Branched Chain Amino Acids

Abstract

Branched chain amino acids (BCAAs) are building blocks for all life-forms. We review here the fundamentals of BCAA metabolism in mammalian physiology. Decades of studies have elicited a deep understanding of biochemical reactions involved in BCAA catabolism. In addition, BCAAs and various catabolic products act as signaling molecules, activating programs ranging from protein synthesis to insulin secretion. How these processes are integrated at an organismal level is less clear. Inborn errors of metabolism highlight the importance of organismal regulation of BCAA physiology. More recently, subtle alterations of BCAA metabolism have been suggested to contribute to numerous prevalent diseases, including diabetes, cancer, and heart failure. Understanding the mechanisms underlying altered BCAA metabolism and how they contribute to disease pathophysiology will keep researchers busy for the foreseeable future.

Keywords: branched chain amino acids; cancer; catabolism; diabetes; heart disease.

Figure 1

BCAA synthesis and catabolism. Synthesis (a) occurs in plants, bacteria, and fungi. Oxidation (b) occurs in plants, bacteria, fungi, and animals. All three BCAAs share the BCAT and BCKDH steps, after which catabolism of each BCAA is unique. The BCKDH complex is composed of a core of 24 E2 subunits, which are docked by E1 heterotetamers and E3 dimers. BCKDK inhibits E1 via phosphorylation, which is reversed by PP2Cm. Abbreviations: ACAD8, acyl-CoA dehydrogenase family member 8; ACADSB, short/branched chain acyl-CoA dehydrogenase; ACAT1, acetyl-CoA acetyltransferase 1; AHAS, acetohydroxyacid synthase; α-KIC, α-ketoisocaproic acid; α-KIV, α-ketoisovaleric acid; α-KMV, α-ketomethylvaleric acid; ALDH6A1, aldehyde dehydrogenase 6 family member A1; AUH, AU RNA-binding protein/enoyl-coenzyme A hydratase; BAIBA, beta-amino-isobutyric acid; BCAA, branched chain amino acid; BCAT, branched chain amino transferase; BCFA, branched chain fatty acid; BCKDH, branched chain amino acid dehydrogenase; BCKDK, BCKDH kinase; CoA, coenzyme A; DHAD, dihydroxyacid dehydratase; HADHA, hydroxyacyl-CoA dehydrogenase subunit alpha; HIBADH, 3-hydroxyisobutyrate dehydrogenase; HIBCH, 3-hydroxyisobutyryl-CoA hydrolase; HMGCL, 3-hydroxymethyl-3-methylglutaryl-CoA lyase; HSD17B0, 2-methyl-3-hydroxybutyryl-CoA dehydrogenase; IPMDH, isopropylmalate dehydrogenase; IPMI, isopropylmalate isomerase; IPMS, isopropylmalate synthase; IVD, isovaleryl-CoA dehydrogenase; MCCC, methylcrotonoyl-CoA carboxylase; MUT, methylmalonyl-CoA mutase; OCFA, odd-chain fatty acid; OXCT1, 3-oxoacid CoA transferase; P, phosphorylation; PCCB, propionyl-CoA carboxylase subunit beta.

Figure 2

(a) Leucine and α-KIC promote insulin release from pancreatic B cells via activation of glutamate dehydrogenase. (b) Leucine promotes mTORC1 activity by relieving Sestrin2-mediated inhibition and promoting LeuRS-mediated pathway activation. (c) Skeletal muscle secretes valine catabolites BAIBA and 3-HIB. BAIBA promotes hepatic B oxidation, adipocyte thermogenesis, and osteocyte survival; 3-HIB induces fatty acid transport across the endothelium and into skeletal muscle. Abbreviations: 3-HIB, 3-hydroxyisobutyrate; ADP, adenosine 5 -diphosphate; αKG, α-ketoglutarate; ATP, adenosine 5 -triphosphate; BAIBA, beta-amino-isobutyric acid; FFA, free fatty acid; GATOR1, GAP activity toward the Rag GTPases 1; GATOR2, GAP activity toward the Rag GTPases 2; GDH, glutamate dehydrogenase; GTP, guanosine triphosphate; Leu, leucine; LeuRS, leucyl tRNA synthetase; mTORC1, mechanistic target of rapamycin complex 1; NADH, nicotinamide adenine dinucleotide; TCA, tricarboxylic acid; ROS, reactive oxygen species; Val, valine; v-ATPase, vacuolar H+-adenosine triphosphatase ATPase.

Figure 3

Two-compartment model of whole-organism branched chain amino acid (BCAA) physiology. BCAAs appear in circulation when released from protein, from either the diet or tissues. BCAAs can leave the circulation to be deposited into new protein. All BCAAs are ultimately cleared from the system when oxidized in tissues. Many factors promote or inhibit each of these processes (grey arrows). The tissue-specific regulation of protein turnover and oxidation is poorly understood.

Figure 4

The graph illustrates increasing public interest in branched chain amino acids (BCAAs) since 2004. The relative frequency of Google searches for the indicated keyword is shown, revealing the rising cyclical interest in “BCAA” in close correlation with the term “workout” and rising each year in January, coincident with the term “New Year resolution.”

Figure 5

Proposed model of casual relationship between altered tissue branched chain amino acid (BCAA) oxidation and elevated circulating BCAA levels in insulin resistance. In healthy conditions (a), BCAA oxidation is balanced among different organs. Genetic and environmental factors suppress BCAA oxidation in the liver and adipose tissues (b), causing increased circulating BCAA levels and overflow of BCAAs into skeletal muscle, which results in lipotoxicity and insulin resistance. Adapted with permission from Reference .