A molecular model of human branched-chain amino acid metabolism

Kitaura

2012

JPFSM

Exercise promotes protein and amino acid breakdown in skeletal muscle. Proper nutrient intake in relation to exercise is thus important to maintain or build up skeletal muscle. It has been demonstrated that supplementation of branched-chain amino acids (BCAAs) before exercise has beneficial effects on skeletal muscle, such as decreasing exercise-induced muscle damage and soreness. Protein synthesis in skeletal muscle is enhanced after exercise, and proper timing of supplementation of protein and amino acids for effectively stimulating muscle protein synthesis is herein discussed. Treatment of elderly individuals with exercise and nutrient supplementation is also demonstrated to have efficacy against age-related sarcopenia.

Section: Increased Amino Acid Breakdown By Exercisesupporting

confidence: 66%

Effects of protein and amino acid supplementation on muscle protein metabolism in relation to exercise

Kitaura

2012

JPFSM

Journal of Biological Chemistry

“…4). In rodents, skeletal muscle is one of the organs with high aminotransferase to oxidative capacity ratio and absence of BCAT in the rodent liver supports extensive inter organ cooperation in the catabolism of BCAA and their metabolites (57). It is possible that a similar regulatory system evolved in the immune system where BCAA metabolites can shuttle between immune and target cells.…”

Section: Discussionmentioning

confidence: 99%

“…The second step or the irreversible oxidative decarboxylation of BCKAs, catalyzed by BCKDC, commits the BCAA carbon skeleton to the degradative pathway (57). In un-stimulated T cells, BCATc was not expressed and therefore all BCAA metabolism occurred in the mitochondria.…”

Section: Discussionmentioning

confidence: 99%

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

Ananieva

Patel

Drake

et al. 2014

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.

Journal of Biological Chemistry

“…However, actual net transfer of BCAA nitrogen occurs when BCKDC is active (BCAAs are oxidized) and is promoted by BCATm-E1␣ complex formation and substrate channeling of BCKA from BCATm to E1. In humans and rodents, the pancreas has one of the highest concentrations of BCATm in the body (48). Leucine is a known insulin secretagogue (19,49).…”

Section: Dcpip Assaymentioning

confidence: 99%

Branched-chain Amino Acid Metabolon

Islam

Nautiyal

Wynn

et al. 2010

The catabolic pathway for branched-chain amino acids includes deamination followed by oxidative decarboxylation of the deaminated product branched-chain ␣-keto acids, catalyzed by the mitochondrial branched-chain aminotransferase (BCATm) and branched-chain ␣-keto acid dehydrogenase enzyme complex (BCKDC). We found that BCATm binds to the E1 decarboxylase of BCKDC, forming a metabolon that allows channeling of branched-chain ␣-keto acids from BCATm to E1. The protein complex also contains glutamate dehydrogenase (GDH1), 4-nitrophenylphosphatase domain and non-neuronal SNAP25-like protein homolog 1, pyruvate carboxylase, and BCKDC kinase. GDH1 binds to the pyridoxamine 5-phosphate (PMP) form of BCATm (PMP-BCATm) but not to the pyridoxal 5-phosphateBCATm and other metabolon proteins. Leucine activates GDH1, and oxidative deamination of glutamate is increased further by addition of PMP-BCATm. Isoleucine and valine are not allosteric activators of GDH1, but in the presence of 5-phosphate-BCATm, they convert BCATm to PMP-BCATm, stimulating GDH1 activity. Sensitivity to ADP activation of GDH1 was unaffected by PMP-BCATm; however, addition of a 3 or higher molar ratio of PMP-BCATm to GDH1 protected GDH1 from GTP inhibition by 50%. Kinetic results suggest that GDH1 facilitates regeneration of the form of BCATm that binds to E1 decarboxylase of the BCKDC, promotes metabolon formation, branched-chain amino acid oxidation, and cycling of nitrogen through glutamate.It has been proposed that the enzymes that are responsible for catalyzing sequential reactions in several metabolic pathways are highly organized in supramolecular complexes termed metabolons (1). The concept of metabolic enzymes associating to form a supramolecular complex was hypothesized 50 years ago (2). Recently, Benkovic and co-workers (3) have shown the in vivo assembly of six proteins in the purine catabolic pathway to form a "purinosome." The formation of the purinosome appears to be dynamically regulated by stimulation of de novo purine biosynthesis in response to changes in purine levels. Another group (4) also has shown that glycolytic enzymes ("glycosome") are organized into complexes, and this assembly is regulated by the oxidation and phosphorylation states of the proteins. The advantages of such a supramolecular assembly include efficient channeling of substrates between enzymes in a pathway, regulating pathway flux by association and dissociation, and by targeting the assembly of the interacting proteins to the appropriate intracellular structures. Previously, using liver mitochondrial extracts and purified BCATm, 2 we showed that the first two enzymes in BCAA catabolism, mitochondrial branched-chain aminotransferase (BCATm) and branchedchain ␣-keto acid decarboxylase (E1) of the BCKDC, associate in vitro (5). It is not yet known if this BCAA metabolon forms in tissues expressing BCATm, and if other associated proteins are functionally involved in the metabolon.BCATs (mitochondrial and cytosolic isozymes) catalyze reversible transamination of BCAA...