EC Number   |
General Information |
Reference |
|---|
    1.2.1.25 | malfunction |
BCKD phosphorylation by BCKD kinase (BCKDK) inactivates BCKD and causes neurocognitive dysfunction, whereas dephosphorylation by specific phosphatase restores BCKD activity. Increased phosphorylated BCKD leads to increased BCKA accumulation causing BCKA-mediated astrocyte activation, cell death, and cognitive dysfunction as found in maple syrup urine disease |
-, 763378 |
| 1.2.1.25 | malfunction |
elevated phosphorylation, and lower activity, of liver BCKDH in various models of diabetes. The decreased liver BCAA oxidation is likely mediated by post-translational inhibition of BCKDH via phosphorylation. When fed a BCAA-restricted diet, fatty acyl-CoA content in the skeletal muscle of rats decreases and insulin resistance is improved. The expression of BCAA catabolic genes has been shown to be reduced in tissue from rodent and human failing hearts |
762713 |
| 1.2.1.25 | malfunction |
genetic deletion in mice of BCKDHA or of a BCAA transporter specifically in brown fat is sufficient to raise plasma BCAAs. Elevated phosphorylation, and lower activity, of liver BCKDH in various models of diabetes. The decreased liver BCAA oxidation is likely mediated by post-translational inhibition of BCKDH via phosphorylation. The expression of BCAA catabolic genes has been shown to be reduced in tissue from rodent and human failing hearts |
762713 |
| 1.2.1.25 | 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 |
762596 |
| 1.2.1.25 | malfunction |
Maple syrup urine disease (MSUD) is caused by autosomal recessive mutations in either the E1 (BCKDHA/BCKDHB) or E2 (DBT) subunits of BCKDH. Because the E3 (DLD) subunit of BCKDH is shared with PDH and OGDH, mutations in DLD cause more complex disease, and though sometimes labeled MSUD, is more appropriately labeled dihydrolipoamide dehydrogenase deficiency. Mutations in PPM1K can cause a mild variant of MSUD. Overall, disease severity is usually inversely related to residual enzyme activity. These mutations lead to elevated plasma BCAA and BCKA levels, as well as elevated urine levels of sotolone, an otherwise rare byproduct of excess leucine and isoleucine that gives urine a maple syrup-like odor. If left untreated, MSUD can cause cerebral edema, encephalopathy, and ultimately death, underscoring the importance of tight homeostatic regulation of BCAAs. Elevated phosphorylation, and lower activity, of liver BCKDH in various models of diabetes. The decreased liver BCAA oxidation is likely mediated by post-translational inhibition of BCKDH via phosphorylation. The expression of BCAA catabolic gene has been shown to be reduced in tissue from rodent and human failing hearts. BT2 might improve outcomes in heart failure either by activating oxidation in another tissue or by impacting signaling from BCAA-derived metabolites within the heart. Activation of BCKDH with 3,6-dichlorobrenzo(b)thiophene-2-carboxylic acid (BT2), a small-molecule BCKDK inhibitor, improves insulin sensitivity |
762713 |
| 1.2.1.25 | malfunction |
maple syrup urine disease (MSUD) results from one or more functional mutations in the E1alpha or E1beta subunit proteins of E1 enzyme or E2 enzyme protein of BCKDC |
763515 |
| 1.2.1.25 | malfunction |
maple syrup urine disease (MSUD) results from one or more functional mutations in the E1alpha or E1beta subunit proteins of E1 enzyme or E2 enzyme protein of BCKDC, phenotype, overview |
763515 |
| 1.2.1.25 | metabolism |
divergent induction of branched-chain aminotransferases and phosphorylation of branched chain keto-acid dehydrogenase is a potential mechanism coupling branched-chain keto-acid-mediated-astrocyte activation to branched-chain amino acid depletion-mediated cognitive deficit after traumatic brain injury. Proposed model depicting the coordination of BCAA metabolism between the putative neuron: astrocyte and microglia postinjury, overview |
-, 763378 |
| 1.2.1.25 | metabolism |
oxidation of branched-chain amino acids (BCAAs: leucine, valine, and isoleucine) is tightly regulated in mammals, distribution and regulation of whole-body BCAA oxidation, key factors influencing the flux of oxidative BCAA disposal in each tissue, detailed overview. Phosphorylation and dephosphorylation of the rate-limiting enzyme, branched-chain alpha-ketoacid dehydrogenase complex directly regulates BCAA oxidation, and various other indirect mechanisms of regulation also exist |
762713 |
| 1.2.1.25 | metabolism |
oxidation of branched-chain amino acids (BCAAs: leucine, valine, and isoleucine) is tightly regulated in mammals, distribution and regulation of whole-body BCAA oxidation, key factors influencing the flux of oxidative BCAA disposal in each tissue, detailed overview. Phosphorylation and dephosphorylation of the rate-limiting enzyme, branched-chain alpha-ketoacid dehydrogenase complex directly regulates BCAA oxidation, and various other indirect mechanisms of regulation also exist. BCAT2 and BCKDH can associate to form a metabolon, a supramolecular complex that allows substrates to channel from enzyme to enzyme. Phosphorylation of BCKDH destabilizes BCAT2's interaction with BCKDH |
762713 |
