Inhibition by the branched-chain 2-oxo acids of the 2-oxoglutarate dehydrogenase complex in developing rat and human brain.
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.
D000367:Age Factors; D000818:Animals; D001921:Brain / Q000201:enzymology / Q000254:growth & development*; D002245:Carbon Dioxide / Q000096:biosynthesis; D003653:Decarboxylation; D006801:Humans; D007532:Isoleucine / Q000494:pharmacology; D007651:Keto Acids / Q000494:pharmacology*; D007655:Ketoglutarate Dehydrogenase Complex / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007658:Ketone Oxidoreductases / Q000037:antagonists & inhibitors*; D007700:Kinetics; D007930:Leucine / Q000494:pharmacology; D008375:Maple Syrup Urine Disease / Q000201:enzymology; D008928:Mitochondria / Q000378:metabolism; D008968:Molecular Conformation; D051381:Rats; D014633:Valine / Q000494:pharmacology
D007651:Keto Acids; D007532:Isoleucine; D002245:Carbon Dioxide; D007658:Ketone Oxidoreductases; D007655:Ketoglutarate Dehydrogenase Complex; D007930:Leucine; D014633:Valine