Neurochemical Research

, Volume 42, Issue 6, pp 1697–1709 | Cite as

Branched-Chain Amino Acids and Brain Metabolism

  • Justin E. SperringerEmail author
  • Adele Addington
  • Susan M. Hutson
Original Paper


This review aims to provide a historical reference of branched-chain amino acid (BCAA) metabolism and provide a link between peripheral and central nervous system (CNS) metabolism of BCAAs. Leucine, isoleucine, and valine (Leu, Ile, and Val) are unlike most other essential amino acids (AA), being transaminated initially in extrahepatic tissues, and requiring interorgan or intertissue shuttling for complete catabolism. Within the periphery, BCAAs are essential AAs and are required for protein synthesis, and are key nitrogen donors in the form of Glu, Gln, and Ala. Leucine is an activator of the mammalian (or mechanistic) target of rapamycin, the master regulator of cell growth and proliferation. The tissue distribution and activity of the catabolic enzymes in the peripheral tissues as well as neurological effects in Maple Syrup Urine Disease (MSUD) show the BCAAs have a role in the CNS. Interestingly, there are significant differences between murine and human CNS enzyme distribution and activities. In the CNS, BCAAs have roles in neurotransmitter synthesis, protein synthesis, food intake regulation, and are implicated in diseases. MSUD is the most prolific disease associated with BCAA metabolism, affecting the branched-chain α-keto acid dehydrogenase complex (BCKDC). Mutations in the branched-chain aminotransferases (BCATs) and the kinase for BCKDC also result in neurological dysfunction. However, there are many questions of BCAA metabolism in the CNS (as well as the periphery) that remain elusive. We discuss areas of BCAA and BCKA metabolism that have yet to be researched adequately.


Maple Syrup Urine Disease Area Postrema Maple Syrup Urine Disease Maple Syrup Urine Disease Patient Arg143Gln Mutation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We would like to thank Dr. Neela Yennawar for analysis of the structural mutations of the mitochondrial BCAT.


  1. 1.
    Kimball SR, Shantz LM, Horetsky RL, Jefferson LS (1999) Leucine regulates translation of specific mRNAs in L6 myoblasts through mTOR-mediated changes in availability of eIF4E and phosphorylation of ribosomal protein S6. J Biol Chem 274:11647–11652PubMedCrossRefGoogle Scholar
  2. 2.
    Sweatt AJ, Wood M, Suryawan A, Wallin R, Willingham MC, Hutson SM (2004) Branched-chain amino acid catabolism: unique segregation of pathway enzymes in organ systems and peripheral nerves. Am J Physiol Endocrinol Metab 286:E64–E76PubMedCrossRefGoogle Scholar
  3. 3.
    Chang TW, Goldberg AL (1978) The metabolic fates of amino acids and the formation of glutamine in skeletal muscle. J Biol Chem 253:3685–3693PubMedGoogle Scholar
  4. 4.
    Hutson SM, Sweatt AJ, Lanoue KF (2005) Branched-chain [corrected] amino acid metabolism: implications for establishing safe intakes. J Nutr 135:1557S–1564SPubMedGoogle Scholar
  5. 5.
    Shinnick FL, Harper AE (1976) Branched-chain amino acid oxidation by isolated rat tissue preparations. Biochim Biophys Acta 437:477–486PubMedCrossRefGoogle Scholar
  6. 6.
    Yudkoff M (1997) Brain metabolism of branched-chain amino acids. Glia 21:92–98PubMedCrossRefGoogle Scholar
  7. 7.
    Yudkoff M (2016) Interactions in the metabolism of glutamate and the branched-chain amino acids and ketoacids in the CNS. Neurochem Res. doi: 10.1007/s11064-016-2057-z PubMedPubMedCentralGoogle Scholar
  8. 8.
    Raju K, Doulias PT, Evans P, Krizman EN, Jackson JG, Horyn O, Daikhin Y, Nissim I, Yudkoff M, Nissim I, Sharp KA, Robinson MB, Ischiropoulos H (2015) Regulation of brain glutamate metabolism by nitric oxide and S-nitrosylation. Sci Signal 8:ra68PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Smith QR, Momma S, Aoyagi M, Rapoport SI (1987) Kinetics of neutral amino acid transport across the blood-brain barrier. J Neurochem 49:1651–1658PubMedCrossRefGoogle Scholar
  10. 10.
    Jayakumar AR, Norenberg MD (2016) Glutamine synthetase: role in neurological disorders. Adv Neurobiol 13:327–350PubMedCrossRefGoogle Scholar
  11. 11.
    DeSantiago S, Torres N, Suryawan A, Tovar AR, Hutson SM (1998) Regulation of branched-chain amino acid metabolism in the lactating rat. J Nutr 128:1165–1171PubMedGoogle Scholar
  12. 12.
    Hutson SM, Fenstermacher D, Mahar C (1988) Role of mitochondrial transamination in branched chain amino acid metabolism. J Biol Chem 263:3618–3625PubMedGoogle Scholar
  13. 13.
    Hutson SM (1988) Subcellular distribution of branched-chain aminotransferase activity in rat tissues. J Nutr 118:1475–1481PubMedGoogle Scholar
  14. 14.
    Ichihara A, Koyama E (1966) Transaminase of branched chain Amino Acids .I. branched chain amino acids-α-ketoglutarate transaminase. J Biochem 59:160–169PubMedCrossRefGoogle Scholar
  15. 15.
    Mcmenamy RH, Shoemaker WC, Elwyn D, Richmond JE (1962) Uptake and metabolism of amino acids by dog liver perfused in situ. Am J Physiol 202:407–414Google Scholar
  16. 16.
    Christen P, Metzler DE (1985) Transaminases. Wiley, New YorkGoogle Scholar
  17. 17.
    Hutson SM, Wallin R, Hall TR (1992) Identification of mitochondrial branched chain aminotransferase and its isoforms in rat tissues. J Biol Chem 267:15681–15686PubMedGoogle Scholar
  18. 18.
    Hall TR, Wallin R, Reinhart GD, Hutson SM (1993) Branched chain aminotransferase isoenzymes. Purification and characterization of the rat brain isoenzyme. J Biol Chem 268:3092–3098PubMedGoogle Scholar
  19. 19.
    Cangiano C, Cardelli-Cangiano P, James JH, Rossi-Fanelli F, Patrizi MA, Brackett KA, Strom R, Fischer JE (1983) Brain microvessels take up large neutral amino acids in exchange for glutamine. Cooperative role of Na+-dependent and Na+-independent systems. J Biol Chem 258:8949–8954PubMedGoogle Scholar
  20. 20.
    Cooper AJ, Plum F (1987) Biochemistry and physiology of brain ammonia. Physiol Rev 67:440–519PubMedGoogle Scholar
  21. 21.
    Reed LJ, Damuni Z, Merryfield ML (1985) Regulation of mammalian pyruvate and branched-chain α-keto acid dehydrogenase complexes by phosphorylation-dephosphorylation. Curr Top Cell Regul 27:41–49PubMedCrossRefGoogle Scholar
  22. 22.
    Shimomura Y, Honda T, Shiraki M, Murakami T, Sato J, Kobayashi H, Mawatari K, Obayashi M, Harris RA (2006) Branched-chain amino acid catabolism in exercise and liver disease. J Nutr 136:250 S-253 SGoogle Scholar
  23. 23.
    Shimomura Y, Kitaura Y, Kadota Y, Ishikawa T, Kondo Y, Xu M, Ota M, Morishita Y, Bariuan JV, Zhen H (2015) Novel physiological functions of branched-chain amino acids. J Nutr Sci Vitaminol (Tokyo) 61:S112–114CrossRefGoogle Scholar
  24. 24.
    Burrage LC, Nagamani SC, Campeau PM, Lee BH (2014) Branched-chain amino acid metabolism: from rare mendelian diseases to more common disorders. Hum Mol Genet 23:R1–R8PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Harper AE (1989) Thoughts on the role of branched-chain alpha-keto acid dehydrogenase complex in nitrogen metabolism. Ann NY Acad Sci 573:267–273PubMedCrossRefGoogle Scholar
  26. 26.
    Hutson SM, Cree TC, Harper AE (1978) Regulation of leucine and alpha-ketoisocaproate metabolism in skeletal muscle. J Biol Chem 253:8126–8133PubMedGoogle Scholar
  27. 27.
    Hutson SM, Zapalowski C, Cree TC, Harper AE (1980) Regulation of leucine and alpha-ketoisocaproic acid metabolism in skeletal muscle. Effects of starvation and insulin. J Biol Chem 255:2418–2426PubMedGoogle Scholar
  28. 28.
    Felig P (1975) Amino acid metabolism in man. Annu Rev Biochem 44:933–955PubMedCrossRefGoogle Scholar
  29. 29.
    Elia M, Livesey G (1983) Effects of ingested steak and infused leucine on forelimb metabolism in man and the fate of the carbon skeletons and amino groups of branched-chain amino acids. Clin Sci (Lond) 64:517–526CrossRefGoogle Scholar
  30. 30.
    Abumrad NN, Miller B (1983) The physiologic and nutritional significance of plasma-free amino acid levels. JPEN J Parenter Enteral Nutr 7:163–170PubMedCrossRefGoogle Scholar
  31. 31.
    Gillim SE, Paxton R, Cook GA, Harris RA (1983) Activity state of the branched chain alpha-ketoacid dehydrogenase complex in heart, liver, and kidney of normal, fasted, diabetic, and protein-starved rats. Biochem Biophys Res Commun 111:74–81PubMedCrossRefGoogle Scholar
  32. 32.
    Goodwin GW, Zhang B, Paxton R, Harris RA (1988) Determination of activity and activity state of branched-chain α-keto acid dehydrogenase in rat tissues. Methods Enzymol 166:189–201PubMedCrossRefGoogle Scholar
  33. 33.
    Hutson SM (1986) Branched chain α-keto acid oxidative decarboxylation in skeletal muscle mitochondria. Effect of isolation procedure and mitochondrial delta pH. J Biol Chem 261:4420–4425PubMedGoogle Scholar
  34. 34.
    Suryawan A, Hawes JW, Harris RA, Shimomura Y, Jenkins AE, Hutson SM (1998) A molecular model of human branched-chain amino acid metabolism. Am J Clin Nutr 68:72–81PubMedGoogle Scholar
  35. 35.
    Felig P (1973) The glucose-alanine cycle. Metabolism 22:179–207PubMedCrossRefGoogle Scholar
  36. 36.
    Windmueller HG, Spaeth AE (1974) Uptake and metabolism of plasma glutamine by the small intestine. J Biol Chem 249:5070–5079PubMedGoogle Scholar
  37. 37.
    White PJ, Lapworth AL, An J, Wang L, McGarrah RW, Stevens RD, Ilkayeva O, George T, Muehlbauer MJ, Bain JR, Trimmer JK, Brosnan MJ, Rolph TP, Newgard CB (2016) Branched-chain amino acid restriction in Zucker-fatty rats improves muscle insulin sensitivity by enhancing efficiency of fatty acid oxidation and acyl-glycine export. Mol Metab 5:538–551PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Lotta LA, Scott RA, Sharp SJ, Burgess S, Luan J, Tillin T, Schmidt AF, Imamura F, Stewart ID, Perry JR, Marney L, Koulman A, Karoly ED, Forouhi NG, Sjogren RJ, Naslund E, Zierath JR, Krook A, Savage DB, Griffin JL, Chaturvedi N, Hingorani AD, Khaw KT, Barroso I, McCarthy MI, O’Rahilly S, Wareham NJ, Langenberg C (2016) Genetic predisposition to an impaired metabolism of the branched-chain amino acids and risk of type 2 diabetes: a Mendelian randomisation analysis. PLoS Med 13:e1002179PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Ananieva EA, Patel CH, Drake CH, Powell JD, Hutson SM (2014) Cytosolic branched chain aminotransferase (BCATc) regulates mTORC1 signaling and glycolytic metabolism in CD4+ T cells. J Biol Chem 289:18793–18804PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Ananieva EA, Powell JD, Hutson SM (2016) Leucine metabolism in T cell activation: mTOR signaling and beyond. Adv Nutr 7:798S–805SPubMedCrossRefGoogle Scholar
  41. 41.
    Mayers JR, Torrence ME, Danai LV, Papagiannakopoulos T, Davidson SM, Bauer MR, Lau AN, Ji BW, Dixit PD, Hosios AM, Muir A, Chin CR, Freinkman E, Jacks T, Wolpin BM, Vitkup D, Vander Heiden MG (2016) Tissue of origin dictates branched-chain amino acid metabolism in mutant Kras-driven cancers. Science 353:1161–1165PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Yudkoff M, Daikhin Y, Melo TM, Nissim I, Sonnewald U, Nissim I (2007) The ketogenic diet and brain metabolism of amino acids: relationship to the anticonvulsant effect. Annu Rev Nutr 27:415–430PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Dodd PR, Williams SH, Gundlach AL, Harper PA, Healy PJ, Dennis JA, Johnston GA (1992) Glutamate and γ-aminobutyric acid neurotransmitter systems in the acute phase of maple syrup urine disease and citrullinemia encephalopathies in newborn calves. J Neurochem 59:582–590PubMedCrossRefGoogle Scholar
  44. 44.
    Waagepetersen HS, Sonnewald U, Schousboe A (2003) Compartmentation of glutamine, glutamate, and GABA metabolism in neurons and astrocytes: functional implications. Neuroscientist 9:398–403PubMedCrossRefGoogle Scholar
  45. 45.
    Yudkoff M, Daikhin Y, Nissim I, Horyn O, Luhovyy B, Lazarow A, Nissim I (2005) Brain amino acid requirements and toxicity: the example of leucine. J Nutr 135:1531S–1538SPubMedGoogle Scholar
  46. 46.
    Gamberino WC, Berkich DA, Lynch CJ, Xu B, LaNoue KF (1997) Role of pyruvate carboxylase in facilitation of synthesis of glutamate and glutamine in cultured astrocytes. J Neurochem 69:2312–2325PubMedCrossRefGoogle Scholar
  47. 47.
    McKenna MC, Sonnewald U, Huang X, Stevenson J, Zielke HR (1996) Exogenous glutamate concentration regulates the metabolic fate of glutamate in astrocytes. J Neurochem 66:386–393PubMedCrossRefGoogle Scholar
  48. 48.
    McKenna MC, Tildon JT, Stevenson JH, Huang X (1996) New insights into the compartmentation of glutamate and glutamine in cultured rat brain astrocytes. Dev Neurosci 18:380–390PubMedCrossRefGoogle Scholar
  49. 49.
    Hutson SM, Berkich D, Drown P, Xu B, Aschner M, LaNoue KF (1998) Role of branched-chain aminotransferase isoenzymes and gabapentin in neurotransmitter metabolism. J Neurochem 71:863–874PubMedCrossRefGoogle Scholar
  50. 50.
    Hutson SM, Lieth E, LaNoue KF (2001) Function of leucine in excitatory neurotransmitter metabolism in the central nervous system. J Nutr 131:846S–850SPubMedGoogle Scholar
  51. 51.
    Lieth E, LaNoue KF, Berkich DA, Xu B, Ratz M, Taylor C, Hutson SM (2001) Nitrogen shuttling between neurons and glial cells during glutamate synthesis. J Neurochem 76:1712–1723PubMedCrossRefGoogle Scholar
  52. 52.
    Yudkoff M, Nissim I, Kim S, Pleasure D, Hummeler K, Segal S (1983) [N-15] leucine as a source of [N-15] glutamate in organotypic cerebellar explants. Biochem Bioph Res Commun 115:174–179CrossRefGoogle Scholar
  53. 53.
    Yudkoff M, Daikhin Y, Lin ZP, Nissim I, Stern J, Pleasure D, Nissim I (1994) Interrelationships of leucine and glutamate metabolism in cultured astrocytes. J Neurochem 62:1192–1202PubMedCrossRefGoogle Scholar
  54. 54.
    Bixel MG, Hutson SM, Hamprecht B (1997) Cellular distribution of branched-chain amino acid aminotransferase isoenzymes among rat brain glial cells in culture. J Histochem Cytochem 45:685–694PubMedCrossRefGoogle Scholar
  55. 55.
    Yudkoff M, Daikhin Y, Grunstein L, Nissim I, Stern J, Pleasure D, Nissim I (1996) Astrocyte leucine metabolism: significance of branched-chain amino acid transamination. J Neurochem 66:378–385PubMedCrossRefGoogle Scholar
  56. 56.
    Hutson SM, Bledsoe RK, Hall TR, Dawson PA (1995) Cloning and expression of the mammalian cytosolic branched chain aminotransferase isoenzyme. J Biol Chem 270:30344–30352PubMedCrossRefGoogle Scholar
  57. 57.
    Garcia-Espinosa MA, Wallin R, Hutson SM, Sweatt AJ (2007) Widespread neuronal expression of branched-chain aminotransferase in the CNS: implications for leucine/glutamate metabolism and for signaling by amino acids. J Neurochem 100:1458–1468PubMedGoogle Scholar
  58. 58.
    Sweatt AJ, Garcia-Espinosa MA, Wallin R, Hutson SM (2004) Branched-chain amino acids and neurotransmitter metabolism: expression of cytosolic branched-chain aminotransferase (BCATc) in the cerebellum and hippocampus. J Comp Neurol 477:360–370PubMedCrossRefGoogle Scholar
  59. 59.
    Bixel M, Shimomura Y, Hutson S, Hamprecht B (2001) Distribution of key enzymes of branched-chain amino acid metabolism in glial and neuronal cells in culture. J Histochem Cytochem 49:407–418PubMedCrossRefGoogle Scholar
  60. 60.
    Kanamori K, Ross BD, Kondrat RW (1998) Rate of glutamate synthesis from leucine in rat brain measured in vivo by 15 N NMR. J Neurochem 70:1304–1315PubMedCrossRefGoogle Scholar
  61. 61.
    Kanamori K (2016) In vivo N-15 MRS study of glutamate metabolism in the rat brain. Anal Biochem. doi: 10.1016/j.ab.2016.08.025
  62. 62.
    Sakai R, Cohen DM, Henry JF, Burrin DG, Reeds PJ (2004) Leucine-nitrogen metabolism in the brain of conscious rats: its role as a nitrogen carrier in glutamate synthesis in glial and neuronal metabolic compartments. J Neurochem 88:612–622PubMedCrossRefGoogle Scholar
  63. 63.
    Rothman DL, De Feyter HM, Maciejewski PK, Behar KL (2012) Is there in vivo evidence for amino acid shuttles carrying ammonia from neurons to astrocytes? Neurochem Res 37:2597–2612PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Conway ME, Hutson SM (2016) BCAA Metabolism and NH3 Homeostasis. Adv Neurobiol 13:99–132PubMedCrossRefGoogle Scholar
  65. 65.
    Hull J, Hindy ME, Kehoe PG, Chalmers K, Love S, Conway ME (2012) Distribution of the branched chain aminotransferase proteins in the human brain and their role in glutamate regulation. J Neurochem 123:997–1009PubMedCrossRefGoogle Scholar
  66. 66.
    Islam MM, Nautiyal M, Wynn RM, Mobley JA, Chuang DT, Hutson SM (2010) Branched-chain amino acid metabolon: interaction of glutamate dehydrogenase with the mitochondrial branched-chain aminotransferase (BCATM). J Biol Chem 285:265–276PubMedCrossRefGoogle Scholar
  67. 67.
    Hutson SM, Islam MM, Zaganas I (2011) Interaction between glutamate dehydrogenase (GDH) and l-leucine catabolic enzymes: Intersecting metabolic pathways. Neurochem Int 59:518–524PubMedCrossRefGoogle Scholar
  68. 68.
    Islam MM, Wallin R, Wynn RM, Conway M, Fujii H, Mobley JA, Chuang DT, Hutson SM (2007) A novel branched-chain amino acid metabolon. Protein–protein interactions in a supramolecular complex. J Biol Chem 282:11893–11903PubMedCrossRefGoogle Scholar
  69. 69.
    Garza-Lombo C, Gonsebatt ME (2016) Mammalian target of rapamycin: its role in early neural development and in adult and aged brain function. Front Cell Neurosci 10:157PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Sarbassov DD, Ali SM, Sabatini DM (2005) Growing roles for the mTOR pathway. Curr Opin Cell Biol 17:596–603PubMedCrossRefGoogle Scholar
  71. 71.
    Weber JD, Gutmann DH (2012) Deconvoluting mTOR biology. Cell Cycle 11:236–248PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Garelick MG, Kennedy BK (2011) TOR on the brain. Exp Gerontol 46:155–163PubMedCrossRefGoogle Scholar
  73. 73.
    Anthony JC, Yoshizawa F, Anthony TG, Vary TC, Jefferson LS, Kimball SR (2000) Leucine stimulates translation initiation in skeletal muscle of postabsorptive rats via a rapamycin-sensitive pathway. J Nutr 130:2413–2419PubMedGoogle Scholar
  74. 74.
    Kimball SR, Jefferson LS (2006) Signaling pathways and molecular mechanisms through which branched-chain amino acids mediate translational control of protein synthesis. J Nutr 136:227S–231SPubMedGoogle Scholar
  75. 75.
    Cota D, Proulx K, Smith KA, Kozma SC, Thomas G, Woods SC, Seeley RJ (2006) Hypothalamic mTOR signaling regulates food intake. Science 312:927–930PubMedCrossRefGoogle Scholar
  76. 76.
    Chantranupong L, Wolfson RL, Sabatini DM (2015) Nutrient-sensing mechanisms across evolution. Cell 161:67–83PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Zoncu R, Bar-Peled L, Efeyan A, Wang SY, Sancak Y, Sabatini DM (2011) mTORC1 senses lysosomal amino acids through an inside–out mechanism that requires the vacuolar H+−ATPase. Science 334:678–683PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Bar-Peled L, Sabatini DM (2014) Regulation of mTORC1 by amino acids. Trends Cell Biol 24:400–406PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Han JM, Jeong SJ, Park MC, Kim G, Kwon NH, Kim HK, Ha SH, Ryu SH, Kim S (2012) Leucyl-tRNA synthetase is an intracellular leucine sensor for the mTORC1-signaling pathway. Cell 149:410–424PubMedCrossRefGoogle Scholar
  80. 80.
    Hu F, Xu Y, Liu F (2016) Hypothalamic roles of mTOR complex I: integration of nutrient and hormone signals to regulate energy homeostasis. Am J Physiol Endocrinol Metab 310:E994–E1002PubMedCrossRefGoogle Scholar
  81. 81.
    Xu Y, Elmquist JK, Fukuda M (2011) Central nervous control of energy and glucose balance: focus on the central melanocortin system. Ann NY Acad Sci 1243:1–14PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Lynch CJ, Gern B, Lloyd C, Hutson SM, Eicher R, Vary TC (2006) Leucine in food mediates some of the postprandial rise in plasma leptin concentrations. Am J Physiol Endocrinol Metab 291:E621–E630PubMedCrossRefGoogle Scholar
  83. 83.
    Kimura N, Tokunaga C, Dalal S, Richardson C, Yoshino K, Hara K, Kemp BE, Witters LA, Mimura O, Yonezawa K (2003) A possible linkage between AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) signalling pathway. Genes Cells 8:65–79PubMedCrossRefGoogle Scholar
  84. 84.
    Andre C, Cota D (2012) Coupling nutrient sensing to metabolic homoeostasis: the role of the mammalian target of rapamycin complex 1 pathway. Proc Nutr Soc 71:502–510PubMedCrossRefGoogle Scholar
  85. 85.
    Zampieri TT, Pedroso JA, Furigo IC, Tirapegui J, Donato J Jr (2013) Oral leucine supplementation is sensed by the brain but neither reduces food intake nor induces an anorectic pattern of gene expression in the hypothalamus. PLoS ONE 8:e84094PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Scaini G, Tonon T, de Souza CF, Schuk PF, Ferreira GC, Neto JS, Amorin T, Schwartz IV, Streck EL (2016) Serum markers of neurodegeneration in maple syrup urine disease. Mol NeurobiolGoogle Scholar
  87. 87.
    Scriver CR (2001) The metabolic & molecular bases of inherited disease. McGraw-Hill, New YorkGoogle Scholar
  88. 88.
    Muelly ER, Moore GJ, Bunce SC, Mack J, Bigler DC, Morton DH, Strauss KA (2013) Biochemical correlates of neuropsychiatric illness in maple syrup urine disease. J Clin Invest 123:1809–1820PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Mazariegos GV, Morton DH, Sindhi R, Soltys K, Nayyar N, Bond G, Shellmer D, Shneider B, Vockley J, Strauss KA (2012) Liver transplantation for classical maple syrup urine disease: long-term follow-up in 37 patients and comparative United Network for Organ Sharing experience. J Pediatr 160(116–121):e111Google Scholar
  90. 90.
    Korein J, Sansaricq C, Kalmijn M, Honig J, Lange B (1994) Maple syrup urine disease: clinical, EEG, and plasma amino acid correlations with a theoretical mechanism of acute neurotoxicity. Int J Neurosci 79:21–45PubMedCrossRefGoogle Scholar
  91. 91.
    Wang XL, Li CJ, Xing Y, Yang YH, Jia JP (2015) Hypervalinemia and hyperleucine-isoleucinemia caused by mutations in the branched-chain-amino-acid aminotransferase gene. J Inherit Metab Dis 38:855–861PubMedCrossRefGoogle Scholar
  92. 92.
    Chen CD, Lin CH, Chuankhayan P, Huang YC, Hsieh YC, Huang TF, Guan HH, Liu MY, Chang WC, Chen CJ (2012) Crystal structures of complexes of the branched-chain aminotransferase from Deinococcus radiodurans with α-ketoisocaproate and l-glutamate suggest the radiation resistance of this enzyme for catalysis. J Bacteriol 194:6206–6216PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Castell A, Mille C, Unge T (2010) Structural analysis of mycobacterial branched-chain aminotransferase: implications for inhibitor design. Acta Crystallogr D Biol Crystallogr 66:549–557PubMedCrossRefGoogle Scholar
  94. 94.
    Goto M, Miyahara I, Hayashi H, Kagamiyama H, Hirotsu K (2003) Crystal structures of branched-chain amino acid aminotransferase complexed with glutamate and glutarate: true reaction intermediate and double substrate recognition of the enzyme. BioChemistry 42:3725–3733PubMedCrossRefGoogle Scholar
  95. 95.
    Yennawar NH, Conway ME, Yennawar HP, Farber GK, Hutson SM (2002) Crystal structures of human mitochondrial branched chain aminotransferase reaction intermediates: ketimine and pyridoxamine phosphate forms. BioChemistry 41:11592–11601PubMedCrossRefGoogle Scholar
  96. 96.
    Sitta A, Ribas GS, Mescka CP, Barschak AG, Wajner M, Vargas CR (2014) Neurological damage in MSUD: the role of oxidative stress. Cell Mol Neurobiol 34:157–165PubMedCrossRefGoogle Scholar
  97. 97.
    de Lima Pelaez P, Funchal C, Loureiro SO, Heimfarth L, Zamoner A, Gottfried C, Latini A, Wajner M, Pessoa-Pureur R (2007) Branched-chain amino acids accumulating in maple syrup urine disease induce morphological alterations in C6 glioma cells probably through reactive species. Int J Dev Neurosci 25:181–189CrossRefGoogle Scholar
  98. 98.
    Cooper AJ, Bruschi SA, Conway M, Hutson SM (2003) Human mitochondrial and cytosolic branched-chain aminotransferases are cysteine S-conjugate beta-lyases, but turnover leads to inactivation. Biochem Pharmacol 65:181–192PubMedCrossRefGoogle Scholar
  99. 99.
    Conway ME, Yennawar N, Wallin R, Poole LB, Hutson SM (2003) Human mitochondrial branched chain aminotransferase: structural basis for substrate specificity and role of redox active cysteines. Biochim Biophys Acta 1647:61–65PubMedCrossRefGoogle Scholar
  100. 100.
    Funchal C, Gottfried C, de Almeida LM, dos Santos AQ, Wajner M, Pessoa-Pureur R (2005) Morphological alterations and cell death provoked by the branched-chain alpha-amino acids accumulating in maple syrup urine disease in astrocytes from rat cerebral cortex. Cell Mol Neurobiol 25:851–867PubMedCrossRefGoogle Scholar
  101. 101.
    Garcia-Cazorla A, Oyarzabal A, Fort J, Robles C, Castejon E, Ruiz-Sala P, Bodoy S, Merinero B, Lopez-Sala A, Dopazo J, Nunes V, Ugarte M, Artuch R, Palacin M, Rodriguez-Pombo P, Alcaide P, Navarrete R, Sanz P, Font-Llitjos M, Vilaseca MA, Ormaizabal A, Pristoupilova A, Agullo SB (2014) Two novel mutations in the BCKDK (branched-chain keto-acid dehydrogenase kinase) gene are responsible for a neurobehavioral deficit in two pediatric unrelated patients. Hum Mutat 35:470–477PubMedCrossRefGoogle Scholar
  102. 102.
    Novarino G, El-Fishawy P, Kayserili H, Meguid NA, Scott EM, Schroth J, Silhavy JL, Kara M, Khalil RO, Ben-Omran T, Ercan-Sencicek AG, Hashish AF, Sanders SJ, Gupta AR, Hashem HS, Matern D, Gabriel S, Sweetman L, Rahimi Y, Harris RA, State MW, Gleeson JG (2012) Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy. Science 338:394–397PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Joshi MA, Jeoung NH, Obayashi M, Hattab EM, Brocken EG, Liechty EA, Kubek MJ, Vattem KM, Wek RC, Harris RA (2006) Impaired growth and neurological abnormalities in branched-chain alpha-keto acid dehydrogenase kinase-deficient mice. Biochem J 400:153–162PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Hutson SM (2006) The case for regulating indispensable amino acid metabolism: the branched-chain α-keto acid dehydrogenase kinase-knockout mouse. Biochem J 400:e1–e3PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Harris RA, Zhang B, Goodwin GW, Kuntz MJ, Shimomura Y, Rougraff P, Dexter P, Zhao Y, Gibson R, Crabb DW (1990) Regulation of the branched-chain alpha-ketoacid dehydrogenase and elucidation of a molecular basis for maple syrup urine disease. Adv Enzyme Regul 30:245–263PubMedCrossRefGoogle Scholar
  106. 106.
    Ashby EL, Kierzkowska M, Hull J, Kehoe PG, Hutson SM, Conway ME (2016) Altered expression of human mitochondrial branched chain aminotransferase in dementia with lewy bodies and vascular dementia. Neurochem Res. doi:  10.1007/s11064-016-1855-7 PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Justin E. Sperringer
    • 1
    Email author
  • Adele Addington
    • 1
  • Susan M. Hutson
    • 1
  1. 1.Department of Human Nutrition, Foods, and ExerciseVirginia Polytechnic Institute and State UniversityBlacksburgUSA

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