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

Biochem J. 1974 Oct;144(1):91-7. doi: 10.1042/bj1440091.

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Age Factors
  • Animals
  • Brain / enzymology
  • Brain / growth & development*
  • Carbon Dioxide / biosynthesis
  • Decarboxylation
  • Humans
  • Isoleucine / pharmacology
  • Keto Acids / pharmacology*
  • Ketoglutarate Dehydrogenase Complex / antagonists & inhibitors*
  • Ketoglutarate Dehydrogenase Complex / metabolism
  • Ketone Oxidoreductases / antagonists & inhibitors*
  • Kinetics
  • Leucine / pharmacology
  • Maple Syrup Urine Disease / enzymology
  • Mitochondria / metabolism
  • Molecular Conformation
  • Rats
  • Valine / pharmacology

Substances

  • Keto Acids
  • Isoleucine
  • Carbon Dioxide
  • Ketone Oxidoreductases
  • Ketoglutarate Dehydrogenase Complex
  • Leucine
  • Valine