Why is leucine toxic

Jouvet , P. Jan , W. Neuroradiology 45 : — Sansaricq , C. Nyhan , W. Wolff , J. Cremer , J. Mawatari , K. Food Chem. Shimomura , Y. Published in a supplement to The Journal of Nutrition. Bier, Luc Cynober, David H. Guest editors for the supplement publication were David H. Baker, Dennis M. Bier, Luc Cynober, John D. Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide.

Sign In or Create an Account. Sign In. Advanced Search. Search Menu. Article Navigation. Close mobile search navigation Article Navigation. Volume Brain glutamate metabolism: the glutamate—glutamine cycle. The BCAAs as brain nitrogen donors. Brain metabolism in maple syrup urine disease. Marc Yudkoff , Marc Yudkoff. E-mail: yudkoff email. Oxford Academic. Yevgeny Daikhin. Ilana Nissim. Oksana Horyn. Bohdan Luhovyy.

Adam Lazarow. Itzhak Nissim. Select Format Select format. Permissions Icon Permissions. Glutamate concentration. Open in new tab. Open in new tab Download slide. Once transported into astrocytes, glutamate is converted to glutamine via glutamine synthetase EC 6. The importance of the BCAAs as nitrogen donors in peripheral tissues has long been understood. Skeletal muscle is a major site of transamination of these compounds 40 because of its high content of BCAA transaminase.

When catabolism of muscle protein increases, there is an increased supply of BCAAs, thereby favoring the generation by myocytes of glutamate, which becomes available to the alanine aminotransferase reaction EC 2. This rendering of altered brain metabolism is consistent with clinical findings. Thus, the cerebrospinal fluid of affected patients during a period of metabolic decompensation shows a marked increase in leucine and a relative depletion of both glutamate and glutamine A depletion of intracellular glutamate is reflected also in the fact that the leucine:alanine ratio is low, even before the development of overt clinical symptoms Glutamate as a neurotransmitter in the brain: review of physiology and pathology.

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Abnormal glutamate metabolism in an adult-onset degenerative neurological disorder. Intracellular metabolic compartmentation assessed by 13C magnetic resonance spectroscopy. Nitrogen shuttling between neurons and glial cells during glutamate synthesis. Role of pyruvate carboxylase in facilitation of synthesis of glutamate and glutamine in cultured astrocytes.

Whole-brain glutamate metabolism evaluated by steady-state kinetics using a double-isotope procedure: effects of gabapentin. Elucidation of the quantitative significance of pyruvate carboxylation in cultured cerebellar neurons and astrocytes. Net amino acid transport between plasma and erythrocytes and pefused dog brain. Studies on the transport of glutamine in vivo between the brain and blood in the resting state and during afferent electrical stimulation.

Cerebral blood flow and metabolic rate of oxygen, glucose, lactate, pyruvate, ketone bodies and amino acids. Brain uptake and release of amino acids in nondiabetic and insulin-dependent diabetic subjects: important role of glutamine release for nitrogen balance.

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Brain microvessels take up large neutral amino acids in exchange for glutamine. Function of leucine in excitatory neurotransmitter Metabolism in the central nervous system. Rate of glutamate synthesis from leucine in rat brain measured in vivo by 15 N NMR.

Brain uptake of radiolabeled amino acids, amines and hexoses after arterial injection. Glucose and alanine metabolism in children with maple syrup urine disease. Branched-chain amino acids and neurotransmitter metabolism: expression of cytosolic branched-chain aminotransferase BCATc in the cerebellum and hippocampus. Identification of mitochondrial branched chain aminotransferase and its isoforms in rat tissues.

Branched chain aminotransferase isoenzymes. Neurotransmitter amino acids in the CNS. Metabolism of branched-chain amino acids in astroglial-rich primary culture. Fetal fuels. Metabolism of 2-oxoacid analogues of leucine, valine and phenylalanine by heart muscle, brain and kidney of the rat. Precursors of glutamic acid nitrogen in primary neuronal cultures: studies with 15N. Inter-relationships of leucine and glutamate metabolism in cultured astrocytes.

Astrocyte leucine metabolism significance of branched-chain amino acid transamination. Expression of monocarboxylic acid transporters MCT in brain cells. Neuronal metabolism of branched-chain amino acids: flux through the aminotransferase pathway in synaptosomes. Alpha-ketoisocaproate alters the production of both lactate and aspartate from [U- 13 C]glutamate in astrocytes: a 13 C NMR study. Arteriovenous differences and tissue concentrations of branched-chain ketoacids.

Molecular and biochemical basis of intermediate maple syrup urine disease. Reduction of large neutral amino acid levels in plasma and brain of hyperleucinemic rats. Mechanisms responsible for regulation of branched-chain amino acid catabolism. Induction of oxidative stress in rat brain by the metabolites accumulating in maple syrup urine disease. Maple syrup urine disease: interrelationship between branched chain amino-, oxo-, and hydroxyacids implications for treatment association with CNS dysmyelination.

Branched chain amino acids induce apoptosis in neural cells without mitochondrial membrane depolarization or cytochrome c release: implications for neurological impairment associated with maple syrup urine disease.

MR diffusion imaging and MR spectroscopy of maple syrup urine disease during acute metabolic decompensation. Alanine decreases the protein requirements of infants with inborn errors of amino acid metabolism. Inhibition, by 2-oxo acids that accumulate in maple-syrup-urine disease, of lactate, pyruvate, and 3-hydroxybutyrate transport across the blood-brain barrier. Prolonged oral treatment with an essential amino acid L-leucine does not affect female reproductive function and embryo-fetal development in rats.

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The cohort of patients with MSUD described here is relatively large compared with the incidence of the disease and the number of patients attending each single metabolic centre. Nevertheless, the potential of statistical examinations is limited by the overall small number of 24 patients.

All patients were born, diagnosed, and treated in Austria, Switzerland, or Germany. However, their parents were immigrants in Children from immigrant families are clearly underrepresented in the low cluster Possible explanations for that may be distinct cultural and health beliefs as well as linguistic deficiencies in the migrant community.

Therefore, proper communication on the basics, characteristics, and treatment measures of that disease between the therapeutic team and the patient's family is essential. The use of written instructions in the patient's and his or her parents' primary language may be helpful in maintaining better outcome. Staff with adequate language skills and knowledge of cultural understanding is also preferred. Despite the fact that all patients received treatment in German-speaking countries, there may be differences in the treatment recommendation among the individual metabolic centers regarding the long-term plasma leucine levels that should be appreciated.

Hence, patients could have been assigned a priori to a specific cluster. Interestingly, the high cluster comprised more patients who were older not significant. Yet, it remains open whether the younger patients had more benefit from improved knowledge of the treatment of MSUD. Another explanation could be that with age and independence from parental surveillance, dietary control became worse.

Finally, children with moderate and poor long-term metabolic control had more severe metabolic decompensations than patients with excellent metabolic long-term control data not shown.

This may suggest that knowledgeable parents may recognize an imminent derangement during catabolic stress in time and start preventive dietary measures early. Previous authors have indicated that early and meticulous treatment of patients with MSUD can result in normal intellectual outcome 9.

The long-term biochemical control is another, and maybe the most important, factor that has an extremely important influence on the intellectual outcome in children with MSUD. Kasinski et al. Araujo and coworkers 12 speculated that a decrease of essential amino acids in brain may lead to reduction of protein and neurotransmitter synthesis in MSUD. However, these observations derive from an animal model and the authors point out that the relevance for MSUD patients yet has to be evaluated.

Additionally, Zielke et al. Recently, Yudkoff et al. The authors concluded that this depletion results in a compromise of energy metabolism and a diminished rate of protein synthesis. In summary, it becomes clear from all these reports that long-term metabolic control is essential for normal brain development and best possible neurocognitive outcome.

To enable parents and patients to come up with the best treatment results, clear and comprehensive information on treatment, including the target range for plasma leucine levels, and continuous training is essential. Furthermore, regular biochemical monitoring and early and sufficient intervention during catabolic episodes is mandatory. This may not be achieved during catabolic episodes that may occur during intercurrent illnesses but should be the goal for long-term treatment.

Pediatrics : — Article Google Scholar. J Med Genet 31 : — Chuang D, Shih V Maple syrup urine disease branched-chain ketoaciduria. McGraw-Hill, New York, pp — Brain Res Mol Brain Res : — J Inherit Metab Dis 20 : — Nephrol Dial Transplant 14 : — Eur J Pediatr : — J Pediatr : 46— Snyderman SE Treatment outcome of maple syrup urine disease. Acta Paediatr Jpn 30 : — Clin Chem 43 : — Neurochem Int 38 : — Neurochem Int 40 : — J Nutr : S—S.

Download references. This paper contains parts of the doctoral thesis of C. The authors very much appreciate the support and efforts of the following colleagues who kindly provided laboratory reports and clinical data of their patients: C. Aring, Cologne; A.

Leupold, Ulm; E. Renner, Erlangen; I. These include isoleucine and valine. Search Encyclopedia. Leucine Other name s : a-amino-isocaproic acid Unproven claims There may be benefits that have not yet been proven through research.

By eating enough protein in your diet, you get all of the amino acids you need. You should take leucine supplements with valine and isoleucine. There are no conditions that increase how much leucine you need. Side effects, toxicity, and interactions Using a single amino acid supplement may lead to negative nitrogen balance. You should not take high doses of single amino acids for long periods of time.