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IUBMB Comments A mitochondrial enzyme associated with the 3-methyl-2-oxobutanoate dehydrogenase complex. Simultaneously dephosphorylates and activates EC 1.2.4.4 3-methyl-2-oxobutanoate dehydrogenase (2-methylpropanoyl-transferring), that has been inactivated by phosphorylation.
The enzyme appears in viruses and cellular organisms
Synonyms ppm1k, more
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alpha-ketoacid dehydrogenase
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branched-chain alpha-keto acid dehydrogenase phosphatase
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branched-chain oxo-acid dehydrogenase phosphatase
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phosphatase, branched-chain 2-keto acid dehydrogenase
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phosphatase, branched-chain oxo acid dehydrogenase
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[3-methyl-2-oxobutanoate dehydrogenase (lipoamide)]-phosphatase
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[3-methyl-2-oxobutanoate dehydrogenase (lipoamide)]-phosphate phosphohydrolase
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BCKDH
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PP2Cm
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PPM1K
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[3-methyl-2-oxobutanoate dehydrogenase (2-methylpropanoyl-transferring)] phosphate + H2O = [3-methyl-2-oxobutanoate dehydrogenase (2-methylpropanoyl-transferring)] + phosphate
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hydrolysis of phosphoric ester
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[3-methyl-2-oxobutanoate dehydrogenase (2-methylpropanoyl-transferring)]-phosphate phosphohydrolase
A mitochondrial enzyme associated with the 3-methyl-2-oxobutanoate dehydrogenase complex. Simultaneously dephosphorylates and activates EC 1.2.4.4 3-methyl-2-oxobutanoate dehydrogenase (2-methylpropanoyl-transferring), that has been inactivated by phosphorylation.
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4-nitrophenyl phosphate + H2O
4-nitrophenol + phosphate
Substrates: - Products: -
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[3-methyl-2-oxobutanoate dehydrogenase (2-methylpropanoyl-transferring)] phosphate + H2O
[3-methyl-2-oxobutanoate dehydrogenase (2-methylpropanoyl-transferring)] + phosphate
Substrates: - Products: -
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[3-methyl-2-oxobutanoate dehydrogenase (lipoamide)] phosphate + H2O
[3-methyl-2-oxobutanoate dehydrogenase (lipoamide)] + phosphate
[ATP-citrate lyase] phosphate + H2O
[ATP-citrate lyase] + phosphate
Substrates: - Products: -
?
additional information
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[3-methyl-2-oxobutanoate dehydrogenase (lipoamide)] phosphate + H2O
[3-methyl-2-oxobutanoate dehydrogenase (lipoamide)] + phosphate
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Substrates: - Products: -
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[3-methyl-2-oxobutanoate dehydrogenase (lipoamide)] phosphate + H2O
[3-methyl-2-oxobutanoate dehydrogenase (lipoamide)] + phosphate
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Substrates: catalyzes the release of phosphate from both sites on the alpha-subunit of the branched-chain 2-oxo acid dehydrogenase E1 component, which results in reactivation of the complex Products: -
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[3-methyl-2-oxobutanoate dehydrogenase (lipoamide)] phosphate + H2O
[3-methyl-2-oxobutanoate dehydrogenase (lipoamide)] + phosphate
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Substrates: role in breakdown of essential branched-chain amino acids Products: -
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[3-methyl-2-oxobutanoate dehydrogenase (lipoamide)] phosphate + H2O
[3-methyl-2-oxobutanoate dehydrogenase (lipoamide)] + phosphate
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Substrates: - Products: -
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additional information
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Substrates: inactive with phosphorylase a and with 4-nitrophenyl phosphate Products: -
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additional information
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Substrates: PP2Cm interacts with the BCKD E2 subunit and competes with the BCKD kinase in a substrate-dependent and mutually exclusive manner Products: -
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[3-methyl-2-oxobutanoate dehydrogenase (lipoamide)] phosphate + H2O
[3-methyl-2-oxobutanoate dehydrogenase (lipoamide)] + phosphate
additional information
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Substrates: PP2Cm interacts with the BCKD E2 subunit and competes with the BCKD kinase in a substrate-dependent and mutually exclusive manner Products: -
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[3-methyl-2-oxobutanoate dehydrogenase (lipoamide)] phosphate + H2O
[3-methyl-2-oxobutanoate dehydrogenase (lipoamide)] + phosphate
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Substrates: - Products: -
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[3-methyl-2-oxobutanoate dehydrogenase (lipoamide)] phosphate + H2O
[3-methyl-2-oxobutanoate dehydrogenase (lipoamide)] + phosphate
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Substrates: role in breakdown of essential branched-chain amino acids Products: -
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[3-methyl-2-oxobutanoate dehydrogenase (lipoamide)] phosphate + H2O
[3-methyl-2-oxobutanoate dehydrogenase (lipoamide)] + phosphate
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Substrates: - Products: -
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Mn2+
Mn2+ may substitute for Mg2+
Mg2+
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required
Mg2+
two Mg2+ ions are located in the active site of wild-type
additional information
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active in absence of divalent cation
additional information
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active in absence of divalent cation
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CDP
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50% inhibition at 400 mM; inhibition is completely reversed by Mg2+
CTP
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50% inhibition at 250 mM; inhibition is completely reversed by Mg2+
guanosine 5'-(beta,gamma-imido)triphosphate
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UDP
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50% inhibition at 250 mM; inhibition is completely reversed by Mg2+
UTP
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50% inhibition at 100 mM; inhibition is completely reversed by Mg2+
acyl-CoA
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acyl-CoA
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inhibition is partially reversed by Mg2+
ADP
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inhibition is completely reversed by Mg2+; inhibition is completely reversed by spermine
ADP
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50% inhibition at 400 mM; inhibition is completely reversed by Mg2+
ATP
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completely reversed by spermine; inhibition is completely reversed by Mg2+
ATP
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50% inhibition at 200 mM; inhibition is completely reversed by Mg2+
CoA
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CoA
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inhibition is not reversed by Mg2+
GDP
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inhibition is completely reversed by Mg2+; inhibition is completely reversed by spermine
GDP
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50% inhibition at 200 mM; inhibition is completely reversed by Mg2+
GTP
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inhibition is completely reversed by Mg2+; inhibition is completely reversed by spermine
GTP
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50% inhibition at 60 mM; inhibition is completely reversed by Mg2+
heparin
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heparin
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50% inhibition at 0.002 mg/ml, partially reversed by Mg2+
Inhibitor protein
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BCKDH phosphatase inhibitor protein, inhibits at nanomolar concentrations
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Inhibitor protein
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purification of heat- and acid-stable inhibitor protein, which regulates activity
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Inhibitor protein
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non competitive; purification of heat- and acid-stable inhibitor protein, which regulates activity
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nucleoside diphosphates
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nucleoside diphosphates
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inhibition is completely reversed by Mg2+
nucleoside triphosphates
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nucleoside triphosphates
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inhibition is completely reversed by Mg2+
additional information
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little inhibitory effect: nucleoside monophosphates; little inhibitory effect: protein phosphatase inhibitor 1 and inhibitor 2
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additional information
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little inhibitory effect: AMP; little inhibitory effect: GMP; little inhibitory effect: NAD+; little inhibitory effect: NADH; little inhibitory effect: UMP
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additional information
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little inhibitory effect: AMP; little inhibitory effect: GMP; little inhibitory effect: NAD+; little inhibitory effect: NADH; little inhibitory effect: UMP
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histone H3
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stimulates at 0.036 mg/ml
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poly(L-arginine)
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stimulates 1.5-3fold at 0.0036 mg/ml
poly(L-lysine)
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stimulates 1.5-3fold at 0.0036 mg/ml
protamine
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stimulates 1.5-3fold at 0.0036 mg/ml
Skeletal muscle factor
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stimulates
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Carcinoma, Hepatocellular
Transcribed pseudogene ?PPM1K generates endogenous siRNA to suppress oncogenic cell growth in hepatocellular carcinoma.
Cardiovascular Diseases
Crystal structure and catalytic activity of the PPM1K N94K mutant.
Cardiovascular Diseases
Effects of PPM1K rs1440581 and rs7678928 on serum branched-chain amino acid levels and risk of cardiovascular disease.
Diabetes Mellitus, Type 2
Crystal structure and catalytic activity of the PPM1K N94K mutant.
Heart Defects, Congenital
The study of copy number variations in the regions of PRKAB2 and PPM1K among congenital heart defects patients.
Heart Septal Defects, Ventricular
The study of copy number variations in the regions of PRKAB2 and PPM1K among congenital heart defects patients.
Insulin Resistance
Effect of the interaction between diet composition and the PPM1K genetic variant on insulin resistance and ? cell function markers during weight loss: results from the Nutrient Gene Interactions in Human Obesity: implications for dietary guidelines (NUGENOB) randomized trial.
Leukemia
PPM1K Regulates Hematopoiesis and Leukemogenesis through CDC20-Mediated Ubiquitination of MEIS1 and p21.
Maple Syrup Urine Disease
A novel regulatory defect in the branched-chain ?-keto acid dehydrogenase complex due to a mutation in the PPM1K gene causes a mild variant phenotype of maple syrup urine disease.
Maple Syrup Urine Disease
Crystal structure and catalytic activity of the PPM1K N94K mutant.
Neoplasms
Transcribed pseudogene ?PPM1K generates endogenous siRNA to suppress oncogenic cell growth in hepatocellular carcinoma.
Non-alcoholic Fatty Liver Disease
Effects of PPM1K rs1440581 and rs7678928 on serum branched-chain amino acid levels and risk of cardiovascular disease.
Obesity
Branched-chain amino acids in metabolic signalling and insulin resistance.
Obesity
Effect of the interaction between diet composition and the PPM1K genetic variant on insulin resistance and ? cell function markers during weight loss: results from the Nutrient Gene Interactions in Human Obesity: implications for dietary guidelines (NUGENOB) randomized trial.
Tetralogy of Fallot
The study of copy number variations in the regions of PRKAB2 and PPM1K among congenital heart defects patients.
[3-methyl-2-oxobutanoate dehydrogenase (2-methylpropanoyl-transferring)]-phosphatase deficiency
PPM1K Regulates Hematopoiesis and Leukemogenesis through CDC20-Mediated Ubiquitination of MEIS1 and p21.
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3.8 - 50.9
4-nitrophenyl phosphate
3.8
4-nitrophenyl phosphate
mutant N94K, presence of Mn2+, 30°C, pH 7.5
4.8
4-nitrophenyl phosphate
wild-type, presence of Mn2+, 30°C, pH 7.5
39.8
4-nitrophenyl phosphate
mutant N94K, presence of Mg2+, 37°C, pH 7.5
50.9
4-nitrophenyl phosphate
wild-type, presence of Mg2+, 37°C, pH 7.5
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0.5 - 40.9
4-nitrophenyl phosphate
0.5
4-nitrophenyl phosphate
mutant N94K, presence of Mg2+, 37°C, pH 7.5
1
4-nitrophenyl phosphate
wild-type, presence of Mg2+, 37°C, pH 7.5
22.9
4-nitrophenyl phosphate
mutant N94K, presence of Mn2+, 30°C, pH 7.5
40.9
4-nitrophenyl phosphate
wild-type, presence of Mn2+, 30°C, pH 7.5
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0.00000013
Inhibitor protein
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pH 7.3, 30°C
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UniProt
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UniProt
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male Sprague-Dawley
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inner membrane-matrix compartment
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Highest Expressing Human Cell Lines
Filter by:
Cell Line Links
Gene Links
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malfunction
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Simvastatin administration increases BCKDH activity state and stimulates branched-chain amino acids (BCAAs) catabolism in rats fed with the low protein diet In contrast to rats subjected to protein restriction simvastatin has no effect on liver BCKDH activity in rats fed with the standard diet
physiological function
inhibition of the kinase BDK or overexpression of the phosphatase PPM1K that regulate branched-chain ketoacid dehydrogenase BCKDH, lowers circulating branched-chain amino acid levels, reduces hepatic steatosis, and improves glucose tolerance in the absence of weight loss in Zucker fatty rats. ATP-citrate lyase is an alternate substrate of BDK and PPM1K. BDK and PPM1K transcript levels are increased and repressed, respectively, in response to fructose feeding or expression of the ChREBP-b transcription factor
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D4A7X5_RAT
372
0
41014
TrEMBL
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PPM1K_HUMAN
372
0
40997
Swiss-Prot
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230000
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gel filtration, under conditions of high dilution, low MW form
33000
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1 * 33000, catalytic subunit, SDS-PAGE
460000
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gel filtration
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additional information
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enzyme is associated with the 3-methyl-2-oxobutanoate dehydrogenase complex
additional information
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1 * 33000, catalytic subunit, SDS-PAGE
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mutant N94K, three Mg2+ ions are located in the active site of mutant N94K instead of two Mg2+ ions in the PPM1K wild type
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A193X
single-nucleotide polymorphisms (SNPs) in human PP2Cm: mutant demonstrate basal activity against branched-chain alpha-keto dehydrogenase (BCKD) but impaired responsiveness to branched-chain-alpha-keto acids (BCKAs)
E321K
single-nucleotide polymorphisms (SNPs) in human PP2Cm: mutant demonstrate basal activity against branched-chain alpha-keto dehydrogenase (BCKD) but impaired responsiveness to branched-chain-alpha-keto acids (BCKAs). Mutant is not detected by immunoblot using human PP2Cm antibody. Therefore, it remains unclear whether this mutant is phosphatase dead due to loss-of-function mutations or unstable due to premature truncation
F359X
single-nucleotide polymorphisms (SNPs) in human PP2Cm: frameshift mutant shows no phosphatase activity at basal or after branched-chain-alpha-keto acids (BCKA) treatment. Mutant is not detected by immunoblot using human PP2Cm antibody. Therefore, it remains unclear whether this mutant is phosphatase dead due to loss-of-function mutations or unstable due to premature truncation
I167T
single-nucleotide polymorphisms (SNPs) in human PP2Cm: mutation has no an elevated activity compared to wild-type
additional information
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motifs responsible for PP2Cm and E2 interaction: using deletion mutants it is shown that the region between the residues 46 and 61 is critical to the association of PP2Cm with the complex
N94K
single-nucleotide polymorphisms (SNPs) in human PP2Cm: mutation has no impact on PP2Cm activity
N94K
missense mutant due to single nucleotide polymorphism. Mutation significantly impairs Mg2+-dependent catalytic activity and induces a conformational change in the key residue in coordinating the Mg2+ in the active site
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-20°C, stable for at least 6 months
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-80°C, stable for at least 2 weeks
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4°C, partially purified enzyme stable for several weeks
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a high and a low MW form
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expressed in HEK293 cells
expression in Escherichia coli
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branched-chain amino acid (BCAA) controls PP2Cm gene transcription
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PP2Cm expression is highly enriched in brain, heart, liver, kidney and diaphragm
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Damuni, Z.; Reed, L.J.
Purification and properties of the catalytic subunit of the branched-chain alpha-keto acid dehydrogenase phosphatase from bovine kidney mitochondria
J. Biol. Chem.
262
5129-5132
1987
Bos taurus
brenda
Fatania, H.R.; Patston, P.A.; Randle, P.J.
Dephosphorylation and reactivation of phosphorylated purified ox-kidney branched-chain dehydrogenase complex by co-purified phosphatase
FEBS Lett.
158
234-238
1983
Bos taurus
brenda
Damuni, Z.; Reed, L.J.
Branched-chain alpha-keto acid dehydrogenase phosphatase and its inhibitor protein from bovine kidney
Methods Enzymol.
166
321-329
1988
Bos taurus
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Damuni, Z.; Merryfield, M.L.; Humphreys, J.S.; Reed, L.J.
Purification and properties of branched-chain alpha-keto acid dehydrogenase phosphatase from bovine kidney
Proc. Natl. Acad. Sci. USA
81
4335-4338
1984
Bos taurus
brenda
Damuni, Z.; Humphreys, J.S.; Reed, L.J.
A potent, heat-stable protein inhibitor of [branched-chain alpha-keto acid dehydrogenase]-phosphatase from bovine kidney mitochondria
Proc. Natl. Acad. Sci. USA
83
285-289
1986
Bos taurus
brenda
Paul, H.S.; Adibi, S.A.
Mechanism of activation of hepatic branched-chain alpha-ketoacid dehydrogenase by a muscle factor
J. Biol. Chem.
258
11471-11475
1983
Rattus norvegicus
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Bradford, A.P.; Cook, K.G.; Yeaman, S.J.
Control of branched-chain 2-oxo acid dehydrogenase complex by reversible phosphorylation
Biochem. Soc. Trans.
13
745-746
1985
Bos taurus
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brenda
Zhou, M.; Lu, G.; Gao, C.; Wang, Y.; Sun, H.
Tissue-specific and nutrient regulation of the branched-chain alpha-keto acid dehydrogenase phosphatase, protein phosphatase 2Cm (PP2Cm)
J. Biol. Chem.
287
23397-23406
2012
Homo sapiens (Q8N3J5), Mus musculus
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Knapik-Czajka, M.
Simvastatin increases liver branched-chain alpha-ketoacid dehydrogenase activity in rats fed with low protein diet
Toxicology
325
107-114
2014
Rattus norvegicus
brenda
White, P.J.; McGarrah, R.W.; Grimsrud, P.A.; Tso, S.C.; Yang, W.H.; Haldeman, J.M.; Grenier-Larouche, T.; An, J.; Lapworth, A.L.; Astapova, I.; Hannou, S.A.; George, T.; Arlotto, M.; Olson, L.B.; Lai, M.; Zhang, G.F.; Ilkayeva, O.; Herman, M.A.; Wynn, R.M.; Chuang, D.T.; Newgard, C.B.
The BCKDH kinase and phosphatase integrate BCAA and lipid metabolism via regulation of ATP-citrate lyase
Cell Metab.
27
1281-1293
2018
Rattus norvegicus (D4A7X5)
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Dolatabad, M.; Guo, L.; Xiao, P.; Zhu, Z.; He, Q.; Yang, D.; Qu, C.; Guo, S.; Fu, X.; Li, R.; Ge, L.; Hu, K.; Liu, H.; Shen, Y.; Yu, X.; Sun, J.; Zhang, P.
Crystal structure and catalytic activity of the PPM1K N94K mutant
J. Neurochem.
148
550-560
2019
Homo sapiens (Q8N3J5), Homo sapiens
brenda
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