Novel Physiological Functions of Branched-Chain Amino Acids

Abstract

Branched-chain amino acids (BCAAs: leucine, isoleucine, and valine) are nutritionally indispensable (essential) amino acids for humans. We acquire these amino acids mainly as food proteins, in which the BCAAs account for ~20% of the amino acids. The ingested BCAAs are used for protein synthesis in the body. The daily requirement for BCAAs in adults is estimated to be 85 mg/kg body weight (BW) (39, 20, and 26 mg/ kg BW for Leu, Ile, and Val, respectively) using methods such as indicator amino acid oxidation and 24-hour balance studies (1). The primary physiological function of BCAAs is as the building blocks of proteins; however, recent studies have contributed to the mounting evidence for other physiological functions. In this review, we summarize the current findings on the physiological functions of BCAAs, including those from our own studies. Regulation of BCAA CatabolismThe main BCAA catabolic pathway occurs within mitochondria. The first 2 steps of the pathway are common to the 3 BCAAs and are especially important for the regulation of BCAA catabolism (2) (Fig. 1). The first step of the pathway is the reversible transamination of BCAAs catalyzed by branched-chain aminotransferase (BCAT) to produce corresponding branched-chain a-ketoacids (BCKAs). The second step involves the oxidative decarboxylation of BCKAs catalyzed by the BCKA dehydrogenase (BCKDH) complex to produce corresponding CoA esters. Since this reaction is irreversible, it is a rate-limiting step in BCAA catabolism. Furthermore, the BCKDH complex is subject to covalent modification; BCKDH kinase (BDK) is responsible for inactivation of the complex by phosphorylation and BCKDH phosphatase reactivates the complex by dephosphorylation (2). Therefore, the enzyme activity of the BCKDH complex can be quickly changed in response to alterations in physiological conditions. Aberrations of the enzymes involved in the first two steps of BCAA catabolism have a great impact on the circulating concentrations of BCAAs; a defect in the mitochondrial BCAT (BCAT2) gene of mice resulted in a markedly high level of plasma BCAAs (3), and BDK-knockout (KO) mice, in which the BCKDH complex in all tissues was almost fully activated, showed significantly low concentrations of plasma BCAAs (4). Regulation of Protein Metabolism by LeucineThe mammalian target of rapamycin complex 1 (mTORC1) is a serine-threonine protein kinase that controls translation initiation and is responsive to cellular levels of free amino acids (5). mTORC1 phosphorylates and activates the protein kinase p70S6K1, which subsequently phosphorylates eukaryotic initiation factor 4B (eIF4B) and programmed cell death 4 (PDCD4), and phosphorylates eIF4E-binding protein 1 (eIF4E-BP1), thereby permitting eIF4E to associate with eIF4G to form eIF4F. Thus, mTORC1 stimulates the joining of mRNA to the 43S preinitiation complex and has a global effect on protein synthesis. Furthermore, mTORC1 regulates cellular proteolysis by inhibiting the formation of autophagosomes (6). It is also known that leucine strongly...

L-Leucine <i>In Ovo</i> Administration Causes Growth Retardation and Modifies Specific Amino Acid Metabolism in Broiler Embryos

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