Regulation of branched-chain α-ketoacid dehydrogenase complex by covalent modification

Harris, Robert A.; Paxton, Ralph; Powell, Stephen M.; Goodwin, Gary W.; Kuntz, Martha J.; Han, Amy

doi:10.1016/0065-2571(86)90016-6

Cited by 80 publications

(70 citation statements)

References 35 publications

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“…Actually, it was found that the protein amount of BCKDH kinase in skeletal muscle was decreased by training for 5 weeks, suggesting that the mechanisms of greater activation of muscle BCKDH complex by acute exercise in trained rats involves an adaptive decrease in the BCKDH kinase content in response to the endurance training for 5 weeks. These results may be (18), who have reported that the decrease in rat liver BCKDH complex activity caused by the protein starvation was associated with an adaptive increase in the BCKDH kinase activity.…”

Section: Discussionmentioning

confidence: 54%

Branched‐chain α‐keto acid dehydrogenase kinase content in rat skeletal muscle is decreased by endurance training

et al. 1998

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Summary: The activity slate of branched-chain a-keto acid dehydrogenase complex in skeletal muscle was elevated by running exercise in trained and untrained rats, but level of this elevation was significantly greater in the former than in the latter. To elucidate the mechanism of the training effect on the exercise-induced activation of the complex, a protein amount of branchedchain c~-keto acid dehydrogenase kinase, which is responsible for inactivation of the complex by phosphorylation, in the muscle was measured by the Western blot analysis. Endurance training decreased the content of the kinase protein in the muscle by ~30%, suggesting that this decrease is involved in the mechanisms for greater activation of the complex by exercise in trained rats.

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Section: Discussionmentioning

confidence: 54%

Branched‐chain α‐keto acid dehydrogenase kinase content in rat skeletal muscle is decreased by endurance training

et al. 1998

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“…In mammals, the BCKDH complex presents three enzymes: α-ketoacid decarboxylase (E1), constituted by the subunits 2α and 2β, dihydrolipoyl transacetylase (E2), and dihydrolipoyl dehydrogenase (E3) (Harris et al, 1986). In tissues, the activity of this complex is regulated by a cycle of phosphorylation and dephosphorylation catalyzed by a specific kinase and a phosphatase.…”

Section: Leucine Metabolismmentioning

confidence: 99%

Protein synthesis regulation by leucine

Vianna

Teodoro

Leal

et al. 2010

Braz. J. Pharm. Sci.

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In vivo and in vitro studies have demonstrated that high protein diets affect both protein synthesis and regulation of several cellular processes. The role of amino acids as substrate for protein synthesis has been established in the literature. However, the mechanism by which these amino acids modulate transcription and regulate the mRNA translation via mTOR-dependent signaling pathway has yet to be fully determined. It has been verified that mTOR is a protein responsible for activating a cascade of biochemical intracellular events which result in the activation of the protein translation process. Of the aminoacids, leucine is the most effective in stimulating protein synthesis and reducing proteolysis. Therefore, it promotes a positive nitrogen balance, possibly by favoring the activation of this protein. This amino acid also directly and indirectly stimulates the synthesis and secretion of insulin, enhancing its anabolic cellular effects. Therefore, this review aimed to identify the role of leucine in protein synthesis modulation and to discuss the metabolic aspects related to this aminoacid. Uniterms:Leucine. Protein synthesis. Transcription Factors. mTOR. Translation Protein.Estudos in vivo e in vitro verificaram que dietas hiperprotéicas influenciam a síntese protéica e regulam vários processos celulares. O papel dos aminoácidos como substrato para a síntese de proteínas já está bem evidenciado na literatura, porém as formas como esses aminoácidos modulam a etapa da transcrição e regulam a tradução do RNAm, pela via de sinalização dependente da mTOR, ainda não estão totalmente esclarecidas. Tem-se verificado que a mTOR é uma proteína responsável por ativar uma cascata de eventos bioquímicos intracelulares que culminam na ativação do processo de tradução protéica. Dentre todos os aminoácidos, a leucina é a mais eficaz em estimular a síntese protéica, reduzir a proteólise e, portanto, favorecer o balanço nitrogenado positivo, possivelmente por favorecer a ativação desta proteína. Além disso, este aminoácido estimula direta e indiretamente a síntese e a secreção de insulina, e, assim, aumenta as propriedades anabólicas celulares. Nesse sentido, a presente revisão tem como objetivo identificar o papel da leucina na modulação da síntese protéica e abordar aspectos metabólicos relacionados a este aminoácido.Unitermos: Leucina. Síntese protéica. Fator de transcrição. mTOR. Tradução de proteínas. INTRODUCTIONProtein synthesis in tissue is rapidly stimulated after nutrient consumption. Insulin and aminoacids stimulate protein anabolism, acting in a posterior step of gene transcription, i.e., on protein translation. However, the mechanism by which the aminoacids stimulate protein translation has yet to be fully determined (Proud, 2002).Some studies have verified that high-protein diets stimulate protein synthesis. Some of the benefits promoted by this diet on body composition can be attributed to high consumption of branched-chain aminoacids (BCAA), which include the aminoacids leucine, valine and isoleucine (Donato...

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“…E3 is a homodimeric flavoprotein that is common to members of the ␣-ketoacid dehydrogenase complexes (3). The kinase and the phosphatase are specific for the BCKD complex and regulate its activity through a reversible phosphorylation (inactivation) and dephosphorylation (activation) cycle (5).…”

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confidence: 99%

Impaired Assembly of E1 Decarboxylase of the Branched-chain α-Ketoacid Dehydrogenase Complex in Type IA Maple Syrup Urine Disease

Wynn

Davie²,

Chuang

et al. 1998

Journal of Biological Chemistry

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The E1 decarboxylase component of the human branched-chain ketoacid dehydrogenase complex comprises two E1␣ (45.5 kDa) and two E1␤ (37.5 kDa) subunits forming an ␣ 2 ␤ 2 tetramer. In patients with type IA maple syrup urine disease, the E1␣ subunit is affected, resulting in the loss of E1 and branched-chain ketoacid dehydrogenase catalytic activities. To study the effect of human E1␣ missense mutations on E1 subunit assembly, we have developed a pulse-chase labeling protocol based on efficient expression and assembly of human (His) 6 -E1␣ and untagged E1␤ subunits in Escherichia coli in the presence of overexpressed chaperonins GroEL and GroES. Assembly of the two 35 S-labeled E1 subunits was indicated by their co-extraction with Ni 2؉ -nitrilotriacetic acid resin. The nine E1␣ maple syrup urine disease mutants studied showed aberrant kinetics of assembly with normal E1␤ in the 2-h chase compared with the wild type and can be classified into four categories of normal (N222S-␣ and R220W-␣), moderately slow (G245R-␣), slow (G204S-␣, A240P-␣, F364C-␣, Y368C-␣, and Y393N-␣), and no (T265R-␣) assembly. Prolonged induction in E. coli grown in the YTGK medium or lowering of induction temperature from 37 to 28°C (in the case of T265R-␣), however, resulted in the production of mutant E1 proteins. Separation of purified E1 proteins by sucrose density gradient centrifugation showed that the wild-type E1 existed entirely as ␣ 2 ␤ 2 tetramers. In contrast, a subset of E1␣ missense mutations caused the occurrence of exclusive ␣␤ dimers (Y393N-␣ and F364C-␣) or of both ␣ 2 ␤ 2 tetramers and lower molecular weight species (Y368C-␣ and T265R-␣). Thermal denaturation at 50°C indicated that mutant E1 proteins aggregated more rapidly than wild type (rate constant, 0.19 min ؊1 ), with the T265R-␣ mutant E1 most severely affected (rate constant, 4.45 min ؊1 ). The results establish that the human E1␣ mutations in the putative thiamine pyrophosphate-binding pocket that are studied, with the exception of G204S-␣, have no effect on E1 subunit assembly. The T265R-␣ mutation adversely impacts both E1␣ folding and subunit interactions. The mutations involving the C-terminal aromatic residues impede both the kinetics of subunit assembly and the formation of the native ␣ 2 ␤ 2 structure.The mammalian mitochondrial branched-chain ␣-ketoacid dehydrogenase (BCKD) 1 complex catalyzes the oxidative decarboxylation of the branched-chain ␣-ketoacids derived from the branched-chain amino acids, leucine, isoleucine, and valine (1). This multienzyme complex is organized around a dihydrolipoyl transacylase (E2) core, to which a branched-chained ␣-ketoacid decarboxylase (E1), a dihydrolipoamide dehydrogenase (E3), a specific kinase, and a specific phosphatase are attached through ionic interactions (2, 3). E1 is a thiamine pyrophosphate (TPP)-dependent enzyme comprising two E1␣ and two E1␤ subunits that assemble into an ␣ 2 ␤ 2 tetramer. E2 is a 24-meric protein consisting of identical lipoic acid-bearing subunits arranged on octahedral 4,3,2-point group...

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Regulation of branched-chain α-ketoacid dehydrogenase complex by covalent modification

Cited by 80 publications

References 35 publications

Branched‐chain α‐keto acid dehydrogenase kinase content in rat skeletal muscle is decreased by endurance training

Branched‐chain α‐keto acid dehydrogenase kinase content in rat skeletal muscle is decreased by endurance training

Protein synthesis regulation by leucine

Impaired Assembly of E1 Decarboxylase of the Branched-chain α-Ketoacid Dehydrogenase Complex in Type IA Maple Syrup Urine Disease

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