Activating Compound | Comment | Organism | Structure |
---|---|---|---|
thiamine diphosphate | E1 binds thiamine diphosphate, possessing two thiamine-binding pockets located between alpha and beta subunits | Homo sapiens |
Localization | Comment | Organism | GeneOntology No. | Textmining |
---|---|---|---|---|
mitochondrial inner membrane | human BCKD complex is likely located on the matrix side of the inner mitochondrial membrane | Homo sapiens | 5743 | - |
Natural Substrates | Organism | Comment (Nat. Sub.) | Natural Products | Comment (Nat. Pro.) | Rev. | Reac. |
---|---|---|---|---|---|---|
3-methyl-2-oxobutanoate + CoA + NAD+ | Homo sapiens | - |
2-methylpropanoyl-CoA + CO2 + NADH + H+ | - |
ir | |
3-methyl-2-oxopentanoate + CoA + NAD+ | Homo sapiens | - |
2-methylbutanoyl-CoA + CO2 + NADH + H+ | - |
ir | |
4-methyl-2-oxopentanoate + CoA + NAD+ | Homo sapiens | - |
3-methylbutanoyl-CoA + CO2 + NADH + H+ | - |
ir | |
additional information | Homo sapiens | the human BCKD complex catalyzes the irreversible oxidative decarboxylation of the branched-chain ketoacids (2-keto-isocaproate derived from leucine, 2-keto-3-methylglutarate obtained from isoleucine, and 2-keto-isovalerate from valine). This reaction produces CO2, NADH, and the respective branched-chain acyl-coA intermediates with a 1:1:1 stoichiometry. The action of BCKD complex generates isovaleryl-CoA from 2-ketoisocaproate (leucine), 2-methylbutyryl-CoA from 2-keto-3-methylglutarate (isoleucine), and isobutyryl-CoA from 2-keto-isovalerate (valine) | ? | - |
- |
Organism | UniProt | Comment | Textmining |
---|---|---|---|
Homo sapiens | P12694 AND P21953 | alpha and beta subunits of complex component E1 (BCKD), a tetramer (alpha2beta2), cf. EC 1.2.4.4 | - |
Posttranslational Modification | Comment | Organism |
---|---|---|
phosphoprotein | the activity of the BCKD complex is regulated by phosphorylation and dephosphorylation catalyzed by a kinase and a phosphatase, respectively. The BCKD kinase inhibits the complex whereas the BCKD phosphatase activates it | Homo sapiens |
Source Tissue | Comment | Organism | Textmining |
---|---|---|---|
adipose tissue | subcutaneous | Homo sapiens | - |
brain | - |
Homo sapiens | - |
colon | - |
Homo sapiens | - |
heart | - |
Homo sapiens | - |
kidney | - |
Homo sapiens | - |
liver | - |
Homo sapiens | - |
additional information | human tissue distribution of the BCKD complex: BCKD is highly found in kidney, liver, brain, and heart, more moderately in skeletal muscle, stomach, and colon. Subcutaneous adipose tissue and small intestine show the lowest BCKD complex activity | Homo sapiens | - |
skeletal muscle | - |
Homo sapiens | - |
small intestine | - |
Homo sapiens | - |
stomach | - |
Homo sapiens | - |
Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
---|---|---|---|---|---|---|
3-methyl-2-oxobutanoate + CoA + NAD+ | - |
Homo sapiens | 2-methylpropanoyl-CoA + CO2 + NADH + H+ | - |
ir | |
3-methyl-2-oxopentanoate + CoA + NAD+ | - |
Homo sapiens | 2-methylbutanoyl-CoA + CO2 + NADH + H+ | - |
ir | |
4-methyl-2-oxopentanoate + CoA + NAD+ | - |
Homo sapiens | 3-methylbutanoyl-CoA + CO2 + NADH + H+ | - |
ir | |
additional information | the human BCKD complex catalyzes the irreversible oxidative decarboxylation of the branched-chain ketoacids (2-keto-isocaproate derived from leucine, 2-keto-3-methylglutarate obtained from isoleucine, and 2-keto-isovalerate from valine). This reaction produces CO2, NADH, and the respective branched-chain acyl-coA intermediates with a 1:1:1 stoichiometry. The action of BCKD complex generates isovaleryl-CoA from 2-ketoisocaproate (leucine), 2-methylbutyryl-CoA from 2-keto-3-methylglutarate (isoleucine), and isobutyryl-CoA from 2-keto-isovalerate (valine) | Homo sapiens | ? | - |
- |
Subunits | Comment | Organism |
---|---|---|
More | the BCKD complex is a multiprotein enzyme composed of three subunits, E1, E2, and E3. A kinase and a phosphatase are attached to the E1 subunit and regulate the complex activity. The E1 subunit of the BCKD complex is a tetramer composed of two alpha and two beta components (alpha2beta2). The crystal structure of the E1 subunit has been determined, showing a tetrahedral arrangement of the two alpha and two beta subunits | Homo sapiens |
Synonyms | Comment | Organism |
---|---|---|
BCKD | - |
Homo sapiens |
branched-chain ketoacid dehydrogenase | - |
Homo sapiens |
More | cf. EC 1.2.4.4 | Homo sapiens |
Cofactor | Comment | Organism | Structure |
---|---|---|---|
CoA | - |
Homo sapiens | |
NAD+ | - |
Homo sapiens |
General Information | Comment | Organism |
---|---|---|
malfunction | inactivating homozygous mutations in the gene encoding BCKD kinase (BCKDK) have been identified in families with autism, epilepsy, and intellectual disability by whole exome sequencing. Affected patients show reduced plasma level of branched-chain amino acids. Disease-causing mutations in the genes encoding the subunits E1alpha, E1beta, E2, and E3 of the BCKD complex have been identified to cause the Maple syrup urine disease (MSUD), an autosomal recessive disorder usually diagnosed by newborn screening. Mutations in the subunits E1alpha, E1beta, and E2 cause MSUD types 1A, 1B, and 2, respectively. Mutations in the E3 subunit cause multiple dehydrogenase deficiency, as E3 is the subunit shared by the three 2-ketoacid dehydrogenase complexes (PDH, 2-ketoglutarate dehydrogenase and BCKD). Congenital deficiencies of enzymes involved in branched-chain amino acid metabolism: clinical phenotypes, overview | Homo sapiens |
metabolism | the enzyme plays an important role in the catabolism of branched-chain amino acids, detailed overview | Homo sapiens |
physiological function | the enzyme system catalyses the oxidative decarboxylation of branched-chain alpha-oxo acids derived from L-leucine, L-isoleucine, and L-valine to branched-chain acyl-CoAs. It belongs to the 2-oxoacid dehydrogenase system family, which also includes EC 1.2.1.104, pyruvate dehydrogenase system, EC 1.2.1.105, 2-oxoglutarate dehydrogenase system, EC 1.4.1.27, glycine cleavage system, and EC 2.3.1.190, acetoin dehydrogenase system. The BCKD complex is a multiprotein enzyme composed of three subunits, E1, E2, and E3. A kinase and a phosphatase are attached to the E1 subunit and regulate the complex activity. The E2 subunit constitutes the center of the complex to which the E1 and E3 components are attached. The E2 subunit consists of 24 identical elements, being a homo-24-meric structure that has three domains: the core domain, the binding domain, and the lipoyl domain (lipoic acid bearing domain). The binding domain attaches the subunits E1 and E3 to E2. The lipoyl domain is essential to substrate channeling within the complex. The core domain contains the active site. The E1 subunit of the BCKD complex is a tetramer composed of two alpha and two beta components (alpha2beta2). E1 is the BCKD complex component, which catalyze the oxidative decarboxylation of branched-chain oxoacid substrates. E1 binds thiamine diphosphate, possessing two thiamine-binding pockets located between alpha and beta subunits. The crystal structure of the E1 subunit has been determined, showing a tetrahedral arrangement of the two alpha and two beta subunits. The branched-chain ketoacid dehydrogenase (BCKD) complex catalyzes the irreversible oxidative decarboxylation of branched-chain ketoacids to produce branched-chain acyl-coenzyme A (coA) derivative esters, which undergo separate catabolic pathways depending on the initial substrate. Ultimately, leucine renders acetoacetate and acetyl-CoA, isoleucine yields propionyl-CoA and acetyl-CoA and the end product of valine catabolism is propionyl-CoA. The activity of the BCKD complex is regulated by phosphorylation and dephosphorylation catalyzed by a kinase and a phosphatase, respectively. The BCKD kinase inhibits the complex whereas the BCKD phosphatase activates it | Homo sapiens |