Oral BCAAs have been examined as treatment for neurological diseases such as mania, motor malfunction, amyotrophic lateral sclerosis, and spinocerebral degeneration. The reader is referred to Fernstrom (2005) for a review of the biochemistry of BCAA transportation to the brain. The decrease in these aromatic amino acids directly affects the synthesis and release of serotonin and catecholamines. Ingestion of BCAAs therefore causes rapid elevation of the plasma concentrations and increases uptake of BCAAs to the brain, but diminishes tryptophan, tyrosine, and phenylalanine uptake. They also compete for transport across the blood-brain barrier (BBB) with tryptophan (the precursor to serotonin), as well as tyrosine and phenylalanine (precursors for catecholamines) (Fernstrom, 2005). As nitrogen donors, they contribute to the synthesis of excitatory glutamate and inhibitory gamma-aminobutyric acid (GABA) (Yudkoff et al., 2005). 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.In the brain, BCAAs have two important influences on the production of neurotransmitters. BAIBA promotes hepatic B oxidation, adipocyte thermogenesis, and osteocyte survival 3-HIB induces fatty acid transport across the endothelium and into skeletal muscle. ( c) Skeletal muscle secretes valine catabolites BAIBA and 3-HIB. ( b) Leucine promotes mTORC1 activity by relieving Sestrin2-mediated inhibition and promoting LeuRS-mediated pathway activation. ( a) Leucine and α-KIC promote insulin release from pancreatic B cells via activation of glutamate dehydrogenase. 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. BCKDK inhibits E1 via phosphorylation, which is reversed by PP2Cm. The BCKDH complex is composed of a core of 24 E2 subunits, which are docked by E1 heterotetamers and E3 dimers. All three BCAAs share the BCAT and BCKDH steps, after which catabolism of each BCAA is unique. Oxidation ( b) occurs in plants, bacteria, fungi, and animals. Synthesis ( a) occurs in plants, bacteria, and fungi. Understanding the mechanisms underlying altered BCAA metabolism and how they contribute to disease pathophysiology will keep researchers busy for the foreseeable future.īranched chain amino acids cancer catabolism diabetes heart disease.īCAA synthesis and catabolism. More recently, subtle alterations of BCAA metabolism have been suggested to contribute to numerous prevalent diseases, including diabetes, cancer, and heart failure. Inborn errors of metabolism highlight the importance of organismal regulation of BCAA physiology. How these processes are integrated at an organismal level is less clear. In addition, BCAAs and various catabolic products act as signaling molecules, activating programs ranging from protein synthesis to insulin secretion. Decades of studies have elicited a deep understanding of biochemical reactions involved in BCAA catabolism. We review here the fundamentals of BCAA metabolism in mammalian physiology. Branched chain amino acids (BCAAs) are building blocks for all life-forms.
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