Branched Chain Amino Acids: Beyond Nutrition Metabolism

Abstract

Branched chain amino acids (BCAAs), including leucine (Leu), isoleucine (Ile), and valine (Val), play critical roles in the regulation of energy homeostasis, nutrition metabolism, gut health, immunity and disease in humans and animals. As the most abundant of essential amino acids (EAAs), BCAAs are not only the substrates for synthesis of nitrogenous compounds, they also serve as signaling molecules regulating metabolism of glucose, lipid, and protein synthesis, intestinal health, and immunity via special signaling network, especially phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signal pathway. Current evidence supports BCAAs and their derivatives as the potential biomarkers of diseases such as insulin resistance (IR), type 2 diabetes mellitus (T2DM), cancer, and cardiovascular diseases (CVDs). These diseases are closely associated with catabolism and balance of BCAAs. Hence, optimizing dietary BCAA levels should have a positive effect on the parameters associated with health and diseases. This review focuses on recent findings of BCAAs in metabolic pathways and regulation, and underlying the relationship of BCAAs to related disease processes.

Keywords: PI3K-AKT-mTOR; amino acid metabolism; biomarkers; branch chain amino acids (BCAAs); insulin resistance; metabolic diseases.

Figure 1

The main steps of BCAAs catabolism. BCAAs catabolic reactions are catalyzed via a series of enzymes (e.g., transamination by BCAT) and decarboxylation by BCKD), and the end products enter to TCA cycle. Abbreviations: BCAAs, branched chain amino acids; BCAT, branched-chain amino acid aminotransferases; BCKD, branched-chain α-keto acid dehydrogenase; TCA, tricarboxylic acid.

Figure 2

BCAAs balance and its multiple roles via PI3K-AKT-mTOR signaling pathway. BCAAs play important role as nitrogen donor for AAs, such as Ala, Glu, and Gln, and also as nutrient signal play critical roles in multiple metabolic functions through special signaling pathway, especially via PI3K-AKT-mTOR pathway. The metabolic imbalance of BCAAs can cause many health issues, such as diabetes and cancer. Abbreviations: AAs, amino acids; AKT, protein kinase B; Ala, alanine; Atg13, autophagy 13; BCAAs, branched chain amino acids; Deptor, domain containing mTOR interacting protein; 4E-BP1, 4E-binding protein 1; EAAs, essential amino acids; FIP200, focal adhesion kinase-interacting protein 200 kDa; Gln, glutamine; GLUT4, glucose transporter; Glu, glutamate; IRS-1, insulin receptor substrate 1; Leu, leucine; Lipin1, phosphatidate phosphatase Lipin1; mLST8, mammalian lethal with Sec13 protein 8 (also known as GβL), mSin1, target of rapamycin complex 2 subunit MAPKAP1; mTOR, mammalian target of rapamycin; mTORC1, mTOR complex 1; mTORC2, mTOR complex 2; p70S6K, p70S6 kinase; PDK1, 3-phosphoinositide dependent protein kinase-1; PI3K, phosphoinositide 3-kinase; PIP3, phosphatidylinositol-3,4,5-trisphosphate; PRAS40, proline-rich Akt substrate 40 kDa; Protor, proline-rich protein; Rag A/B, Ras-related GTP-binding protein A/B; Raptor, regulatory-associated protein of mTOR; Rheb, Ras homolog enriched in brain; Rictor, apamycin-insensitive companion of mTOR; Tel2, telomere length regulation protein; TSC, Tuberous sclerosis; Tti1, TELO2-interacting protein 1; ULK1, UNC51-like kinase 1. (The current understanding of the signaling pathway was based on annotations from the Kyoto Encyclopaedia of Genes and Genomes (KEGG)).