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Biochem J. Oct 1974; 144(1): 91–97.
PMCID: PMC1168468

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[1-14C]glutarate to 14CO2 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 Km value for 2-oxoglutarate of the 2-oxoglutarate dehydrogenase complex in rat and human brain was 100 and 83μm 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 Ki 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.

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Selected References

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  • Appel SH. Inhibition of brain protein synthesis: an approach to the biochemical basis of neurological dysfunction in the amino-acidurias. Trans N Y Acad Sci. 1966 Nov;29(1):63–70. [PubMed]
  • Blass JP, Lewis CA. Kinetic properties of the partially purified pyruvate dehydrogenase complex of ox brain. Biochem J. 1973 Jan;131(1):31–37. [PMC free article] [PubMed]
  • Bowden JA, McArthur CL, 3rd, Fried M. The inhibition of pyruvate decarboxylation in rat brain by -ketoisocaproic acid. Biochem Med. 1971 Apr;5(2):101–108. [PubMed]
  • Carver MJ. Free amino acids of fetal brain. Influence of the branched chain amino acids. J Neurochem. 1969 Jan;16(1):113–116. [PubMed]
  • Clark JB, Nicklas WJ. The metabolism of rat brain mitochondria. Preparation and characterization. J Biol Chem. 1970 Sep 25;245(18):4724–4731. [PubMed]
  • DANCIS J, LEVITZ M, MILLER S, WESTALL RG. Maple syrup urine disease. Br Med J. 1959 Jan 10;1(5114):91–93. [PMC free article] [PubMed]
  • DENT CE, WESTALL RG. Studies in maple syrup urine disease. Arch Dis Child. 1961 Jun;36:259–268. [PMC free article] [PubMed]
  • Dreyfus PM, Prensky AL. Further observations on the biochemical lesion in maple syrup urine disease. Nature. 1967 Apr 15;214(5085):276–276. [PubMed]
  • Edmond J. Ketone bodies as precursors of sterols and fatty acids in the developing rat. J Biol Chem. 1974 Jan 10;249(1):72–80. [PubMed]
  • HOPPER S, SEGAL HL. Kinetic studies of rat liver glutamicalanine transaminase. J Biol Chem. 1962 Oct;237:3189–3195. [PubMed]
  • HOWELL RK, LEE M. Influence of alpha-ketoacids on the respiration of brain in vitro. Proc Soc Exp Biol Med. 1963 Jul;113:660–663. [PubMed]
  • Johnson WA, Connelly JL. Studies on the mutual influences of substrates on bovine -keto acid metabolism. Biochemistry. 1972 Jun 20;11(13):2416–2421. [PubMed]
  • Kanzaki T, Hayakawa T, Hamada M, Fukuyoshi Y, Koike M. Mammalian alpha-keto acid dehydrogenase complexes. IV. Substrate specificities and kinetic properties of the pig heart pyruvate and 2-oxyoglutarate dehydrogenase complexes. J Biol Chem. 1969 Mar 10;244(5):1183–1187. [PubMed]
  • LOWRY OH, ROSEBROUGH NJ, FARR AL, RANDALL RJ. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed]
  • Lysiak W, Muzalewska A, Angielski S. Branched-chain aminotransferase in brain tissue. Acta Biochim Pol. 1970;17(2):121–130. [PubMed]
  • MACKENZIE DY, WOOLF LI. Maple syrup urine disease; an inborn error of the metabolism of valine, leucine, and isoleucine associated with gross mental deficiency. Br Med J. 1959 Jan 10;1(5114):90–91. [PMC free article] [PubMed]
  • MENKES JH. Maple syrup disease; isolation and identification of organic acids in the urine. Pediatrics. 1959 Feb;23(2):348–353. [PubMed]
  • Menkes JH, Solcher H. Maple syrup disease. Effects of dietary therapy on cerebral lipids. Arch Neurol. 1967 May;16(5):486–491. [PubMed]
  • MENKES JH, HURST PL, CRAIG JM. A new syndrome: progressive familial infantile cerebral dysfunction associated with an unusual urinary substance. Pediatrics. 1954 Nov;14(5):462–467. [PubMed]
  • MENKES JH, PHILIPPART M, FIOL RE. CEREBRAL LIPIDS IN MAPLE SYRUP DISEASE. J Pediatr. 1965 Mar;66:584–594. [PubMed]
  • Patel MS. The effect of phenylpyruvate on pyruvate metabolism in rat brain. Biochem J. 1972 Jul;128(3):677–684. [PMC free article] [PubMed]
  • Patel MS, Auerbach VH, Grover WD, Wilbur DO. Effect of the branched-chain alpha-keto acids on pyruvate metabolism by homogenates of human brain. J Neurochem. 1973 Jun;20(6):1793–1796. [PubMed]
  • PATRICK AD. Maple syrup urine disease. Arch Dis Child. 1961 Jun;36:269–272. [PMC free article] [PubMed]
  • Prensky AL, Moser HW. Brain lipids, proteolipids, and free amino acids in maple syrup urine disease. J Neurochem. 1966 Sep;13(9):863–874. [PubMed]
  • Prensky AL, Carr S, Moser HW. Development of myelin in inherited disorders of amino acid metabolism. Arch Neurol. 1968 Dec;19(6):552–558. [PubMed]
  • Robinson BH, Chappell JB. The inhibition of malate, tricarboxylate and oxoglutarate entry into mitochondria by 2-n-butylmalonate. Biochem Biophys Res Commun. 1967 Jul 21;28(2):249–255. [PubMed]
  • Silberberg DH. Maple syrup urine disease metabolites studies in cerebellum cultures. J Neurochem. 1969 Jul;16(7):1141–1146. [PubMed]
  • SNYDERMAN SE, NORTON PM, ROITMAN E, HOLT LE., Jr MAPLE SYRUP URINE DISEASE, WITH PARTICULAR REFERENCE TO DIETOTHERAPY. Pediatrics. 1964 Oct;34:454–472. [PubMed]
  • Wilbur DO, Patel MS. Development of mitochondrial pyruvate metabolism in rat brain. J Neurochem. 1974 May;22(5):709–715. [PubMed]
  • WOODY NC, HARRIS JA. FAMILY SCREENING STUDIES IN MAPLE SYRUP URINE DISEASE (BRANCHED-CHAIN KETOACIDURIA). J Pediatr. 1965 Jun;66:1042–1048. [PubMed]
  • Yuwiler A, Geller E. Serotonin depletion by dietary leucine. Nature. 1965 Oct 2;208(5005):83–84. [PubMed]

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