Branched-chain amino acid
A branched-chain amino acid (BCAA) is an amino acid having an aliphatic side-chain with a branch (a central carbon atom bound to three or more carbon atoms). Among the proteinogenic amino acids, there are three BCAAs: leucine, isoleucine, and valine. Non-proteinogenic BCAAs include 2-aminoisobutyric acid.
The three proteinogenic BCAAs are among the nine essential amino acids for humans, accounting for 35% of the essential amino acids in muscle proteins and 40% of the preformed amino acids required by mammals. Synthesis for BCAAs occurs in all locations of plants, within the plastids of the cell, as determined by presence of mRNAs which encode for enzymes in the metabolic pathway.
BCAAs fill several metabolic and physiologic roles. Metabolically, BCAAs promote protein synthesis and turnover, signaling pathways, and metabolism of glucose. Oxidation of BCAAs may increase fatty acid oxidation and play a role in obesity. Physiologically, BCAAs take on roles in the immune system and in brain function. BCAAs are broken down effectively by dehydrogenase and decarboxylase enzymes expressed by immune cells, and are required for lymphocyte growth and proliferation and cytotoxic T lymphocyte activity. Lastly, BCAAs share the same transport protein into the brain with aromatic amino acids (Trp, Tyr, and Phe). Once in the brain BCAAs may have a role in protein synthesis, synthesis of neurotransmitters, and production of energy.
The Food and Nutrition Board (FNB) of the U.S. Institute of Medicine set Recommended Dietary Allowances (RDAs) for essential amino acids in 2002. For leucine, for adults 19 years and older, 42 mg/kg body weight/day; for isoleucine 19 mg/kg body weight/day; for valine 24 mg/kg body weight/day. For a 70 kg (154 lb) person this equates to 2.9, 1.3 and 1.7 g/day. Diets that meet or exceed the RDA for total protein (0.8 g/kg/day; 56 grams for a 70 kg person), meet or exceed the RDAs for branched-chain amino acids.
Dietary BCAAs have been used in an attempt to treat some cases of hepatic encephalopathy. They can have the effect of alleviating symptoms of hepatic encephalophathy, but there is no evidence they benefit mortality rates, nutrition, or overall quality of life as further research is necessary.
Certain studies suggested a possible link between a high incidence of amyotrophic lateral sclerosis (ALS) among professional American football players and Italian soccer players, and certain sports supplements including BCAAs. In mouse studies, BCAAs were shown to cause cell hyper-excitability resembling that usually observed in ALS patients. The proposed underlying mechanism is that cell hyper-excitability results in increased calcium absorption by the cell and thus brings about cell death, specifically of neuronal cells which have particularly low calcium buffering capabilities. Yet any link between BCAAs and ALS remains to be fully established. While BCAAs can induce a hyperexcitability similar to the one observed in mice with ALS, current work does not show if a BCAA-enriched diet, given over a prolonged period, actually induces ALS-like symptoms.
Blood levels of the BCAAs are elevated in obese, insulin resistant humans and in mouse and rat models of diet-induced diabetes, suggesting the possibility that BCAAs contribute to the pathogenesis of obesity and diabetes. BCAA-restricted diets improve glucose tolerance and promote leanness in normal weight mice, restores insulin sensitivity and normal body weight to obese mice and promotes insulin sensitivity in obese rats.
Five enzymes play a major role in the parallel synthesis pathways for isoleucine, valine, and leucine: threonine dehydrogenase, acetohydroxyacid synthase, ketoacid reductoisomerase, dihydroxyacid dehygrogenase and aminotransferase. Threonine dehydrogenase catalyzes the deamination and dehydration of threonine to 2-ketobutyrate and ammonia. Isoleucine forms a negative feedback loop with threonine dehydrogenase. Acetohydroxyacid synthase is the first enzyme for the parallel pathway performing condensation reaction in both steps – condensation of pyruvate to acetoacetate in the valine pathway and condensation of pyruvate and 2-ketobutyrate to form acetohydroxybtylrate in the isoleucine pathway. Next ketoacid reductisomerase reduces the acetohydroxy acids from the previous step to yield dihydroxyacids in both the valine and isoleucine pathways. Dihydroxyacid dehygrogenase converts the dihyroxyacids in the next step. The final step in the parallel pathway is conducted by amino transferase, which yields the final products of valine and isoleucine. A series of four more enzymes – isopropylmalate synthase, isopropylmalate isomerase, isopropylmalate dehydrogenase, and aminotransferase – are necessary for the formation of leucine from 2-oxolsovalerate.
Degradation of branched-chain amino acids involves the branched-chain alpha-keto acid dehydrogenase complex (BCKDH). A deficiency of this complex leads to a buildup of the branched-chain amino acids (leucine, isoleucine, and valine) and their toxic by-products in the blood and urine, giving the condition the name maple syrup urine disease.
The BCKDH complex converts branched-chain amino acids into acyl-CoA derivatives, which after subsequent reactions are converted either into acetyl-CoA or succinyl-CoA that enter the citric acid cycle.
While most amino acids are oxidized in the liver, BCAAs are primarily oxidized in the skeletal muscle and other peripheral tissues. The effects of BCAA administration on muscle growth in rat diaphragm was tested, and concluded that not only does a mixture of BCAAs alone have the same effect on growth as a complete mixture of amino acids, but an amino acid mixture with all but BCAAs has no effect on rat diaphragm muscle growth. Administration of either isoleucine or valine alone had no effect on muscle growth, although administration of leucine alone appears to be nearly as effective as the complete mixture of BCAAs. Leucine indirectly activates p70 S6 kinase as well as stimulates assembly of the eIF4F complex, which are essential for mRNA binding in translational initiation. P70 S6 kinase is part of the mammalian target of rapamycin complex (mTOR) signaling pathway, and has been shown to allow adaptive hypertrophy and recovery of rat muscle. At rest protein infusion stimulates protein synthesis 30 minutes after start of infusion, and protein synthesis stays elevated for another 90 minutes. Infusion of leucine at rest produces a six-hour stimulatory effect and increased protein synthesis by phosphorylation of p70 S6 kinase in skeletal muscles. Following resistance exercise, without BCAA administration, a resistance exercise session does not affect mTOR phosphorylation and even produces a decrease in Akt phosphorylation. Some phosphorylation of p70 S6 kinase was discovered. When BCAAs were administered following a training session, sufficient phosphorylation of p70 S6 kinase and S6 indicated activation of the signaling cascade.
Role in diabetes mellitus type 2
In addition to cell signaling, the mTOR pathway also plays a role in beta cell growth leading to insulin secretion. High glucose in the blood begins the process of the mTOR signaling pathway, which leucine plays an indirect role. The combination of glucose, leucine, and other activators cause mTOR to start signaling for the proliferation of beta cells and the secretion of insulin. Higher concentrations of leucine cause hyperactivity in the mTOR pathway, and S6 kinase is activated leading to inhibition of insulin receptor substrate through serine phosphorylation. In the cell the increased activity of mTOR complex causes eventual inability of beta cells to release insulin and the inhibitory effect of S6 kinase leads to insulin resistance in the cells, contributing to development of type 2 diabetes.
Metformin is able to activate AMP kinase which phosphorylates proteins involved in the mTOR pathway, as well as leads to the progression of mTOR complex from its inactive state to its active state. It is suggested that metformin acts as a competitive inhibitor to the amino acid leucine in the mTOR pathway.
- Sowers S. "A Primer On Branched Chain Amino Acids" (PDF). Huntington College of Health Sciences. Retrieved 22 March 2011.
- Shimomura Y, Murakami T, Nakai N, Nagasaki M, Harris RA (June 2004). "Exercise promotes BCAA catabolism: effects of BCAA supplementation on skeletal muscle during exercise". The Journal of Nutrition. 134 (6 Suppl): 1583S–1587S. doi:10.1093/jn/134.6.1583S. PMID 15173434.
- Singh BK, Shaner DL (July 1995). "Biosynthesis of Branched Chain Amino Acids: From Test Tube to Field". The Plant Cell. 7 (7): 935–944. doi:10.1105/tpc.7.7.935. PMC 160890. PMID 12242394.
- Monirujjaman M (2014). "Metabolic and Physiological Roles of Branched-Chain Amino Acids". Advances in Molecular Biology. 2014: 1–6. doi:10.1155/2014/364976.
- Babchia N, Calipel A, Mouriaux F, Faussat AM, Mascarelli F (January 2010). "The PI3K/Akt and mTOR/P70S6K signaling pathways in human uveal melanoma cells: interaction with B-Raf/ERK". Investigative Ophthalmology & Visual Science. 51 (1): 421–9. doi:10.1167/iovs.09-3974. PMID 19661225.
- Institute of Medicine (2002). "Protein and Amino Acids". Dietary Reference Intakes for Energy, Carbohydrates, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids. Washington, DC: The National Academies Press. pp. 589–768.
- Chadalavada R, Sappati Biyyani RS, Maxwell J, Mullen K (June 2010). "Nutrition in hepatic encephalopathy". Nutrition in Clinical Practice. 25 (3): 257–64. doi:10.1177/0884533610368712. PMID 20581319.
- Gluud, Lise Lotte; Dam, Gitte; Les, Iñigo; Marchesini, Giulio; Borre, Mette; Aagaard, Niels Kristian; Vilstrup, Hendrik (18 May 2017). "Branched-chain amino acids for people with hepatic encephalopathy". Cochrane Database of Systematic Reviews. 5: CD001939. doi:10.1002/14651858.cd001939.pub4. ISSN 1465-1858. PMID 28518283.
- Manuel M, Heckman CJ (March 2011). "Stronger is not always better: could a bodybuilding dietary supplement lead to ALS?". Experimental Neurology. 228 (1): 5–8. doi:10.1016/j.expneurol.2010.12.007. PMC 3049458. PMID 21167830.
- Lynch CJ, Adams SH (December 2014). "Branched-chain amino acids in metabolic signalling and insulin resistance". Nature Reviews. Endocrinology. 10 (12): 723–36. doi:10.1038/nrendo.2014.171. PMC 4424797. PMID 25287287.
- Newgard CB, An J, Bain JR, Muehlbauer MJ, Stevens RD, Lien LF, Haqq AM, Shah SH, Arlotto M, Slentz CA, Rochon J, Gallup D, Ilkayeva O, Wenner BR, Yancy WS, Eisenson H, Musante G, Surwit RS, Millington DS, Butler MD, Svetkey LP (April 2009). "A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance". Cell Metabolism. 9 (4): 311–26. doi:10.1016/j.cmet.2009.02.002. PMC 3640280. PMID 19356713.
- Fontana L, Cummings NE, Arriola Apelo SI, Neuman JC, Kasza I, Schmidt BA, Cava E, Spelta F, Tosti V, Syed FA, Baar EL, Veronese N, Cottrell SE, Fenske RJ, Bertozzi B, Brar HK, Pietka T, Bullock AD, Figenshau RS, Andriole GL, Merrins MJ, Alexander CM, Kimple ME, Lamming DW (July 2016). "Decreased Consumption of Branched-Chain Amino Acids Improves Metabolic Health". Cell Reports. 16 (2): 520–530. doi:10.1016/j.celrep.2016.05.092. PMC 4947548. PMID 27346343.
- Cummings NE, Williams EM, Kasza I, Konon EN, Schaid MD, Schmidt BA, Poudel C, Sherman DS, Yu D, Arriola Apelo SI, Cottrell SE, Geiger G, Barnes ME, Wisinski JA, Fenske RJ, Matkowskyj KA, Kimple ME, Alexander CM, Merrins MJ, Lamming DW (December 2017). "Restoration of metabolic health by decreased consumption of branched-chain amino acids". The Journal of Physiology. 596 (4): 623–645. doi:10.1113/JP275075. PMC 5813603. PMID 29266268.
- White PJ, Lapworth AL, An J, Wang L, McGarrah RW, Stevens RD, Ilkayeva O, George T, Muehlbauer MJ, Bain JR, Trimmer JK, Brosnan MJ, Rolph TP, Newgard CB (July 2016). "Branched-chain amino acid restriction in Zucker-fatty rats improves muscle insulin sensitivity by enhancing efficiency of fatty acid oxidation and acyl-glycine export". Molecular Metabolism. 5 (7): 538–51. doi:10.1016/j.molmet.2016.04.006. PMC 4921791. PMID 27408778.
- Sears DD, Hsiao G, Hsiao A, Yu JG, Courtney CH, Ofrecio JM, Chapman J, Subramaniam S (November 2009). "Mechanisms of human insulin resistance and thiazolidinedione-mediated insulin sensitization". Proceedings of the National Academy of Sciences of the United States of America. 106 (44): 18745–50. doi:10.1073/pnas.0903032106. PMC 2763882. PMID 19841271.
- Kimball SR, Jefferson LS (January 2006). "Signaling pathways and molecular mechanisms through which branched-chain amino acids mediate translational control of protein synthesis". The Journal of Nutrition. 136 (1 Suppl): 227S–31S. doi:10.1093/jn/136.1.227S. PMID 16365087.
- Bodine SC, Stitt TN, Gonzalez M, Kline WO, Stover GL, Bauerlein R, Zlotchenko E, Scrimgeour A, Lawrence JC, Glass DJ, Yancopoulos GD (November 2001). "Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo". Nature Cell Biology. 3 (11): 1014–9. doi:10.1038/ncb1101-1014. PMID 11715023.
- Blomstrand E, Eliasson J, Karlsson HK, Köhnke R (January 2006). "Branched-chain amino acids activate key enzymes in protein synthesis after physical exercise". The Journal of Nutrition. 136 (1 Suppl): 269S–73S. doi:10.1093/jn/136.1.269S. PMID 16365096.
- Melnik BC (March 2012). "Leucine signaling in the pathogenesis of type 2 diabetes and obesity". World Journal of Diabetes. 3 (3): 38–53. doi:10.4239/WJD.v3.i3.38. PMC 3310004. PMID 22442749.
- Balcazar Morales N, Aguilar de Plata C (July 2012). "Role of AKT/mTORC1 pathway in pancreatic β-cell proliferation". Colombia Medica. 43 (3): 235–43. PMC 4001958. PMID 24893199.
|Wikimedia Commons has media related to Branched-chain amino acids.|
- Branched-chain+amino+acids at the US National Library of Medicine Medical Subject Headings (MeSH)
- Branched-chain amino acid degradation pathway
- Synthesic pathway in yeast (WikiPathways)