Branched-Chain Amino Acids and Brain Metabolism

Abstract

This review aims to provide a historical reference of branched-chain amino acid (BCAA) metabolism and provide a link between peripheral and central nervous system (CNS) metabolism of BCAAs. Leucine, isoleucine, and valine (Leu, Ile, and Val) are unlike most other essential amino acids (AA), being transaminated initially in extrahepatic tissues, and requiring interorgan or intertissue shuttling for complete catabolism. Within the periphery, BCAAs are essential AAs and are required for protein synthesis, and are key nitrogen donors in the form of Glu, Gln, and Ala. Leucine is an activator of the mammalian (or mechanistic) target of rapamycin, the master regulator of cell growth and proliferation. The tissue distribution and activity of the catabolic enzymes in the peripheral tissues as well as neurological effects in Maple Syrup Urine Disease (MSUD) show the BCAAs have a role in the CNS. Interestingly, there are significant differences between murine and human CNS enzyme distribution and activities. In the CNS, BCAAs have roles in neurotransmitter synthesis, protein synthesis, food intake regulation, and are implicated in diseases. MSUD is the most prolific disease associated with BCAA metabolism, affecting the branched-chain α-keto acid dehydrogenase complex (BCKDC). Mutations in the branched-chain aminotransferases (BCATs) and the kinase for BCKDC also result in neurological dysfunction. However, there are many questions of BCAA metabolism in the CNS (as well as the periphery) that remain elusive. We discuss areas of BCAA and BCKA metabolism that have yet to be researched adequately.

L‐carnitine prevents ammonia‐induced cytotoxicity and disturbances in intracellular amino acid levels in human astrocytes

“…As recently reported, ammonia stimulated the production of Gln, which subsequently enhanced the uptake of BCAAs into astrocytes . In the present study, NH 4 Cl‐treated cells showed higher levels of intracellular BCAAs.…”

“…As recently reported, ammonia stimulated the production of Gln, which subsequently enhanced the uptake of BCAAs into astrocytes. [42][43][44] In the present study, NH 4 Cl-treated cells showed higher levels of intracellular BCAAs. Moreover, 3-methyl-2oxovaleric acid was significantly elevated in the NH 4 Cl-treated cells (Fig.…”

“…This metabolite, which is mainly produced from isoleucine by cytosolic branched‐chain aminotransferase, plays a critical role in neurological damage and is used as a clinical marker for maple syrup urine disease . BCAAs provide nitrogen for synthesis of the Glu neurotransmitter that communicates between astrocytes and neurons . In general, the concentration of BCAAs in the blood is reduced, whereas concentrations of aromatic AAs are increased in LC patients, leading to abnormalities of neurotransmitters in the brain .…”

“…45 BCAAs provide nitrogen for synthesis of the Glu neurotransmitter that communicates between astrocytes and neurons. [42][43][44] In general, the concentration of BCAAs in the blood is reduced, whereas concentrations of aromatic AAs are increased in LC patients, leading to abnormalities of neurotransmitters in the brain. 20,21 In addition, the excessive accumulation of intracellular BCAA results in oxidative stress and cytotoxicity.…”

Poly(I:C) alters placental and fetal brain amino acid transport in a rat model of maternal immune activation

“…Furthermore, many of the specific amino acids that were altered as a result of poly(I:C) play important roles in fetal brain development. 51 Previous studies have shown that decreased BCAA transport into the brain or increased BCAA catabolism within the brain is associated with ASD in both mice and humans. We also observed a significant decrease in the concentration of taurine, which is imperative to optimal proliferation, development, and maturation of brain cells.…”