Any feedback?
Please rate this page
(literature.php)
(0/150)

BRENDA support

Literature summary for 1.2.1.25 extracted from

  • Adeva-Andany, M.; Lopez-Maside, L.; Donapetry-Garcia, C.; Fernanndez-Fernanndez, C.; Sixto-Leal, C.
    Enzymes involved in branched-chain amino acid metabolism in humans (2017), Amino Acids, 49, 1005-1028 .
    View publication on PubMed

Activating Compound

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

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/ Products (Substrates)

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

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

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

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 and Products (Substrate)

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

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

Synonyms Comment Organism
BCKD
-
Homo sapiens
branched-chain ketoacid dehydrogenase
-
Homo sapiens
More cf. EC 1.2.4.4 Homo sapiens

Cofactor

Cofactor Comment Organism Structure
CoA
-
Homo sapiens
NAD+
-
Homo sapiens

General Information

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