Regulation of the branched-chain α-ketoacid dehydrogenase and elucidation of a molecular basis for maple syrup urine disease

Harris, Robert A.; Zhang, Bei; Goodwin, Gary W.; Kuntz, Martha J.; Shimomura, Yoshiharu; Rougraff, Paul M.; Dexter, Paul; Zhao, Yu; Gibson, Robert L.; Crabb, David W.

doi:10.1016/0065-2571(90)90021-s

Cited by 73 publications

(50 citation statements)

References 47 publications

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“…), a transacylase, and a dehydrogenase (EC 1.8.1.4. ), and two regulatory enzymes, i.e., a specific kinase (EC 2.7.1.115) and a specific phosphatase, that regulate decarboxylase activity through a phosphorylation (inactive)/dephosphorylation (active) cycle (Harris et al, 1990). KIC, through inhibition of the kinase, activates the complex.…”

Section: Brain Glu Synthesis From Leu In Vivo 1305mentioning

confidence: 99%

Rate of Glutamate Synthesis from Leucine in Rat Brain Measured In Vivo by ¹⁵N NMR

Kanamori

Ross

Kondrat

1998

Journal of Neurochemistry

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Abstract:The rate of glutamate synthesis from leucine by the branched-chain aminotransferase was measured in rat brain in vivo at steady state. The rats were fed exclusively by intravenous infusion of a nutrient solution containing [15N]leucine. The rate of glutamate synthesis from leucine, determined from the rate of increase of brain [15N]glutamate measured by 15N NMR and the 15N enrichments of brain and blood leucine analyzed by gas chromatography-mass spectrometry, was 0.7-1.8 j.tmol/g/ h at a steady-state brain leucine concentration of 0.25 mol/g. A comparison of the observed fractional 15N enrichments of brain leucine (0.42 ±0.03) and glutamate (0.21 ±0.015) showed that leucine provides '-.~50%of glutamate nitrogen under our experimental condition. From the observed rate (0.7-1.8 j.imol/g) and the known Km of the branched-chain aminotransferase for leucine (1.2 mM), the rate of glutamate synthesis from leucine at physiological brain leucine concentration (0.11~mol/ g) was estimated to be 0.35-0.9~mol/g/h, with leucine providing~25% of glutamate nitrogen. The results strongly suggest that plasma leucine from dietary source, transported into the brain, is an important external source of nitrogen for replenishment of brain glutamate in vivo. Implications of the results for treatment of maple-syrup urine disease patients with leucine-restricted diet are discussed. Key Words: Leucine-Glutamate-BrainBranched-chain aminotransferase-1 5N NMR-In vivo. J. Neurochem. 70, 1304Neurochem. 70, -1315Neurochem. 70, (1998.The branched-chain amino acids (BCAA) -leucine, isoleucine, and valine-are essential amino acids that readily cross the blood-brain barrier. Leucine is the predominant BCAA in most dietary proteins (Berry et al., 1989) and has the highest influx rate into the brain (Smith et al., 1987). In the brain, leucine has two metabolic fates: (a) incorporation into proteins and (b) transamination to a-ketoglutarate to form glutamate, catalyzed by branched-chain aminotransferase (BCAT; EC 2.6.1.42):

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Section: Brain Glu Synthesis From Leu In Vivo 1305mentioning

confidence: 99%

Rate of Glutamate Synthesis from Leucine in Rat Brain Measured In Vivo by ¹⁵N NMR

Kanamori

Ross

Kondrat

1998

Journal of Neurochemistry

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“…It has been shown that insulin, glucocorticoid, thyroid hormone, and sex hormones regulate the activity and expression of BCKDK as well (17,20). In addition, the BCKDK activity is also subject to allosteric regulation by BCKAs, thiamine diphosphate, and other factors (7,21). BCKAs inhibit the BCKDK activity and attenuates its interaction with the BCKD complex.…”

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confidence: 99%

Tissue-specific and Nutrient Regulation of the Branched-chain α-Keto Acid Dehydrogenase Phosphatase, Protein Phosphatase 2Cm (PP2Cm)

Zhou

Lü²,

Gao³

et al. 2012

Journal of Biological Chemistry

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“…BCKDC catalyzes irreversible oxidative decarboxylation of the BCKAs to produce the branched chain acyl-CoAs and NADH and contains multiple copies of three enzymes: branched chain ␣-keto acid decarboxylase/dehydrogenase (E1), dihydrolipoyl transcylase (E2), and dihydrolipoamide dehydrogenase (E3) (8). BCKDC is inactivated by phosphorylation of the E1␣ subunit of the E1 enzyme, catalyzed by a specific kinase (BDK), which is inhibited by the ␣-keto acid of Leu (KIC, ␣-ketoisocaproate) (9,10).…”

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confidence: 99%

Cytosolic Branched Chain Aminotransferase (BCATc) Regulates mTORC1 Signaling and Glycolytic Metabolism in CD4+ T Cells

Ananieva

Patel

Drake

et al. 2014

Journal of Biological Chemistry

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Background: Cytosolic branched chain aminotransferase (BCATc) initiates Leu catabolism. In T cells, Leu activates mTORC1, the role of BCATc is unknown. Results: BCATc stimulates Leu transamination, whereas loss of BCATc expression increases Leu concentrations, mTORC1 signaling, and glycolysis in T cells. Conclusion: BCATc is a novel immunosuppressive enzyme controlling Leu supply for mTORC1 in T cells. Significance: A new link is revealed between amino acid metabolism and the immune response.

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Regulation of the branched-chain α-ketoacid dehydrogenase and elucidation of a molecular basis for maple syrup urine disease

Cited by 73 publications

References 47 publications

Rate of Glutamate Synthesis from Leucine in Rat Brain Measured In Vivo by ¹⁵N NMR

Rate of Glutamate Synthesis from Leucine in Rat Brain Measured In Vivo by ¹⁵N NMR

Tissue-specific and Nutrient Regulation of the Branched-chain α-Keto Acid Dehydrogenase Phosphatase, Protein Phosphatase 2Cm (PP2Cm)

Cytosolic Branched Chain Aminotransferase (BCATc) Regulates mTORC1 Signaling and Glycolytic Metabolism in CD4+ T Cells

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Regulation of the branched-chain α-ketoacid dehydrogenase and elucidation of a molecular basis for maple syrup urine disease

Cited by 73 publications

References 47 publications

Rate of Glutamate Synthesis from Leucine in Rat Brain Measured In Vivo by 15N NMR

Rate of Glutamate Synthesis from Leucine in Rat Brain Measured In Vivo by 15N NMR

Tissue-specific and Nutrient Regulation of the Branched-chain α-Keto Acid Dehydrogenase Phosphatase, Protein Phosphatase 2Cm (PP2Cm)

Cytosolic Branched Chain Aminotransferase (BCATc) Regulates mTORC1 Signaling and Glycolytic Metabolism in CD4+ T Cells

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Rate of Glutamate Synthesis from Leucine in Rat Brain Measured In Vivo by ¹⁵N NMR

Rate of Glutamate Synthesis from Leucine in Rat Brain Measured In Vivo by ¹⁵N NMR