Branched-Chain Amino Acids

Branched-chain amino acids (BCAAs) leucine, isoleucine, and valine in the muscle are converted into branched-chain α-ketoacids (BCKAs) through transamination. BCKAs circulated to the liver then undergo oxidative decarboxylation, mediated by the mitochondrial BCKA dehydrogenase complex (BCKDC), to produce branched-chain acyl-coenzymes. Genetic defects in the BCKDC result in maple syrup urine disease (MSUD), characterized by often-fatal ketoacidosis, neurological derangements, and mental retardation. The rate-limiting step in BCAA oxidation is at the BCKDC, which is acutely regulated by phosphorylation (inactivation)/dephosphorylation (reactivation), in response to hormonal and nutritional stimuli. Among BCAAs, leucine serves as key nutrition and endocrine signals to promote protein synthesis in muscle and trigger insulin release from pancreatic β-islet cells. A murine knockout model with block at the transamination step provokes a leucine-mediated energy-wasting futile cycle, resulting in significantly reduced body weight and body fat mass. Similar effects were obtained with dietary supplements of leucine or BCAAs. In the brain, a leucine-glutamate cycle is responsible for maintaining a steady supply of glutamate, a major excitatory neurotransmitter for interneuronal communication. BCKAs accumulated in MSUD compromise brain energy metabolism by blocking the respiratory chain and inhibiting creatine kinase activity. The above advances indicate that BCAAs and BCKAs are important amino acids that play a multifaceted role in metabolism, neurophysiology, and clinical applications.