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Branched chain amino acids: Passive biomarkers or the key to the pathogenesis of cardiometabolic diseases?
Siomkajło, M, Daroszewski, J
Advances in clinical and experimental medicine : official organ Wroclaw Medical University. 2019;(9):1263-1269
Abstract
The metabolomic approach to research on lifestyle diseases has led to the discovery of new potential biomarkers of pathological conditions as well as key metabolic pathways that may become targets of therapeutic intervention. Current evidence supports plasma branched chain amino acids (BCAAs) as potential diagnostic and prognostic biomarkers of cardiometabolic diseases. However, the biological mechanisms of the associations that have been identified are still not completely understood and should be clarified before implementing BCAA-based biomarkers in the clinical setting. The most crucial issue that needs to be solved first is determining whether BCAA plasma profile disturbances are only passive biomarkers or whether they facilitate dysmetabolic processes. In this context, further research is also warranted to investigate the role of dietary BCAAs. Gaining this knowledge would be significant progress in molecular nutrition research, providing perspective for target therapeutic and prophylactic interventions. This paper provides a comprehensive review of the main hypotheses and mechanistic models that consider circulating BCAAs both as passive biomarkers and as contributors to cardiometabolic diseases.
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2.
Branched Chain Amino Acids in Metabolic Disease.
Arany, Z, Neinast, M
Current diabetes reports. 2018;(10):76
Abstract
PURPOSE OF REVIEW Elevations in circulating branched chain amino acids (BCAAs) have gained attention as potential contributors to the development of insulin resistance and diabetes. RECENT FINDINGS Epidemiological evidence strongly supports this conclusion. Suppression of BCAA catabolism in adipose and hepatic tissues appears to be the primary drivers of plasma BCAA elevations. BCAA catabolism may be shunted to skeletal muscle, where it indirectly leads to FA accumulation and insulin resistance, via a number of proposed mechanisms. BCAAs have an important role in the development of IR, but our understanding of how plasma BCAA elevations occur, and how these elevations lead to insulin resistance, is still limited.
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3.
Branching Out: Alterations in Bacterial Physiology and Virulence Due to Branched-Chain Amino Acid Deprivation.
Kaiser, JC, Heinrichs, DE
mBio. 2018;(5)
Abstract
The branched-chain amino acids (BCAAs [Ile, Leu, and Val]) represent important nutrients in bacterial physiology, with roles that range from supporting protein synthesis to signaling and fine-tuning the adaptation to amino acid starvation. In some pathogenic bacteria, the adaptation to amino acid starvation includes induction of virulence gene expression: thus, BCAAs support not only proliferation during infection, but also the evasion of host defenses. A body of research has accumulated over the years to describe the multifaceted physiological roles of BCAAs and the mechanisms bacteria use to maintain their intracellular levels. More recent studies have focused on understanding how fluctuations in their intracellular levels impact global regulatory pathways that coordinate the adaptation to nutrient limitation, especially in pathogenic bacteria. In this minireview, we discuss how these studies have refined the individual roles of BCAAs, shed light on how BCAA auxotrophy might promote higher sensitivity to exogenous BCAA levels, and revealed pathogen-specific responses to BCAA deprivation. These advancements improve our understanding of how bacteria meet their nutritional requirements for growth while simultaneously remaining responsive to changes in environmental nutrient availability to promote their survival in a range of environments.
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4.
A Role for Branched-Chain Amino Acids in the Pathophysiology of Diabetes: Using Data to Guide Discovery.
Katz, DH, Gerszten, RE
Clinical chemistry. 2018;(8):1250-1251
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5.
Branched-Chain Amino Acids as Critical Switches in Health and Disease.
Zhang, ZY, Monleon, D, Verhamme, P, Staessen, JA
Hypertension (Dallas, Tex. : 1979). 2018;(5):1012-1022
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6.
Dietary management and supplementation with branched-chain amino acids in cirrhosis of the liver.
Ruiz-Margáin, A, Méndez-Guerrero, O, Román-Calleja, BM, González-Rodríguez, S, Fernández-Del-Rivero, G, Rodríguez-Córdova, PA, Torre, A, Macías-Rodríguez, RU
Revista de gastroenterologia de Mexico (English). 2018;(4):424-433
Abstract
One of the most important characteristics of malnutrition is the loss of muscle mass and the severe depletion of the protein reserve, secondarily affecting energy metabolism. That impacts nutritional status and the progression of disease-related complications. Nutritional treatment is one of the main factors in the comprehensive management of those patients. Achieving adequate energy intake that provides the macronutrients and micronutrients necessary to prevent or correct malnutrition is attempted through dietary measures. ESPEN, the European Society for Clinical Nutrition and Metabolism, recommends a caloric intake of 30-40kcal/kg/day, in which carbohydrates provide 45-60% of the daily energy intake and proteins supply 1.0-1.5g/kg/day. The remaining portion of the total energy expenditure should be covered by lipids. The administration of branched-chain amino acids has been shown to be beneficial not only in counteracting malnutrition, but also as a coadjuvant treatment in specific complications, thus playing a favorable role in outcome and quality of life. Therefore, branched-chain amino acids should be considered part of nutritional treatment in patients with advanced stages of cirrhosis of the liver, particularly in the presence of complications.
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7.
Enzymes involved in branched-chain amino acid metabolism in humans.
Adeva-Andany, MM, López-Maside, L, Donapetry-García, C, Fernández-Fernández, C, Sixto-Leal, C
Amino acids. 2017;(6):1005-1028
Abstract
Branched-chain amino acids (leucine, isoleucine and valine) are structurally related to branched-chain fatty acids. Leucine is 2-amino-4-methyl-pentanoic acid, isoleucine is 2-amino-3-methyl-pentanoic acid, and valine is 2-amino-3-methyl-butanoic acid. Similar to fatty acid oxidation, leucine and isoleucine produce acetyl-coA. Additionally, leucine generates acetoacetate and isoleucine yields propionyl-coA. Valine oxidation produces propionyl-coA, which is converted into methylmalonyl-coA and succinyl-coA. Branched-chain aminotransferase catalyzes the first reaction in the catabolic pathway of branched-chain amino acids, a reversible transamination that converts branched-chain amino acids into branched-chain ketoacids. Simultaneously, glutamate is converted in 2-ketoglutarate. The branched-chain ketoacid dehydrogenase complex catalyzes the irreversible oxidative decarboxylation of branched-chain ketoacids to produce branched-chain acyl-coA intermediates, which then follow separate catabolic pathways. Human tissue distribution and function of most of the enzymes involved in branched-chain amino acid catabolism is unknown. Congenital deficiencies of the enzymes involved in branched-chain amino acid metabolism are generally rare disorders. Some of them are associated with reduced pyruvate dehydrogenase complex activity and respiratory chain dysfunction that may contribute to their clinical phenotype. The biochemical phenotype is characterized by accumulation of the substrate to the deficient enzyme and its carnitine and/or glycine derivatives. It was established at the beginning of the twentieth century that the plasma level of the branched-chain amino acids is increased in conditions associated with insulin resistance such as obesity and diabetes mellitus. However, the potential clinical relevance of this elevation is uncertain.
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8.
CodY, a master integrator of metabolism and virulence in Gram-positive bacteria.
Brinsmade, SR
Current genetics. 2017;(3):417-425
Abstract
A growing body of evidence points to CodY, a global regulator in Gram-positive bacteria, as a critical link between microbial physiology and pathogenesis in diverse environments. Recent studies uncovering graded regulation of CodY gene targets reflect the true nature of this transcription factor controlled by ligands and reveal nutrient availability as a potentially critical factor in modulating pathogenesis. This review will serve to update the status of the field and raise new questions to be answered.
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9.
Influence of Amino Acids in Dairy Products on Glucose Homeostasis: The Clinical Evidence.
Chartrand, D, Da Silva, MS, Julien, P, Rudkowska, I
Canadian journal of diabetes. 2017;(3):329-337
Abstract
Dairy products have been hypothesized to protect against type 2 diabetes because of their high content of whey proteins, rich in branched-chain amino acids (BCAAs) - leucine, isoleucine and valine - and lysine, which may decrease postprandial glucose responses and stimulate insulin secretion. Paradoxically, epidemiologic studies also show that higher levels of plasma BCAAs have been linked to insulin resistance and type 2 diabetes. Therefore, the objective was to review the recent clinical evidence concerning the intake of amino acids found in dairy proteins so as to determine their impact on glucose homeostasis in healthy persons and in those with prediabetes and type 2 diabetes. Clinical studies have reported that the major dairy amino acids, namely, leucine, isoleucine, glutamine, phenylalanine, proline and lysine, have beneficial effects on glucose homeostasis. Yet the reported doses of amino acids investigated are too elevated to be reached through adequate dairy product intake. The minor dairy amino acids, arginine and glycine, may improve glucose homeostasis by improving other risk factors for type 2 diabetes. Further, the combination of amino acids may also improve glucose-related outcomes, suggesting additive or synergistic effects. Nevertheless, additional long-term studies in individuals with prediabetes and type 2 diabetes are needed to ascertain the benefits for glucose homeostasis of amino acids found in dairy foods.
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10.
Properties of Bacterial and Archaeal Branched-Chain Amino Acid Aminotransferases.
Bezsudnova, EY, Boyko, KM, Popov, VO
Biochemistry. Biokhimiia. 2017;(13):1572-1591
Abstract
Branched-chain amino acid aminotransferases (BCATs) catalyze reversible stereoselective transamination of branched-chain amino acids (BCAAs) L-leucine, L-isoleucine, and L-valine. BCATs are the key enzymes of BCAA metabolism in all organisms. The catalysis proceeds through the ping-pong mechanism with the assistance of the cofactor pyridoxal 5'-phosphate (PLP). BCATs differ from other (S)-selective transaminases (TAs) in 3D-structure and organization of the PLP-binding domain. Unlike other (S)-selective TAs, BCATs belong to the PLP fold type IV and are characterized by the proton transfer on the re-face of PLP, in contrast to the si-specificity of proton transfer in fold type I (S)-selective TAs. Moreover, BCATs are the only (S)-selective enzymes within fold type IV TAs. Dual substrate recognition in BCATs is implemented via the "lock and key" mechanism without side-chain rearrangements of the active site residues. Another feature of the active site organization in BCATs is the binding of the substrate α-COOH group on the P-side of the active site near the PLP phosphate group. Close localization of two charged groups seems to increase the effectiveness of external aldimine formation in BCAT catalysis. In this review, the structure-function features and the substrate specificity of bacterial and archaeal BCATs are analyzed. These BCATs differ from eukaryotic ones in the wide substrate specificity, optimal temperature, and reactivity toward pyruvate as the second substrate. The prospects of biotechnological application of BCATs in stereoselective synthesis are discussed.