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Inhibition by the branched-chain 2-oxo acids of the 2-oxoglutarate dehydrogenase complex in developing rat and human brain.

ABSTRACT: 1. The effect of the branched-chain amino acids, namely leucine, isoleucine and valine and their corresponding 2-oxo acids on the metabolism of 2-oxoglutarate by developing rat and human brain preparations was investigated. 2. The decarboxylation of 2-oxo[1-(14)C]glutarate to (14)CO(2) by mitochondria from adult rat brain was inhibited by the branched-chain 2-oxo acids whereas the branched-chain amino acids had no inhibitory effect on this process. 3. The activity of 2-oxoglutarate dehydrogenase complex was about 0.2unit/g of brain from 2-day-old rats and increased by about fourfold reaching an adult value by the end of the third postnatal week. 4. The K(m) value for 2-oxoglutarate of the 2-oxoglutarate dehydrogenase complex in rat and human brain was 100 and 83mum respectively. 5. The branched-chain 2-oxo acids competitively inhibited this enzyme from suckling and adult rats brains as well as from foetal and adult human brains, whereas the branched-chain amino acids had no effect on this enzyme. 6. Approximate K(i) values for the branched-chain 2-oxo acids found for this enzyme were in the range found for these 2-oxo acids in plasma from patients with maple-syrup-urine disease. 7. The possible significance of the inhibition by the branched-chain 2-oxo acids of the 2-oxoglutarate dehydrogenase complex in brains of untreated patients with maple-syrup-urine disease is discussed in relation to the energy metabolism and the biosynthesis of lipids from ketone bodies.

SUBMITTER: Patel MS

PROVIDER: S-EPMC1168468 | biostudies-other | 1974 Oct

REPOSITORIES: biostudies-other

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Adrenergic inhibition of branched-chain 2-oxo acid dehydrogenase in rat diaphragm muscle in vitro.

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Project description:The developmental pattern of the branched-chain 2-oxo acid dehydrogenase complex was examined in the liver and heart of the rat throughout the suckling period. Basal activity and total activity of the complex were measured as a function of age. The hepatic enzyme activity increased dramatically and was 100% active (dephosphorylated) during the suckling period. The level of protein kinase associated with the complex was particularly low at birth, but like the complex increased throughout the suckling period. The level of heart enzyme also increased as a function of age, but only about 30-45% of the enzyme was active throughout the suckling period. Very low protein levels of liver and heart branched-chain 2-oxo acid dehydrogenase were detected by immunoblot analysis in newborn rats. The mRNA levels for the liver E1 alpha, E1 beta, and E2 subunits in newborn rat were 30%, 19%, and 4% of adult levels respectively. The capacity of the neonatal rat for oxidizing leucine in vivo was low at birth and increased with age. 4-Methyl-2-oxopentanoate was more toxic when given to newborn and 3-day-old pups than 21-day-old pups, as expected from the relative capacities of their tissues to dispose of branched-chain 2-oxo acids by oxidation. Force-feeding suckling rats a protein-free artificial milk formula resulted in partial inactivation of the hepatic branched-chain 2-oxo acid dehydrogenase complex, indicating that the liver of the suckling rat can adapt to conserve branched-chain amino acid residues during periods of protein deficiency.

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