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Information on EC 2.7.11.4 - [3-methyl-2-oxobutanoate dehydrogenase (acetyl-transferring)] kinase and Organism(s) Homo sapiens
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2.7.11.4 [3-methyl-2-oxobutanoate 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 branched-chain 2-oxoacid dehydrogenase complex. Phosphorylation inactivates EC 1.2.4.4, 3-methyl-2-oxobutanoate dehydrogenase (2-methylpropanoyl-transferring).
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Word Map
- 2.7.11.4
- alpha-ketoacids
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bckas
- alpha-chloroisocaproate
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maple
- e1alpha
- syrup
- alpha-ketoisocaproate
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transacylase
- alpha-ketoisovalerate
The taxonomic range for the selected organisms is: Homo sapiens
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Reaction Schemes
Synonyms
bckdk, bckdh kinase, branched-chain alpha-ketoacid dehydrogenase kinase, bckd kinase, branched-chain alpha-keto acid dehydrogenase kinase, bckd-kinase, branched-chain 2-oxo acid dehydrogenase kinase, branched chain alpha-ketoacid dehydrogenase kinase, bcka dehydrogenase kinase, bckdc kinase, 
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topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
BCK
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BCKDH kinase
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BCKDK
branched-chain 2-oxo acid dehydrogenase kinase
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branched-chain alpha-keto acid dehydrogenase kinase
branched-chain alpha-ketoacid dehydrogenase kinase
branched-chain keto acid dehydrogenase kinase
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kinase, branched-chain oxo acid dehydrogenase (phosphorylating)
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branched-chain alpha-keto acid dehydrogenase kinase
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branched-chain alpha-ketoacid dehydrogenase kinase
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
phospho group transfer
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SYSTEMATIC NAME
IUBMB Comments
ATP:[3-methyl-2-oxobutanoate dehydrogenase (acetyl-transferring)] phosphotransferase
The enzyme has no activating compound but is specific for its substrate. It is a mitochondrial enzyme associated with the branched-chain 2-oxoacid dehydrogenase complex. Phosphorylation inactivates EC 1.2.4.4, 3-methyl-2-oxobutanoate dehydrogenase (2-methylpropanoyl-transferring).
CAS REGISTRY NUMBER
COMMENTARY
82391-38-6
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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 + mitogen-activated protein kinase kinase
ADP + phosphorylated mitogen-activated protein kinase kinase
ATP + [3-methyl-2-oxobutanoate dehydrogenase (acetyl-transferring)]
ADP + [3-methyl-2-oxobutanoate dehydrogenase (acetyl-transferring)] phosphate
additional information
?
-
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the branched-chain oxoacid dehydrogenase complex, BCOAD, is rate determining for the oxidation of branched-chain amino acids in skeletal muscle
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-
?
ATP + mitogen-activated protein kinase kinase
ADP + phosphorylated mitogen-activated protein kinase kinase
the enzyme promotes cell transformation or colorectal cancer by enhancing the MAPK signaling pathway through direct MEK phosphorylation
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?
ATP + mitogen-activated protein kinase kinase
ADP + phosphorylated mitogen-activated protein kinase kinase
phosphorylation of mitogen-activated protein kinase kinase (MEK) at Ser221
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-
?
ATP + [3-methyl-2-oxobutanoate dehydrogenase (acetyl-transferring)]
ADP + [3-methyl-2-oxobutanoate dehydrogenase (acetyl-transferring)] phosphate
Q14874
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?
ATP + [3-methyl-2-oxobutanoate dehydrogenase (acetyl-transferring)]
ADP + [3-methyl-2-oxobutanoate dehydrogenase (acetyl-transferring)] phosphate
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?
ATP + [3-methyl-2-oxobutanoate dehydrogenase (acetyl-transferring)]
ADP + [3-methyl-2-oxobutanoate dehydrogenase (acetyl-transferring)] phosphate
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phosphorylation-mediated inactivation of the E1alpha subunit of branched-chain ketoacid dehydrogenase, BCKDH
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-
?
ATP + [3-methyl-2-oxobutanoate dehydrogenase (acetyl-transferring)]
ADP + [3-methyl-2-oxobutanoate dehydrogenase (acetyl-transferring)] phosphate
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phosphorylation of residue Ser293 of the E1alpha subunit of branched-chain ketoacid dehydrogenase, BCKDH
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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 + mitogen-activated protein kinase kinase
ADP + phosphorylated mitogen-activated protein kinase kinase
the enzyme promotes cell transformation or colorectal cancer by enhancing the MAPK signaling pathway through direct MEK phosphorylation
-
-
?
ATP + [3-methyl-2-oxobutanoate dehydrogenase (acetyl-transferring)]
ADP + [3-methyl-2-oxobutanoate dehydrogenase (acetyl-transferring)] phosphate
additional information
?
-
-
the branched-chain oxoacid dehydrogenase complex, BCOAD, is rate determining for the oxidation of branched-chain amino acids in skeletal muscle
-
-
?
ATP + [3-methyl-2-oxobutanoate dehydrogenase (acetyl-transferring)]
ADP + [3-methyl-2-oxobutanoate dehydrogenase (acetyl-transferring)] phosphate
Q14874
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-
-
?
ATP + [3-methyl-2-oxobutanoate dehydrogenase (acetyl-transferring)]
ADP + [3-methyl-2-oxobutanoate dehydrogenase (acetyl-transferring)] phosphate
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-
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-
?
ATP + [3-methyl-2-oxobutanoate dehydrogenase (acetyl-transferring)]
ADP + [3-methyl-2-oxobutanoate dehydrogenase (acetyl-transferring)] phosphate
-
phosphorylation-mediated inactivation of the E1alpha subunit of branched-chain ketoacid dehydrogenase, BCKDH
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-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
N,N'-(1,2,5-oxadiazole-3,4-diyl)bis(3,6-dichlorobenzo[b]thiophene-2-carboxamide
Q14874
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N-(4-acetamido-1,2,5-oxadiazol-3-yl)-3,6-dichlorobenzo[b]thiophene-2-carboxamide
Q14874
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
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exercise training increases branched-chain oxoacid dehydrogenase kinase content in human skeletal muscle, mechanism, overview
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IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.00319
3,6-dichlorobenzo[b]thiophene-2-carboxylic acid
Homo sapiens
Q14874
pH and temperature not specified in the publication
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
the enzyme (BCKDK) is widely expressed in colorectal cancer patients, and patients that express higher levels of BCKDK have shorter survival times than those with lower levels
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
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patients with homozygous BCKDK mutations display reductions in BCKDK messenger RNA and protein, E1alpha phosphorylation, and plasma branched-chain amino acids. Inactivating mutations in the gene BCKDK in consanguineous families are associated with autism, epilepsy, and intellectual disability, geno- and phenotyping, overview
physiological function
physiological function
rate-limiting enzyme in branched-chain amino acids catabolism
physiological function
rate-limiting enzyme in branched-chain amino acids catabolism, which plays an important role in many serious human diseases. The enzyme promotes cell transformation or colorectal cancer by enhancing the MAPK signaling pathway through direct mitogen-activated protein kinase kinase (MEK) phosphorylation, rather than by branched-chain amino acids catabolism
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). BCKD_HUMAN
412
0
46360
Swiss-Prot
Mitochondrion (Reliability: 2)
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
G671C
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naturally occuring mutation, on chromosome 16, leads to the substitution of a highly conserved arginine with a proline at position 224 in BCKDK
L389P
Q14874
the mutation is associated with developmental delay, microcephaly, and neurobehavioral abnormalities
R174G
Q14874
the mutation is associated with developmental delay, microcephaly, and neurobehavioral abnormalities
R224P
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naturally occuring mutation, leading to disruption of the beta sheet in a flexible linker domain, structure modeling
additional information
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identification of mutations from autism patients , e.g. in exon 4 (C466T) resulting in a premature stop codon at amino acid position 156, prior to the kinase domain, or a single base deletion (c.G222del) in exon 2 leading to frame-shift terminating the protein at position 74 of 412 amino acids, whole-exome sequencing from two consanguineous families
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Howarth, K.R.; Burgomaster, K.A.; Phillips, S.M.; Gibala, M.J.
Exercise training increases branched-chain oxoacid dehydrogenase kinase content in human skeletal muscle
Am. J. Physiol.
293
R1335-R1341
2007
Homo sapiens
Novarino, G.; El-Fishawy, P.; Kayserili, H.; Meguid, N.; Scott, E.; Schroth, J.; Silhavy, J.; Kara, M.; Khalil, R.; Ben-Omran, T.; Ercan-Sencicek, A.; Hashish, A.; Sanders, S.; Gupta, A.; Hashem, H.; Matern, D.; Gabriel, S.; Sweetman, L.; Rahimi, Y.; Harr
Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy
Science
338
394-397
2012
Homo sapiens
Garcia-Cazorla, A.; Oyarzabal, A.; Fort, J.; Robles, C.; Castejon, E.; Ruiz-Sala, P.; Bodoy, S.; Merinero, B.; Lopez-Sala, A.; Dopazo, J.; Nunes, V.; Ugarte, M.; Artuch, R.; Palacin, M.; Rodriguez-Pombo, P.; Alcaide, P.; Navarrete, R.; Sanz, P.; Font-Llitjos, M.; Vilaseca, M.A.; Ormaizabal, A.; P, P.r.
Two novel mutations in the BCKDK (branched-chain keto-acid dehydrogenase kinase) gene are responsible for a neurobehavioral deficit in two pediatric unrelated patients
Hum. Mutat.
35
470-477
2014
Homo sapiens (Q14874), Homo sapiens
Tso, S.C.; Gui, W.J.; Wu, C.Y.; Chuang, J.L.; Qi, X.; Skvora, K.J.; Dork, K.; Wallace, A.L.; Morlock, L.K.; Lee, B.H.; Hutson, S.M.; Strom, S.C.; Williams, N.S.; Tambar, U.K.; Wynn, R.M.; Chuang, D.T.
Benzothiophene carboxylate derivatives as novel allosteric inhibitors of branched-chain alpha-ketoacid dehydrogenase kinase
J. Biol. Chem.
289
20583-20593
2014
Homo sapiens (Q14874), Homo sapiens, Mus musculus (O55028), Mus musculus
Xue, P.; Zeng, F.; Duan, Q.; Xiao, J.; Liu, L.; Yuan, P.; Fan, L.; Sun, H.; Malyarenko, O.S.; Lu, H.; Xiu, R.; Liu, S.; Shao, C.; Zhang, J.; Yan, W.; Wang, Z.; Zheng, J.; Zhu, F.
BCKDK of BCAA catabolism cross-talking with the MAPK pathway promotes tumorigenesis of colorectal cancer
EBioMedicine
20
50-60
2017
Homo sapiens (O13874), Homo sapiens
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