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Literature summary for 1.2.1.25 extracted from
- Whole-body metabolic fate of branched-chain amino acids (2021), Biochem. J., 478, 765-776 .
Activating Compound
| Activating Compound | Comment | Organism | Structure |
|---|---|---|---|
| additional information | BCAT2 binding to BCKDH also increases BCKDH activity. Activation of BCKDH with 3,6-dichlorobrenzo(b)thiophene-2-carboxylic acid (BT2), a small-molecule BCKDK inhibitor, improves insulin sensitivity | Homo sapiens |
Inhibitors
| Inhibitors | Comment | Organism | Structure |
|---|---|---|---|
| additional information | product inhibition of BCKDH by acyl-CoA can occur | Homo sapiens | |
| NADH | product inhibition of BCKDH by NADH | Homo sapiens |  |
Localization
| Localization | Comment | Organism | GeneOntology No. | Textmining |
|---|---|---|---|---|
| mitochondrion | - |
Homo sapiens | 5739 | - |
| mitochondrion | - |
Mus musculus | 5739 | - |
| mitochondrion | - |
Rattus norvegicus | 5739 | - |
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-oxobutanoate + CoA + NAD+ | Mus musculus | - |
2-methylpropanoyl-CoA + CO2 + NADH + H+ | - |
ir | |
| 3-methyl-2-oxobutanoate + CoA + NAD+ | Rattus norvegicus | - |
2-methylpropanoyl-CoA + CO2 + NADH + H+ | - |
ir | |
| 3-methyl-2-oxopentanoate + CoA + NAD+ | Homo sapiens | - |
2-methylbutanoyl-CoA + CO2 + NADH + H+ | - |
ir | |
| 3-methyl-2-oxopentanoate + CoA + NAD+ | Mus musculus | - |
2-methylbutanoyl-CoA + CO2 + NADH + H+ | - |
ir | |
| 3-methyl-2-oxopentanoate + CoA + NAD+ | Rattus norvegicus | - |
2-methylbutanoyl-CoA + CO2 + NADH + H+ | - |
ir | |
| 4-methyl-2-oxopentanoate + CoA + NAD+ | Homo sapiens | - |
3-methylbutanoyl-CoA + CO2 + NADH + H+ | - |
ir | |
| 4-methyl-2-oxopentanoate + CoA + NAD+ | Mus musculus | - |
3-methylbutanoyl-CoA + CO2 + NADH + H+ | - |
ir | |
| 4-methyl-2-oxopentanoate + CoA + NAD+ | Rattus norvegicus | - |
3-methylbutanoyl-CoA + CO2 + NADH + H+ | - |
ir | |
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 | - |
| Mus musculus | P50136 AND Q6P3A8 | alpha and beta subunits of complex component E1 (BCKD), a tetramer (alpha2beta2), cf. EC 1.2.4.4 | - |
| Rattus norvegicus | 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 | human BCKDH has two phosphorylation sites targeted by BCKDK, Ser292-alpha and Ser302-alpha, that both reside in the E1 catalytic site. Phosphorylation of Ser292-alpha alone inactivates BCKDH, while phosphorylation of Ser302-alpha appears to have no impact. Dephosphorylation of E1 is carried out by the protein phosphatase Mg2+/Mn2+ dependent 1K (PP2Cm, encoded by PPM1K), thereby activating BCKDH. Phosphorylation of BCKDH destabilizes BCAT2's interaction with BCKDH | Homo sapiens |
Source Tissue
| Source Tissue | Comment | Organism | Textmining |
|---|---|---|---|
| adipose tissue | - |
Homo sapiens | - |
| adipose tissue | - |
Mus musculus | - |
| adipose tissue | - |
Rattus norvegicus | - |
| brown adipose tissue | - |
Homo sapiens | - |
| brown adipose tissue | - |
Mus musculus | - |
| brown adipose tissue | - |
Rattus norvegicus | - |
| liver | - |
Homo sapiens | - |
| liver | - |
Mus musculus | - |
| liver | - |
Rattus norvegicus | - |
| additional information | tissue-specific preference for BCAA oxidation relative to other fuels | Homo sapiens | - |
| additional information | tissue-specific preference for BCAA oxidation relative to other fuels | Rattus norvegicus | - |
| additional information | tissue-specific preference for BCAA oxidation relative to other fuels. The greatest fraction of total BCAA oxidation occurs in skeletal muscle, liver, and brown fat | Mus musculus | - |
| pancreas | - |
Mus musculus | - |
| skeletal muscle | - |
Homo sapiens | - |
| skeletal muscle | - |
Mus musculus | - |
| skeletal muscle | - |
Rattus norvegicus | - |
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-oxobutanoate + CoA + NAD+ | - |
Mus musculus | 2-methylpropanoyl-CoA + CO2 + NADH + H+ | - |
ir | |
| 3-methyl-2-oxobutanoate + CoA + NAD+ | - |
Rattus norvegicus | 2-methylpropanoyl-CoA + CO2 + NADH + H+ | - |
ir | |
| 3-methyl-2-oxopentanoate + CoA + NAD+ | - |
Homo sapiens | 2-methylbutanoyl-CoA + CO2 + NADH + H+ | - |
ir | |
| 3-methyl-2-oxopentanoate + CoA + NAD+ | - |
Mus musculus | 2-methylbutanoyl-CoA + CO2 + NADH + H+ | - |
ir | |
| 3-methyl-2-oxopentanoate + CoA + NAD+ | - |
Rattus norvegicus | 2-methylbutanoyl-CoA + CO2 + NADH + H+ | - |
ir | |
| 4-methyl-2-oxopentanoate + CoA + NAD+ | - |
Homo sapiens | 3-methylbutanoyl-CoA + CO2 + NADH + H+ | - |
ir | |
| 4-methyl-2-oxopentanoate + CoA + NAD+ | - |
Mus musculus | 3-methylbutanoyl-CoA + CO2 + NADH + H+ | - |
ir | |
| 4-methyl-2-oxopentanoate + CoA + NAD+ | - |
Rattus norvegicus | 3-methylbutanoyl-CoA + CO2 + NADH + H+ | - |
ir | |
Subunits
| Subunits | Comment | Organism |
|---|---|---|
| heterotetramer | E1 is a heterotetramer composed of two alpha subunits and two beta subunits, encoded by BCKDHA and BCKDHB, respectively | Homo sapiens |
| heterotetramer | E1 is a heterotetramer composed of two alpha subunits and two beta subunits, encoded by BCKDHA and BCKDHB, respectively | Mus musculus |
| heterotetramer | E1 is a heterotetramer composed of two alpha subunits and two beta subunits, encoded by BCKDHA and BCKDHB, respectively | Rattus norvegicus |
Synonyms
| Synonyms | Comment | Organism |
|---|---|---|
| BCKDH | - |
Homo sapiens |
| BCKDH | - |
Mus musculus |
| BCKDH | - |
Rattus norvegicus |
| branched-chain alpha-ketoacid dehydrogenase | - |
Homo sapiens |
| branched-chain alpha-ketoacid dehydrogenase | - |
Mus musculus |
| branched-chain alpha-ketoacid dehydrogenase | - |
Rattus norvegicus |
| branched-chain alpha-ketoacid dehydrogenase complex | - |
Homo sapiens |
| branched-chain alpha-ketoacid dehydrogenase complex | - |
Mus musculus |
| branched-chain alpha-ketoacid dehydrogenase complex | - |
Rattus norvegicus |
| More | cf. EC 1.2.4.4 | Homo sapiens |
| More | cf. EC 1.2.4.4 | Mus musculus |
| More | cf. EC 1.2.4.4 | Rattus norvegicus |
Cofactor
| Cofactor | Comment | Organism | Structure |
|---|---|---|---|
| CoA | - |
Homo sapiens | |
| CoA | - |
Mus musculus | |
| CoA | - |
Rattus norvegicus | |
| NAD+ | - |
Homo sapiens | |
| NAD+ | - |
Mus musculus | |
| NAD+ | - |
Rattus norvegicus | |
General Information
| General Information | Comment | Organism |
|---|---|---|
| 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 | Rattus norvegicus |
| 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 | Mus musculus |
| 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 | Homo sapiens |
| 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 | Mus musculus |
| 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 | Rattus norvegicus |
| 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 | Homo sapiens |
| physiological function | BCKDH is a member of the mitochondrial alpha-oxoacid dehydrogenase complex family, along with PDH and OGDH, which together share primary and tertiary structure, as well as likely evolutionary origin. BCKDH is a multienzyme complex made up of three components, E1, E2, and E3. E1 is a heterotetramer composed of two alpha subunits and two beta subunits, encoded by BCKDHA and BCKDHB, respectively. Despite being essential, BCAAs are surprisingly abundant and make up about 35% of essential amino acids and 18% of all amino acids in animal protein. Because BCAAs are essential, animals must balance their intake and loss. All intake comes from diet, and loss occurs through oxidation. The relative abundance of BCAAs in protein is almost always 2.2 : 1.6 : 1.0 leucine : valine : isoleucine, illustrating that the synthesis and oxidation of each individual BCAA are linked to one another. Circulating plasma levels of BCAAs in mammals remain consistent at about 0.2 mM valine, 0.1 mM leucine, and 0.06 mM isoleucine in the fasted state, after feeding, these levels rise briefly but fall back to baseline after a few hours. Together this indicates homeostatic regulation of BCAAs. Basic BCAA oxidative pathway, including a simplified structure showing the regulation of the rate-limiting enzyme, BCKDH. BCAT2 binding to BCKDH also increases BCKDH activity, while phosphorylation of BCKDH destabilizes BCAT2's interaction with BCKDH. Activation of BCKDH with BT2 improves insulin sensitivity. The redistribution of BCAA oxidation towards skeletal muscle drives insulin resistance | Homo sapiens |
| physiological function | BCKDH is a member of the mitochondrial alpha-oxoacid dehydrogenase complex family, along with PDH and OGDH, which together share primary and tertiary structure, as well as likely evolutionary origin. BCKDH is a multienzyme complex made up of three components, E1, E2, and E3. E1 is a heterotetramer composed of two alpha subunits and two beta subunits, encoded by BCKDHA and BCKDHB, respectively. Despite being essential, BCAAs are surprisingly abundant and make up about 35% of essential amino acids and 18% of all amino acids in animal protein. Because BCAAs are essential, animals must balance their intake and loss. All intake comes from diet, and loss occurs through oxidation. The relative abundance of BCAAs in protein is almost always 2.2 : 1.6 : 1.0 leucine : valine : isoleucine, illustrating that the synthesis and oxidation of each individual BCAA are linked to one another. Circulating plasma levels of BCAAs in mammals remain consistent at about 0.2 mM valine, 0.1 mM leucine, and 0.06 mM isoleucine in the fasted state, after feeding, these levels rise briefly but fall back to baseline after a few hours. Together this indicates homeostatic regulation of BCAAs. Basic BCAA oxidative pathway, including a simplified structure showing the regulation of the rate-limiting enzyme, BCKDH. The pancreas in mice fills nearly a third of its TCA cycle with carbons derived from BCAAs. The redistribution of BCAA oxidation towards skeletal muscle drives insulin resistance | Mus musculus |
| physiological function | BCKDH is a member of the mitochondrial alpha-oxoacid dehydrogenase complex family, along with PDH and OGDH, which together share primary and tertiary structure, as well as likely evolutionary origin. BCKDH is a multienzyme complex made up of three components, E1, E2, and E3. E1 is a heterotetramer composed of two alpha subunits and two beta subunits, encoded by BCKDHA and BCKDHB, respectively. Despite being essential, BCAAs are surprisingly abundant and make up about 35% of essential amino acids and 18% of all amino acids in animal protein. Because BCAAs are essential, animals must balance their intake and loss. All intake comes from diet, and loss occurs through oxidation. The relative abundance of BCAAs in protein is almost always 2.2 : 1.6 : 1.0 leucine : valine : isoleucine, illustrating that the synthesis and oxidation of each individual BCAA are linked to one another. Circulating plasma levels of BCAAs in mammals remain consistent at about 0.2 mM valine, 0.1 mM leucine, and 0.06 mM isoleucine in the fasted state, after feeding, these levels rise briefly but fall back to baseline after a few hours. Together this indicates homeostatic regulation of BCAAs. Basic BCAA oxidative pathway, including a simplified structure showing the regulation of the rate-limiting enzyme, BCKDH. The redistribution of BCAA oxidation towards skeletal muscle drives insulin resistance | Rattus norvegicus |
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