recombinant His-tagged-alpha2,beta2 tetramer, K3Fe(CN)6 as artificial electron acceptor
0.367
-
recombinant alpha2,His-tagged-beta2 tetramer, assay with pyruvate and 2,6-dichlorphenolindophenol
10.9
-
recombinant alpha2,His-tagged-beta2 tetramer, reduction of NAD+, overall reaction
14.4
-
recombinant His-tagged-alpha2,beta2 tetramer, reduction of NAD+, overall reaction
8.13
-
recombinant enzyme from liver
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
-
UniProt
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION?
ODPA_HUMAN
390
0
43296
Swiss-Prot
Mitochondrion (Reliability: 1)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
160000
-
recombinant alpha2,beta2 tetramer
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
heterotetramer
-
-
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
phosphoprotein
the PDC is tightly regulated by reversible phosphorylation at three known phosphorylation sites on PDHE1a: Ser293, Ser300, and Ser232
phosphorylation
phosphorylation of Ser264 slows the preceding binding of substrate to the enzyme's active site via the substrate channel and the subsequent reductive acetylation of the E2 component
proteolytic modification
-
cleavage of 29 amino acid long leader peptide from alpha subunit suggested from deduced protein sequence
side-chain modification
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phosphorylation of recombinant alpha2,beta2 tetramer, 3.25 phosphoryl groups per mol tetramer are incorporated, 50% phosphorylation within 10 min, only the alpha subunit is phosphorylated
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
vapour diffusion method with 14-18% PEG 3350, 0.1 mM sodium azide, and 200 mM NaSCN in 50 mM potassium phosphate (pH 8.0)
full and dynamic structural model of full human pyruvate dehydrogenase complex, including binding of the linking arms to the surrounding E1 (pyruvate decarboxylase) and E3 (dihydrolipoamide dehydrogenase) enzymes via their binding domains with variable stoichiometries. An optimalsetting of approximately 30 copies of E1 ensures stability of the surrounding E1 and E3 clouds. Decreasing the number of E1s increases the flexibility of the now nonoccupied arms. Their flexibility depends on the presence of other E1s and E3s in the vicinity, even if they are associated with other arms. As one consequence, the radius of gyration decreases with decreasing number of E1s
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recombinant enzyme, orthorhombic crystals in polyethylene glycol 3350 by vapor-diffusion method, space group P222
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PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
S264E
pseudophosphorylation mutant, the preceding binding of substrate to the enzyme's active site via the substrate channel and the subsequent reductive acetylation of the E2 component are severely slowed in the mutant enzyme
S264Q
selectively deficient in pyruvate binding and reductive acetylation of component E2
D289A
-
the beta subunit mutant does not have any detectable activity in assays with NAD+ and shows no change in activity in 2,6-dichlorophenolindophenol assays
D289N
-
the beta subunit mutant shows by 36% reduced activity in assays with NAD+
E229A
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the beta subunit mutant does not show drastic changes compared to the wild type E1 activities
E229Q
-
the beta subunit mutant does not show drastic changes compared to the wild type E1 activities
E232A
-
the beta subunit mutant does not show drastic changes compared to the wild type E1 activities
E232Q
-
the beta subunit mutant does not show drastic changes compared to the wild type E1 activities
E234A
-
the beta subunit mutant does not show drastic changes compared to the wild type E1 activities
E234Q
-
the beta subunit mutant does not show drastic changes compared to the wild type E1 activities
I329A
-
shows 37-43% reduction in activity compared to the wild type enzyme
R253G
-
the mutation is associated with low PDHc activity and absence of subunit alpha of pyruvate dehydrogenase E1
additional information
-
mutant I329DELTA (deletion at the C-terminal of E1) shows 62% reduction in activity compared to the wild type enzyme
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
Ni-NTA column chromatography
-
recombinant alpha and beta subunits and recombinant alpha2,beta2 tetramer
-
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expressed in Escherichia coli M15 cells
alpha-subunit
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beta-subunit
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co-expression of alpha subunit with human liver beta subunit in Escherichia coli
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expressed in Escherichia coli BL21 cells
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expression of alpha and beta subunits in Escherichia coli
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His-tagged alpha and beta subunits and alpha2,beta2 tetramer, expression in Escherichia coli
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
synthesis
coexpression of pyruvate dehydrogenase (PDH) E1 alpha and E1 beta subunitsin Escherichia coli leads to fully active E1 protein. The production of E1 alpha alone results in a catalytically inactive protein. The PDH E1 protein produced in Escherichia coli is capable of being phosphorylated by PDH-specific kinase
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Ho, L.; Patel, M.S.
Cloning and cDNA sequence of the beta-subunit component of human pyruvate dehydrogenase complex
Gene
86
297-302
1990
Homo sapiens
Manually annotated by BRENDA team
Ho, L.; Wexler, I.D.; Liu, T.C.; Thekkumara, T.J.; Patel, M.S.
Characterization of cDNAs encoding human pyruvate dehydrogenase alpha subunit
Proc. Natl. Acad. Sci. USA
86
5330-5334
1989
Homo sapiens
Manually annotated by BRENDA team
Dahl, H.H.M.; Hunt, S.M.; Hutchison, W.M.; Brown, G.K.
The human pyruvate dehydrogenase complex. Isolation of cDNA clones for the E1 alpha subunit, sequence analysis, and characterization of the mRNA
J. Biol. Chem.
262
7398-7403
1987
Homo sapiens
Manually annotated by BRENDA team
Korotchkina, L.G.; Tucker, M.M.; Thekkumkara, T.J.; Madhusudhan, K.T.; Pons, G.; Kim, H.; Patel, M.S.
Overexpression and characterization of human tetrameric pyruvate dehydrogenase and its individual subunits
Protein Expr. Purif.
6
79-90
1995
Bos taurus, Homo sapiens
Manually annotated by BRENDA team
Jeng, J.; Kallarakal, A.T.; Kim, S.F.; Popov, K.M.; Song, B.J.
Pyruvate dehydrogenase E1alpha isoform in rat testis: cDNA cloning, characterization, and biochemical comparison of the recombinant testis and liver enzymes
Comp. Biochem. Physiol. B
120
205-216
1998
Homo sapiens, Rattus norvegicus
Manually annotated by BRENDA team
Ciszak, E.; Korotchkina, L.G.; Hong, Y.S.; Joachimiak, A.; Patel, M.S.
Crystallization and initial x-ray diffraction analysis of human pyruvate dehydrogenase
Acta Crystallogr. Sect. D
57
465-468
2001
Homo sapiens
Manually annotated by BRENDA team
Nemeria, N.; Yan, Y.; Zhang, Z.; Brown, A.M.; Arjunan, P.; Furey, W.; Guest, J.R.; Jordan, F.
Inhibition of the Escherichia coli pyruvate dehydrogenase complex E1 subunit and its tyrosine 177 variants by thiamin 2-thiazolone and thiamin 2-thiothiazolone diphosphates. Evidence for reversible tight-binding inhibition
J. Biol. Chem.
276
45969-45978
2001
Escherichia coli, Homo sapiens
Manually annotated by BRENDA team
Seifert, F.; Golbik, R.; Brauer, J.; Lilie, H.; Schroeder-Tittmann, K.; Hinze, E.; Korotchkina, L.G.; Patel, M.S.; Tittmann, K.
Direct kinetic evidence for half-of-the-sites reactivity in the E1 component of the human pyruvate dehydrogenase multienzyme complex through alternating sites cofactor activation
Biochemistry
45
12775-12785
2006
Homo sapiens
Manually annotated by BRENDA team
Gurd, B.J.; Peters, S.J.; Heigenhauser, G.J.; LeBlanc, P.J.; Doherty, T.J.; Paterson, D.H.; Kowalchuk, J.M.
O2 uptake kinetics, pyruvate dehydrogenase activity, and muscle deoxygenation in young and older adults during the transition to moderate-intensity exercise
Am. J. Physiol. Regul. Integr. Comp. Physiol.
294
R577-R584
2008
Homo sapiens
Manually annotated by BRENDA team
Seifert, F.; Ciszak, E.; Korotchkina, L.; Golbik, R.; Spinka, M.; Dominiak, P.; Sidhu, S.; Brauer, J.; Patel, M.S.; Tittmann, K.
Phosphorylation of serine 264 impedes active site accessibility in the E1 component of the human pyruvate dehydrogenase multienzyme complex
Biochemistry
46
6277-6287
2007
Homo sapiens (P08559), Homo sapiens
Manually annotated by BRENDA team
Korotchkina, L.G.; Patel, M.S.
Binding of pyruvate dehydrogenase to the core of the human pyruvate dehydrogenase complex
FEBS Lett.
582
468-472
2008
Homo sapiens
Manually annotated by BRENDA team
Joao Silva, M.; Pinheiro, A.; Eusebio, F.; Gaspar, A.; Tavares de Almeida, I.; Rivera, I.
Pyruvate dehydrogenase deficiency: identification of a novel mutation in the PDHA1 gene which responds to amino acid supplementation
Eur. J. Pediatr.
168
17-22
2009
Homo sapiens
Manually annotated by BRENDA team
Li, J.; Kato, M.; Chuang, D.T.
Pivotal role of the C-terminal DW-motif in mediating inhibition of pyruvate dehydrogenase kinase 2 by dichloroacetate
J. Biol. Chem.
284
34458-34467
2009
Homo sapiens
Manually annotated by BRENDA team
Glushakova, L.G.; Lisankie, M.J.; Eruslanov, E.B.; Ojano-Dirain, C.; Zolotukhin, I.; Liu, C.; Srivastava, A.; Stacpoole, P.W.
AAV3-mediated transfer and expression of the pyruvate dehydrogenase E1 alpha subunit gene causes metabolic remodeling and apoptosis of human liver cancer cells
Mol. Genet. Metab.
98
289-299
2009
Homo sapiens
Manually annotated by BRENDA team
Rardin, M.J.; Wiley, S.E.; Naviaux, R.K.; Murphy, A.N.; Dixon, J.E.
Monitoring phosphorylation of the pyruvate dehydrogenase complex
Anal. Biochem.
389
157-164
2009
Mus musculus, Homo sapiens (P08559)
Manually annotated by BRENDA team
Jeng, J.; Huh, T.L.; Song, B.J.
Production of an enzymatically active E1 component of human pyruvate dehydrogenase complex in Escherichia coli supporting role of E1 beta subunit in E1 activity
Biochem. Biophys. Res. Commun.
203
225-230
1994
Homo sapiens (P08559 and P11177), Homo sapiens
Manually annotated by BRENDA team
Hezaveh, S.; Zeng, A.P.; Jandt, U.
Full enzyme complex simulation interactions in human pyruvate dehydrogenase complex
J. Chem. Inf. Model.
58
362-369
2018
Homo sapiens
Manually annotated by BRENDA team
Grabowska, E.; Czerniecka, M.; Czyzewska, U.; Zambrzycka, A.; Lotowski, Z.; Tylicki, A.
Differences in the efficiency of 3-deazathiamine and oxythiamine pyrophosphates as inhibitors of pyruvate dehydrogenase complex and growth of HeLa cells in vitro
J. Enzyme Inhib. Med. Chem.
36
122-129
2021
Homo sapiens, Sus scrofa
Manually annotated by BRENDA team