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1
Lounès, Anissa, Ahmed Lebrihi, Chouki Benslimane, Gérard Lefebvre i Pierre Germain. "Regulation of valine catabolism by ammonium in Streptomyces ambofaciens, producer of spiramycin". Canadian Journal of Microbiology 41, nr 9 (1.09.1995): 800–808. http://dx.doi.org/10.1139/m95-110.
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In Streptomyces ambofaciens, valine favored spiramycin biosynthesis by supplying aglycone precursors. The kinetics of valine consumption and isobutyrate production showed that isobutyrate accumulated in the cell during the growth phase, was excreted in the stationary phase, and then was reassimilated during spiramycin production. When valine was in excess, its deamination led to high ammonium excretion and to a significant drop in spiramycin production. We demonstrated that ammonium ions were the cause of the negative effect. Addition of a chelator agent, Ca3(PO4)2, improved spiramycin production by sixfold. In contrast, addition of ammonium, between 0 and 48 h, severely reduced spiramycin production. The negative effect of ammonium was reversed by addition of a catabolic intermediate of valine, isobutyrate. In addition to stimulating the specific growth rate, ammonium ions slowed down valine catabolism: the specific valine uptake rate, excretion, and reassimilation of isobutyrate were lowered by the pulse of ammonium. Our study showed that in addition to valine dehydrogenase, which provided the nitrogen necessary to the cell, ammonium ions repressed ketoisovalerate dehydrogenase, which introduced valine as carbon, energy, and aglycone precursor sources. However, valine dehydrogenase and ketoisovalerate dehydrogenase did not constitute the principal enzymatic targets of the negative effect of ammonium in spiramycin production.Key words: spiramycin, Streptomyces ambofaciens, valine catabolism, ammonium.
2
Xu, Yanyan, Haojie Jiang, Li Li, Fengwu Chen, Yunxia Liu, Meiyi Zhou, Ji Wang i in. "Branched-Chain Amino Acid Catabolism Promotes Thrombosis Risk by Enhancing Tropomodulin-3 Propionylation in Platelets". Circulation 142, nr 1 (7.07.2020): 49–64. http://dx.doi.org/10.1161/circulationaha.119.043581.
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Background: Branched-chain amino acids (BCAAs), essential nutrients including leucine, isoleucine, and valine, serve as a resource for energy production and the regulator of important nutrient and metabolic signals. Recent studies have suggested that dysfunction of BCAA catabolism is associated with the risk of cardiovascular disease. Platelets play an important role in cardiovascular disease, but the functions of BCAA catabolism in platelets remain unknown. Methods: The activity of human platelets from healthy subjects before and after ingestion of BCAAs was measured. Protein phosphatase 2Cm specifically dephosphorylates branched-chain α-keto acid dehydrogenase and thereby activates BCAA catabolism. Protein phosphatase 2Cm–deficient mice were used to elucidate the impacts of BCAA catabolism on platelet activation and thrombus formation. Results: We found that ingestion of BCAAs significantly promoted human platelet activity (n=5; P <0.001) and arterial thrombosis formation in mice (n=9; P <0.05). We also found that the valine catabolite α-ketoisovaleric acid and the ultimate oxidation product propionyl-coenzyme A showed the strongest promotion effects on platelet activation, suggesting that the valine/α-ketoisovaleric acid catabolic pathway plays a major role in BCAA-facilitated platelet activation. Protein phosphatase 2Cm deficiency significantly suppresses the activity of platelets in response to agonists (n=5; P <0.05). Our results also suggested that BCAA metabolic pathways may be involved in the integrin αIIbβ3–mediated bidirectional signaling pathway that regulates platelet activation. Mass spectrometry identification and immunoblotting revealed that BCAAs enhanced propionylation of tropomodulin-3 at K255 in platelets or Chinese hamster ovary cells expressing integrin αIIbβ3. The tropomodulin-3 K255A mutation abolished propionylation and attenuated the promotion effects of BCAAs on integrin-mediated cell spreading, suggesting that K255 propionylation of tropomodulin-3 is an important mechanism underlying integrin αIIbβ3–mediated BCAA-facilitated platelet activation and thrombosis formation. In addition, the increased levels of BCAAs and the expression of positive regulators of BCAA catabolism in platelets from patients with type 2 diabetes mellitus are significantly correlated with platelet hyperreactivity. Lowering dietary BCAA intake significantly reduced platelet activity in ob/ob mice (n=4; P <0.05). Conclusions: BCAA catabolism is an important regulator of platelet activation and is associated with arterial thrombosis risk. Targeting the BCAA catabolism pathway or lowering dietary BCAA intake may serve as a novel therapeutic strategy for metabolic syndrome–associated thrombophilia.
3
Grantham, Barbara D., i J. Barrett. "Amino acid catabolism in the nematodes Heligmosomoides polygyrus and Panagrellus redivivus 2. Metabolism of the carbon skeleton". Parasitology 93, nr 3 (grudzień 1986): 495–504. http://dx.doi.org/10.1017/s0031182000081208.
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SUMMARYAll of the enzymes of proline catabolism were present in Heligmosomoides polygyrus and Panagrellus redivivus and the activities were, in general, similar to those found in rat liver. Both nematodes were also shown to be able to catabolize the branched-chain amino acids leucine, isoleucine and valine, by pathways similar to those found in mammalian liver. There were no significant differences in amino acid catabolism between the animal-parasitic and free-living species of nematode.
4
Letto, J., M. E. Brosnan i J. T. Brosnan. "Valine metabolism Gluconeogenesis from 3-hydroxyisobutyrate". Biochemical Journal 240, nr 3 (15.12.1986): 909–12. http://dx.doi.org/10.1042/bj2400909.
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During valine catabolism in muscle both 2-oxoisovalerate and 3-hydroxyisobutyrate can be released into the circulation. 3-Hydroxyisobutyrate is a good gluconeogenic substrate in isolated cortical tubules and hepatocytes. The maximal rate of gluconeogenesis from 3-hydroxyisobutyrate was greater than from 2-oxoisovalerate. We propose that 3-hydroxyisobutyrate is an inter-organ metabolite by which the gluconeogenic potential of valine, whose catabolism has been initiated in muscle, may be conserved.
5
Wolf, Dwayne A., i Hugh A. Akers. "Uncertainties remain in the catabolism of valine". Trends in Biochemical Sciences 11, nr 10 (październik 1986): 390–92. http://dx.doi.org/10.1016/0968-0004(86)90147-7.
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Bøhmer, Thomas. "Certainties and uncertainties in the catabolism of valine". Trends in Biochemical Sciences 12 (styczeń 1987): 19. http://dx.doi.org/10.1016/0968-0004(87)90008-9.
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van KUILENBURG, André B. P., Alida E. M. STROOMER, Henk van LENTHE, Nico G. G. M. ABELING i Albert H. van GENNIP. "New insights in dihydropyrimidine dehydrogenase deficiency: a pivotal role for beta-aminoisobutyric acid?" Biochemical Journal 379, nr 1 (1.04.2004): 119–24. http://dx.doi.org/10.1042/bj20031463.
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DPD (dihydropyrimidine dehydrogenase) constitutes the first step of the pyrimidine degradation pathway, in which the pyrimidine bases uracil and thymine are catabolized to β-alanine and the R-enantiomer of β-AIB (β-aminoisobutyric acid) respectively. The S-enantiomer of β-AIB is predominantly derived from the catabolism of valine. It has been suggested that an altered homoeostasis of β-alanine underlies some of the clinical abnormalities encountered in patients with a DPD deficiency. In the present study, we demonstrated that only a slightly decreased concentration of β-alanine was present in the urine and plasma, whereas normal levels of β-alanine were present in the cerebrospinal fluid of patients with a DPD deficiency. Therefore the metabolism of β-alanine-containing peptides, such as carnosine, may be an important factor involved in the homoeostasis of β-alanine in patients with DPD deficiency. The mean concentration of β-AIB was approx. 2–3-fold lower in cerebrospinal fluid and urine of patients with a DPD deficiency, when compared with controls. In contrast, strongly decreased levels (10-fold) of β-AIB were present in the plasma of DPD patients. Our results demonstrate that, under pathological conditions, the catabolism of valine can result in the production of significant amounts of β-AIB. Furthermore, the observation that the R-enantiomer of β-AIB is abundantly present in the urine of DPD patients suggests that significant cross-over exists between the thymine and valine catabolic pathways.
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Dimou, Aikaterini, Vasilis Tsimihodimos i Eleni Bairaktari. "The Critical Role of the Branched Chain Amino Acids (BCAAs) Catabolism-Regulating Enzymes, Branched-Chain Aminotransferase (BCAT) and Branched-Chain α-Keto Acid Dehydrogenase (BCKD), in Human Pathophysiology". International Journal of Molecular Sciences 23, nr 7 (5.04.2022): 4022. http://dx.doi.org/10.3390/ijms23074022.
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Branched chain amino acids (BCAAs), leucine, isoleucine and valine, are essential amino acids widely studied for their crucial role in the regulation of protein synthesis mainly through the activation of the mTOR signaling pathway and their emerging recognition as players in the regulation of various physiological and metabolic processes, such as glucose homeostasis. BCAA supplementation is primarily used as a beneficial nutritional intervention in chronic liver and kidney disease as well as in muscle wasting disorders. However, downregulated/upregulated plasma BCAAs and their defective catabolism in various tissues, mainly due to altered enzymatic activity of the first two enzymes in their catabolic pathway, BCAA aminotransferase (BCAT) and branched-chain α-keto acid dehydrogenase (BCKD), have been investigated in many nutritional and disease states. The current review focused on the underlying mechanisms of altered BCAA catabolism and its contribution to the pathogenesis of a numerous pathological conditions such as diabetes, heart failure and cancer. In addition, we summarize findings that indicate that the recovery of the dysregulated BCAA catabolism may be associated with an improved outcome and the prevention of serious disease complications.
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Boulette, Megan L., Patricia J. Baynham, Peter A. Jorth, Irena Kukavica-Ibrulj, Aissa Longoria, Karla Barrera, Roger C. Levesque i Marvin Whiteley. "Characterization of Alanine Catabolism in Pseudomonas aeruginosa and Its Importance for Proliferation In Vivo". Journal of Bacteriology 191, nr 20 (7.08.2009): 6329–34. http://dx.doi.org/10.1128/jb.00817-09.
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ABSTRACT The opportunistic pathogen Pseudomonas aeruginosa causes a variety of infections in immunocompromised individuals, including individuals with the heritable disease cystic fibrosis. Like the carbon sources metabolized by many disease-causing bacteria, the carbon sources metabolized by P. aeruginosa at the host infection site are unknown. We recently reported that l-alanine is a preferred carbon source for P. aeruginosa and that two genes potentially involved in alanine catabolism (dadA and dadX) are induced during in vivo growth in the rat peritoneum and during in vitro growth in sputum (mucus) collected from the lungs of individuals with cystic fibrosis. The goals of this study were to characterize factors required for alanine catabolism in P. aeruginosa and to assess the importance of these factors for in vivo growth. Our results reveal that dadA and dadX are arranged in an operon and are required for catabolism of l-alanine. The dad operon is inducible by l-alanine, d-alanine, and l-valine, and induction is dependent on the transcriptional regulator Lrp. Finally, we show that a mutant unable to catabolize dl-alanine displays decreased competitiveness in a rat lung model of infection.
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Pollitt, Rodney J. "The catabolism of valine: clues from recent studies in man". Trends in Biochemical Sciences 12 (styczeń 1987): 18. http://dx.doi.org/10.1016/0968-0004(87)90007-7.
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Loun�s, Anissa, Ahmed Lebrihi, Chouki Benslimane, G�rard Lefebvre i Pierre Germain. "Glycerol effect on spiramycin production and valine catabolism in Streptomyces ambofaciens". Current Microbiology 31, nr 5 (listopad 1995): 304–11. http://dx.doi.org/10.1007/bf00314585.
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Priestley, N. D., i J. A. Robinson. "Purification and catalytic properties of l-valine dehydrogenase from Streptomyces cinnamonensis". Biochemical Journal 261, nr 3 (1.08.1989): 853–61. http://dx.doi.org/10.1042/bj2610853.
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NAD+-dependent L-valine dehydrogenase was purified 180-fold from Streptomyces cinnamonensis, and to homogeneity, as judged by gel electrophoresis. The enzyme has an Mr of 88,000, and appears to be composed of subunits of Mr 41,200. The enzyme catalyses the oxidative deamination of L-valine, L-leucine, L-2-aminobutyric acid, L-norvaline and L-isoleucine, as well as the reductive amination of their 2-oxo analogues. The enzyme requires NAD+ as the only cofactor, which cannot be replaced by NADP+. The enzyme activity is significantly decreased by thiol-reactive reagents, although purine and pyrimidine bases, and nucleotides, do not affect activity. Initial-velocity and product-inhibition studies show that the reductive amination proceeds through a sequential ordered ternary-binary mechanism; NADH binds to the enzyme first, followed by 2-oxoisovalerate and NH3, and valine is released first, followed by NAD+. The Michaelis constants are as follows; L-valine, 1.3 mM; NAD+, 0.18 mM; NADH, 74 microM; 2-oxoisovalerate, 0.81 mM; and NH3, 55 mM. The pro-S hydrogen at C-4′ of NADH is transferred to the substrate; the enzyme is B-stereospecific. It is proposed that the enzyme catalyses the first step of valine catabolism in this organism.
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Lee, S. H. C., i E. J. Davis. "Amino acid catabolism by perfused rat hindquarter. The metabolic fates of valine". Biochemical Journal 233, nr 3 (1.02.1986): 621–30. http://dx.doi.org/10.1042/bj2330621.
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Hindquarters from starved rats were perfused with plasma concentrations of amino acids, but without other added substrates. Release of amino acids was similar to that previously reported, but, if total amino acid changes were recorded, alanine and glutamine were not formed in excess of their occurrence in muscle proteins. In protein balance (excess insulin) there was no net formation of either alanine or glutamine, even though the branched-chain amino acids and methionine were consumed. If [U-14C]valine was present, radiolabelled 3-hydroxyisobutyrate and, to a lesser extent, 2-oxo-3-methylbutyrate accumulated and radiolabel was incorporated into citrate-cycle intermediates and metabolites closely associated with the citrate cycle (glutamine and glutamate, and, to a smaller extent, lactate and alanine). If a 2-chloro-4-methylvalerate was present to stimulate the branched-chain oxo acid dehydrogenase, flux through this step was accelerated, resulting in increased accumulation of 3-hydroxyisobutyrate, decreased accumulation of 2-oxo-3-methylbutyrate, and markedly increased incorporation of radiolabel (specific and total) into all measured metabolites formed after 3-hydroxyisobutyrate. It is concluded that: amino acid catabolism by skeletal muscle is confined to degradation of the branched-chain amino acids, methionine and those that are interconvertible with the citrate cycle; amino acid catabolism is relatively minor in supplying carbon for net synthesis of alanine and glutamine; and partial degradation products of the branched-chain amino acids are quantitatively significant substrates released from muscle for hepatic gluconeogenesis. For valine, 3-hydroxyisobutyrate appears to be quantitatively the most important intermediate released from muscle. A side path for inter-organ disposition of the branched-chain amino acids is proposed.
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Lange, Peter R., Peter J. Eastmond, Kathryn Madagan i Ian A. Graham. "AnArabidopsismutant disrupted in valine catabolism is also compromised in peroxisomal fatty acid β-oxidation". FEBS Letters 571, nr 1-3 (6.07.2004): 147–53. http://dx.doi.org/10.1016/j.febslet.2004.06.071.
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Hood, D. A., i R. L. Terjung. "Effect of alpha-ketoacid dehydrogenase phosphorylation on branched-chain amino acid metabolism in muscle". American Journal of Physiology-Endocrinology and Metabolism 261, nr 5 (1.11.1991): E628—E634. http://dx.doi.org/10.1152/ajpendo.1991.261.5.e628.
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The regulation of leucine and valine metabolism was evaluated in skeletal muscle of perfused rat hindlimb. Control of the branched-chain alpha-ketoacid dehydrogenase (BCKADH) via phosphorylation was removed with 0.4 mM alpha-chloroisocaproate (CIC). CIC activated the BCKADH complex 13- to 26-fold and led to increased rates of leucine and valine uptake into muscle, transamination to the corresponding alpha-ketoacid, and leucine (3- to 4-fold) and valine (6-fold) decarboxylation but led to decreased rates of alpha-ketoacid efflux from muscle. Although the increased rates of branched-chain amino acid (BCAA) decarboxylation were extensive, they were far below the extent of BCKADH activation as measured in vitro, suggesting that factors other than BCKADH activation become dominant in controlling the flux through alpha-ketoacid decarboxylation in skeletal muscle in situ. When the BCKADH capacity of muscle was increased 70–90% by a training-induced increase in mitochondrial content, the same 13- to 26-fold activation of the complex by CIC led to a rate of BCAA decarboxylation, which was only marginally greater (10–20%; P less than 0.05) than that of normal muscle. In addition, increasing the energy demand via muscle contractions led to a significant increase in leucine decarboxylation in the presence of complete activation of BCKADH by dephosphorylation. Thus BCKADH phosphorylation-dephosphorylation plays an important though not exclusive role in modulating the rates of BCAA metabolism in skeletal muscle. Differences in valine and leucine metabolism were apparent as valine catabolism bolstered citric acid cycle contents by increasing malate in red muscle with high mitochondrial content.(ABSTRACT TRUNCATED AT 250 WORDS)
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Sohail, Muhammad, Ron Wills, Michael Bowyer i Penta Pristijono. "Multiple Amino Acids Inhibit Postharvest Senescence of Broccoli". Horticulturae 7, nr 4 (4.04.2021): 71. http://dx.doi.org/10.3390/horticulturae7040071.
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The function of free amino acids in protein synthesis, as a source of energy and unique roles in catabolism have been well studied in plant development but their function in postharvest fruit and vegetables has received little attention. This study evaluated 11 amino acids—arginine, alanine, aspartic acid, glutamic acid, glycine, ornithine, phenylalanine, serine, tyrosine, tryptophan and valine—on the development of senescence of broccoli. Broccoli florets were dipped in 5 mM solution of amino acids, then stored at 10 °C in air containing 0.1 µL L−1 ethylene. Senescence was assessed by green life, ethylene production, respiration rate and ion leakage. Green life was increased by all the amino acids except valine. Similarly, ethylene production and ion leakage were decreased by all the amino acids except valine, while respiration rate was reduced by all amino acids. It is speculated that the early reduction in ethylene production could be the mechanism by which the amino acids delayed senescence. The beneficial effect of naturally occurring amino acids in inhibiting senescence has potential commercial relevance, as the amino acids have Generally Recognised As Safe (GRAS) status which should assist gain regulatory approval, and gain acceptance by consumers wary of synthetic chemicals on foods.
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Däschner, Klaus, Ivan Couée i Stefan Binder. "The Mitochondrial Isovaleryl-Coenzyme A Dehydrogenase of Arabidopsis Oxidizes Intermediates of Leucine and Valine Catabolism". Plant Physiology 126, nr 2 (1.06.2001): 601–12. http://dx.doi.org/10.1104/pp.126.2.601.
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May, R. C., Y. Hara, R. A. Kelly, K. P. Block, M. G. Buse i W. E. Mitch. "Branched-chain amino acid metabolism in rat muscle: abnormal regulation in acidosis". American Journal of Physiology-Endocrinology and Metabolism 252, nr 6 (1.06.1987): E712—E718. http://dx.doi.org/10.1152/ajpendo.1987.252.6.e712.
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Branched-chain amino acid (BCAA) metabolism is frequently abnormal in pathological conditions accompanied by chronic metabolic acidosis. To study how metabolic acidosis affects BCAA metabolism in muscle, rats were gavage fed a 14% protein diet with or without 4 mmol NH4Cl X 100 g body wt-1 X day-1. Epitrochlearis muscles were incubated with L-[1-14C]-valine and L-[1-14C]leucine, and rates of decarboxylation, net transamination, and incorporation into muscle protein were measured. Plasma and muscle BCAA levels were lower (P less than 0.05) in acidotic rats. Rates of valine and leucine decarboxylation and net transamination were higher (P less than 0.05) in muscles from acidotic rats; these differences were associated with a 79% increase in the total activity of branched-chain alpha-keto acid dehydrogenase and a 146% increase in the activated form of the enzyme. We conclude that acidosis affects the regulation of BCAA metabolism by enhancing flux through the transaminase and by directly stimulating oxidative catabolism through activation of branched-chain alpha-keto acid dehydrogenase.
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Letto, Joan, John T. Brosnan i Margaret E. Brosnan. "Oxidation of 2-oxoisocaproate and 2-oxoisovalerate by the perfused rat heart. Interactions with fatty acid oxidation". Biochemistry and Cell Biology 68, nr 1 (1.01.1990): 260–65. http://dx.doi.org/10.1139/o90-036.
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The interactions between fatty acid oxidation and the oxidation of the 2-oxo acids of the branched chain amino acids were studied in the isolated Langendorff-perfused heart. 2-Oxoisocaproate inhibited the oxidation of oleate, but 2-oxoisovalerate and 2-oxo-3-methylvalerate did not. This difference was not attributable to the magnitude of the flux through the branched chain 2-oxo acid dehydrogenase, which was slightly higher with 2-oxoisovalerate than with 2-oxoisocaproate. Oxidation of 2-oxoisocaproate in the perfused heart was virtually complete, since more than 80% of the isovaleryl-CoA formed from 2-oxo[1-14C]isocaproate was further metabolized to CO2, as determined by comparing 14CO2 production from 2-oxo[14C(U)]isocaproate with that from the 1-14C-labelled compound. Only twice as much 14CO2 was produced from 2-oxo[14C(U)]isovalerate as from the 1-14C-labelled compound, indicating incomplete oxidation. This was confirmed by the accumulation in the perfusion medium of substantial quantities of labelled 3-hydroxyisobutyrate (an intermediate in the pathway of valine catabolism), when hearts were perfused with 2-oxo[14C(U)]isovalerate. The failure of 2-oxoisovalerate to inhibit fatty acid oxidation, then, can be attributed to the fact that its partial metabolism in the heart produces little ATP. We have previously shown that 3-hydroxyisobutyrate is a good gluconeogenic substrate in liver and kidney, and postulate that 3-hydroxyisobutyrate serves as an interorgan metabolite such that valine can serve as a glucogenic amino acid, even when its catabolism proceeds beyond the irreversible 2-oxo acid dehydrogenase in muscle.Key words: branched chain amino acids, branched chain 2-oxoacids, perfused heart, fatty acid metabolism, 3 -hydroxyisobutyrate.
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Ishigure, Kiyoshi, Yoshiharu Shimomura, Taro Murakami, Tetsuya Kaneko, Shin Takeda, Sohichiro Inoue, Shuji Nomoto, Katsumi Koshikawa, Toshiaki Nonami i Akimasa Nakao. "Human liver disease decreases methacrylyl-CoA hydratase and β-hydroxyisobutyryl-CoA hydrolase activities in valine catabolism". Clinica Chimica Acta 312, nr 1-2 (październik 2001): 115–21. http://dx.doi.org/10.1016/s0009-8981(01)00597-6.
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Rani, Nidhi, Samannaya Hazra, Amrita Singh i Avadhesha Surolia. "Functional annotation of putative fadE9 of Mycobacterium tuberculosis as isobutyryl-CoA dehydrogenase involved in valine catabolism". International Journal of Biological Macromolecules 122 (luty 2019): 45–57. http://dx.doi.org/10.1016/j.ijbiomac.2018.10.040.
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Tokach, Mike D., Henrique S. Cemin, Hayden R. Kerkaert, Jason C. Woodworth, Steve S. Dritz, Joel M. DeRouchey i Robert D. Goodband. "17 Challenges and implications of feeding diets with excess concentrations of leucine to growing-finishing pigs". Journal of Animal Science 98, Supplement_3 (2.11.2020): 16. http://dx.doi.org/10.1093/jas/skaa054.026.
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Abstract Excess dietary leucine stimulates the key enzymes involved in branched-chain catabolism causing breakdown of all branched-chain amino acids, including isoleucine and valine. Branched-chain amino acids share a common brain transporter with other large neutral amino acids (LNAA). Excess levels of one of the LNAA increases brain uptake of that amino acid and decreases the uptake of the other LNAA, including tryptophan. Thus, excess leucine can impact the requirements for many amino acids. From a practical basis, this effect was first demonstrated with diets containing blood meal, but was thought to be of limited concern unless high blood meal diets were fed. Use of corn dried distillers grains with solubles (DDGS) or high protein DDGS in corn-based diets results in diets containing excess leucine. These high leucine levels are of limited concern if adequate levels of other branched-chain amino acids and LNAA are fed, which is often the case if the diet consists largely of intact protein sources. Feed grade amino acids, such as L-lysine, L-threonine, L-tryptophan, DL-methionine, L-valine, and L-isoleucine have been widely adopted as a means to lower nitrogen excretion and diet cost. Including these amino acids in diets containing corn products reduces dietary leucine; but the resulting diets are formulated near the requirement for the first 6 limiting amino acids, including valine, isoleucine, and tryptophan, while still being high in leucine. The excess leucine increases the requirements for valine, isoleucine, and possibly other LNAA, such as tryptophan and possibly others. The exact relationship between these amino acids and how to handle them in practical diet formulation is still being elucidated; however, recent meta-analysis and experimental data confirm the importance of these ratios and provide useful direction for future research.
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Scully, Sean Michael, i Johann Orlygsson. "Amino Acid Metabolism of Thermoanaerobacter Strain AK90: The Role of Electron-Scavenging Systems in End Product Formation". Journal of Amino Acids 2015 (27.08.2015): 1–10. http://dx.doi.org/10.1155/2015/410492.
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The catabolism of the 20 amino acids by Thermoanaerobacter strain AK90 (KR007667) was investigated under three different conditions: as single amino acids without an electron-scavenging system, in the presence of thiosulfate, and in coculture with a hydrogenotrophic methanogen. The strain degraded only serine without an alternative electron acceptor but degraded 11 amino acids (alanine, cysteine, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, tyrosine, and valine) under both of the electron-scavenging systems investigated. Acetate was the dominant end product from alanine, cysteine, lysine, serine, and threonine under electron-scavenging conditions. The branched-chain amino acids, isoleucine, leucine, and valine, were degraded to their corresponding fatty acids under methanogenic conditions and to a mixture of their corresponding fatty acids and alcohols in the presence of thiosulfate. The partial pressure of hydrogen seems to be of importance for the branched-chain alcohol formation. This was suggested by low but detectable hydrogen concentrations at the end of cultivation on the branched-chain amino acid in the presence of thiosulfate but not when cocultured with the methanogen. A more detailed examination of the role of thiosulfate as an electron acceptor was performed with Thermoanaerobacter ethanolicus (DSM 2246) and Thermoanaerobacter brockii (DSM 1457).
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Price, S. R., D. Reaich, A. C. Marinovic, B. K. England, J. L. Bailey, R. Caban, W. E. Mitch i B. J. Maroni. "Mechanisms contributing to muscle-wasting in acute uremia: activation of amino acid catabolism." Journal of the American Society of Nephrology 9, nr 3 (marzec 1998): 439–43. http://dx.doi.org/10.1681/asn.v93439.
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Acute uremia (ARF) causes metabolic defects in glucose and protein metabolism that contribute to muscle wasting. To examine whether there are also defects in the metabolism of essential amino acids in ARF, we measured the activity of the rate-limiting enzyme for branched-chain amino acid catabolism, branched-chain ketoacid dehydrogenase (BCKAD), in rat muscles. Because chronic acidosis activates muscle BCKAD, we also evaluated the influence of acidosis by studying ARF rats given either NaCl (ARF-NaCl) or NaHCO3 (ARF-HCO3) to prevent acidosis, and sham-operated, control rats given NaHCO3. ARF-NaCl rats became progressively acidemic (serum [HCO3] = 21.3 +/- 0.7 mM within 18 h and 14.7 +/- 0.8 mM after 44 h; mean +/- SEM), but this was corrected with NaHCO3. Plasma valine was low in ARF-NaCl and ARF-HCO3 rats. Plasma isoleucine, but not leucine, was low in ARF-NaCl rats, and isoleucine tended to be lower in ARF-HCO3 rats. Basal BCKAD activity (a measure of active BCKAD in muscle) was increased more than 17-fold (P < 0.01) in ARF-NaCl rat muscles, and this response was partially suppressed by NaHCO3. Maximal BCKAD activity (an estimate of BCKAD content), subunit mRNA levels, and BCKAD protein content were not different in ARF and control rat muscles. Thus, ARF increases branched-chain amino acid catabolism by activating BCKAD by a mechanism that includes acidosis. Moreover, in a muscle-wasting condition such as ARF, there is a coordinated increase in protein and essential amino acid catabolism.
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Wiltafsky, Markus Karl, Michael Walter Pfaffl i Franz Xaver Roth. "The effects of branched-chain amino acid interactions on growth performance, blood metabolites, enzyme kinetics and transcriptomics in weaned pigs". British Journal of Nutrition 103, nr 7 (3.03.2010): 964–76. http://dx.doi.org/10.1017/s0007114509992212.
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The impact of excess dietary leucine (Leu) was studied in two growth assays with pigs (8–25 kg). In each trial, forty-eight pigs were allotted to one of six dietary groups. The dietary Leu supply increased from treatment L100 to L200 (three increments). To guarantee that interactions between the branched-chain amino acids (BCAA) were not cushioned either surpluses of isoleucine (Ile, expt 1) or valine (Val; expt 2) were avoided. In the fifth treatment, the effects of a simultaneous excess of Leu and Val (expt 1), or of Leu and Ile (expt 2) were investigated. The sixth treatment was a positive control. An increase in dietary Leu decreased growth performance, and increased plasma Leu and serum α-keto-isocaproate levels in a linear, dose-dependent manner. Levels of plasma Ile and Val, and of serum α-keto-β-methylvalerate and α-keto-isovalerate, indicated increased catabolism. Linear increases in the activity of basal branched-chain α-keto acid dehydrogenase in the liver confirmed these findings. No major alterations occurred in the mRNA of branched-chain amino acid catabolism genes. In liver tissue from expt 2, however, the mRNA levels of growth hormone receptor, insulin-like growth factor acid labile subunit and insulin-like growth factor 1 decreased significantly with increasing dietary Leu. In conclusion, excess dietary Leu increased the catabolism of BCAA mainly through posttranscriptional mechanisms. The impact of excess Leu on the growth hormone–insulin-like growth factor-1 axis requires further investigation.
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Madsen, Søren M., Hans Christian Beck, Peter Ravn, Astrid Vrang, Anne Maria Hansen i Hans Israelsen. "Cloning and Inactivation of a Branched-Chain-Amino-Acid Aminotransferase Gene from Staphylococcus carnosus and Characterization of the Enzyme". Applied and Environmental Microbiology 68, nr 8 (sierpień 2002): 4007–14. http://dx.doi.org/10.1128/aem.68.8.4007-4014.2002.
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ABSTRACT Staphylococcus carnosus and Staphylococcus xylosus are widely used as aroma producers in the manufacture of dried fermented sausages. Catabolism of branched-chain amino acids (BCAAs) by these strains contributes to aroma formation by production of methyl-branched aldehydes and carboxy acids. The first step in the catabolism is most likely a transamination reaction catalyzed by BCAA aminotransferases (IlvE proteins). In this study, we cloned the ilvE gene from S. carnosus by using degenerate oligonucleotides and PCR. We found that the deduced amino acid sequence was 80% identical to that of the corresponding enzyme in Staphylococcus aureus and that the ilvE gene was constitutively expressed as a monocistronic transcript. To study the influence of ilvE on BCAA catabolism, we constructed an ilvE deletion mutant by gene replacement. The IlvE protein from S. carnosus was shown mainly to catalyze the transamination of isoleucine, valine, leucine, and, to some extent, methionine using pyridoxal 5′-phosphate as a coenzyme. The ilvE mutant degraded less than 5% of the BCAAs, while the wild-type strain degraded 75 to 95%. Furthermore, the mutant strain produced approximately 100-fold less of the methyl-branched carboxy acids, 2-methylpropanoic acid, 2-methylbutanoic acid, and 3-methylbutanoic acid, which derived from the BCAA catabolism, clearly emphasizing the role of IlvE in aroma formation. In contrast to previous reports, we found that IlvE was the only enzyme that catalyzed the deamination of BCAAs in S. carnosus. The ilvE mutant strain showed remarkably lower growth rate and biomass yield compared to those of the wild-type strain when grown in rich medium. Normal growth rate and biomass yield were restored by addition of the three BCAA-derived α-keto acids, showing that degradation products of BCAAs were essential for optimal cell growth.
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TANIGUCHI, K. "P-208 Regulation of the valine catabolism in human liver: Comparison between normal liver and cirrhotic liver". International Hepatology Communications 3 (lipiec 1995): S88. http://dx.doi.org/10.1016/0928-4346(95)90504-z.
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Plamondon, Pascale, Denis Brochu, Suzanne Thomas, Julie Fradette, Lucie Gauthier, Katy Vaillancourt, Nicole Buckley, Michel Frenette i Christian Vadeboncoeur. "Phenotypic Consequences Resulting from a Methionine-to-Valine Substitution at Position 48 in the HPr Protein of Streptococcus salivarius". Journal of Bacteriology 181, nr 22 (15.11.1999): 6914–21. http://dx.doi.org/10.1128/jb.181.22.6914-6921.1999.
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ABSTRACT In gram-positive bacteria, the HPr protein of the phosphoenolpyruvate:sugar phosphotransferase system (PTS) can be phosphorylated on a histidine residue at position 15 (His15) by enzyme I (EI) of the PTS and on a serine residue at position 46 (Ser46) by an ATP-dependent protein kinase (His∼P and Ser-P, respectively). We have isolated fromStreptococcus salivarius ATCC 25975, by independent selection from separate cultures, two spontaneous mutants (Ga3.78 and Ga3.14) that possess a missense mutation in ptsH (the gene encoding HPr) replacing the methionine at position 48 by a valine. The mutation did not prevent the phosphorylation of HPr at His15 by EI nor the phosphorylation at Ser46 by the ATP-dependent HPr kinase. The levels of HPr(Ser-P) in glucose-grown cells of the parental and mutant Ga3.78 were virtually the same. However, mutant cells growing on glucose produced two- to threefold less HPr(Ser-P)(His∼P) than the wild-type strain, while the levels of free HPr and HPr(His∼P) were increased 18- and 3-fold, respectively. The mutants grew as well as the wild-type strain on PTS sugars (glucose, fructose, and mannose) and on the non-PTS sugars lactose and melibiose. However, the growth rate of both mutants on galactose, also a non-PTS sugar, decreased rapidly with time. The M48V substitution had only a minor effect on the repression of α-galactosidase, β-galactosidase, and galactokinase by glucose, but this mutation abolished diauxie by rendering cells unable to prevent the catabolism of a non-PTS sugar (lactose, galactose, and melibiose) when glucose was available. The results suggested that the capacity of the wild-type cells to preferentially metabolize glucose over non-PTS sugars resulted mainly from inhibition of the catabolism of these secondary energy sources via a HPr-dependent mechanism. This mechanism was activated following glucose but not lactose metabolism, and it did not involve HPr(Ser-P) as the only regulatory molecule.
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Thierry, Anne, Marie-Bernadette Maillard i Mireille Yvon. "Conversion of l-Leucine to Isovaleric Acid by Propionibacterium freudenreichii TL 34 and ITGP23". Applied and Environmental Microbiology 68, nr 2 (luty 2002): 608–15. http://dx.doi.org/10.1128/aem.68.2.608-615.2002.
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ABSTRACT Several branched-chain volatile compounds are involved in the flavor of Swiss cheese. These compounds are probably produced by enzymatic conversion of branched-chain amino acids, but the flora and the pathways involved remain hypothetical. Our aim was to determine the ability of Propionibacterium freudenreichii, which is one of the main components of the secondary flora of Swiss cheese, to produce flavor compounds during leucine catabolism. Cell extracts and resting cells of two strains were incubated in the presence of l-leucine, α-ketoglutaric acid, and cofactors, and the metabolites produced were determined by high-performance liquid chromatography and gas chromatography. The first step of leucine catabolism was a transamination that produced α-ketoisocaproic acid, which was enzymatically converted to isovaleric acid. Both reactions were faster at pH 8.0 than at acidic pHs. Cell extracts catalyzed only the transamination step under our experimental conditions. Small amounts of 3-methylbutanol were also produced by resting cells, but neither 3-methylbutanal norα-hydroxyisocaproic acid was detected. l-Isoleucine and l-valine were also converted to the corresponding acids and alcohols. Isovaleric acid was produced by both strains during growth in a complex medium, even under conditions simulating Swiss cheese conditions (2.1% NaCl, pH 5.4, 24�C). Our results show that P. frendenreichii could play a significant role in the formation of isovaleric acid during ripening.
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De Clercq, Erik. "The development of BVDU: An odyssey". Antiviral Chemistry and Chemotherapy 31 (styczeń 2023): 204020662311529. http://dx.doi.org/10.1177/20402066231152971.
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Brivudin, (( E)-5-(2-bromovinyl)-2’-deoxyuridine (BVDU) can be considered the gold standard for the treatment of varicella-zoster virus (VZV) infections, such as herpes zoster (shingles). It is available for clinical use in most European countries (except for the UK) and over the whole world (except for the US and Canada). Besides VZV its activity spectrum also includes various other herpesviruses, such as herpes simplex virus type 1 (HSV-1). Its activity against VZV and HSV-1 depends on phosphorylation by the virus-encoded thymidine kinase (TK). In its active form (BVDU TP or BVDU 5’-triphosphate), it can act as both substrate and inhibitor of the viral (i.e., HSV-1) DNA polymerase. It has proven to be effective against herpes zoster, including post-herpetic neuralgia (PHN). It is contra-indicated in patients concomitantly treated by 5-fluorouracil (FU), since its degradation product, ( E)-5-(2-bromovinyl)uracil, is inhibitory to the catabolism of FU, which may enhance the toxicity of the latter. A new compound, the bicyclic nucleoside analogue (BCNA) Cf-1743, has been described, which is a more potent inhibitor of VZV replication than BVDU and which does not interfere with the catabolism of FU. It is applicable orally, as its 5’-valine ester FV-100 (Fermavir), but has not (yet) been marketed for clinical use.
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Kalita-de Croft, Priyakshi, Jasmin Straube, Malcolm Lim, Fares Al-Ejeh, Sunil R. Lakhani i Jodi M. Saunus. "Proteomic Analysis of the Breast Cancer Brain Metastasis Microenvironment". International Journal of Molecular Sciences 20, nr 10 (22.05.2019): 2524. http://dx.doi.org/10.3390/ijms20102524.
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Patients with brain-metastatic breast cancer face a bleak prognosis marked by morbidity and premature death. A deeper understanding of molecular interactions in the metastatic brain tumour microenvironment may inform the development of new therapeutic strategies. In this study, triple-negative MDA-MB-231 breast cancer cells or PBS (modelling traumatic brain injury) were stereotactically injected into the cerebral cortex of NOD/SCID mice to model metastatic colonization. Brain cells were isolated from five tumour-associated samples and five controls (pooled uninvolved and injured tissue) by immunoaffinity chromatography, and proteomic profiles were compared using the Sequential Window Acquisition of All Theoretical Mass Spectra (SWATH-MS) discovery platform. Ontology and cell type biomarker enrichment analysis of the 125 differentially abundant proteins (p < 0.05) showed the changes largely represent cellular components involved in metabolic reprogramming and cell migration (min q = 4.59 × 10−5), with high-throughput PubMed text mining indicating they have been most frequently studied in the contexts of mitochondrial dysfunction, oxidative stress and autophagy. Analysis of mouse brain cell type-specific biomarkers suggested the changes were paralleled by increased proportions of microglia, mural cells and interneurons. Finally, we orthogonally validated three of the proteins in an independent xenograft cohort, and investigated their expression in craniotomy specimens from triple-negative metastatic breast cancer patients, using a combination of standard and fluorescent multiplex immunohistochemistry. This included 3-Hydroxyisobutyryl-CoA Hydrolase (HIBCH), which is integral for gluconeogenic valine catabolism in the brain, and was strongly induced in both graft-associated brain tissue (13.5-fold by SWATH-MS; p = 7.2 × 10−4), and areas of tumour-associated, reactive gliosis in human clinical samples. HIBCH was also induced in the tumour compartment, with expression frequently localized to margins and haemorrhagic areas. These observations raise the possibility that catabolism of valine is an effective adaptation in metastatic cells able to access it, and that intermediates or products could be transferred from tumour-associated glia. Overall, our findings indicate that metabolic reprogramming dominates the proteomic landscape of graft-associated brain tissue in the intracranial MDA-MB-231 xenograft model. Brain-derived metabolic provisions could represent an exploitable dependency in breast cancer brain metastases.
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Brat, Dawid, Christian Weber, Wolfram Lorenzen, Helge B. Bode i Eckhard Boles. "Cytosolic re-localization and optimization of valine synthesis and catabolism enables inseased isobutanol production with the yeast Saccharomyces cerevisiae". Biotechnology for Biofuels 5, nr 1 (2012): 65. http://dx.doi.org/10.1186/1754-6834-5-65.
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Hsu, Jean Wei, Paras Bharatesh Mehta, Nupur Kikani, Kelly Keene, Ruchi Gaba, Nalini Ram, William F. Peacock i in. "Serum Branch Chain Amino Acids (BCAAs) Are Elevated Due to Decreased Catabolism in Patients With Ketosis-Prone Diabetes at the Time of Presentation With DKA". Journal of the Endocrine Society 5, Supplement_1 (1.05.2021): A430. http://dx.doi.org/10.1210/jendso/bvab048.877.
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Abstract Patients with “A-β+” Ketosis-Prone Diabetes (KPD) develop diabetic ketoacidosis (DKA) despite lacking islet autoantibodies and a phenotype of T1D, have good beta cell function and can come off insulin therapy 4–8 weeks after the DKA episode. When near-normoglycemic and stable on metformin, they have accelerated BCAA catabolism which promotes ketogenesis (Patel SG et al, Diabetes 2013). Here we measured BCAAs, their metabolites and acylcarnitine esters (C5,C3) in blood samples obtained from adults with DKA (N=74) compared to those with non-ketotic hyperglycemic crisis (N=21) at the time of acute presentation to the emergency center, and to healthy controls (N=17). Of the DKA patients, 53 were classified as likely A-β+ KPD based on absence of GAD65Ab and C-peptide levels or clinical features, and the 21 patients with non-ketotic hyperglycemia were classified as T2D. Serum concentrations of leucine, isoleucine and valine and their respective branch chain keto acids (BCKA) were higher (p<0.05) in KPD patients compared to T2D and control. The ratio of each BCKA to its precursor BCAA was calculated as an index of its rate of transamination. Serum KIC/Leu, KMV/Ile and KIV/Val were significantly lower (p<0.05) in KPD compared to T2D. The ratio of each acylcarnitine to its precursor BCKA was calculated as an index of its rate of entry and metabolism within mitochondria. Serum C5/KIC, C5/KMV and C5/KIC+KMV were lower (p<0.05) in KPD patients compared to T2D patients. Serum C3/KIV, C3/KMV and C3/KIV+KMV were significantly lower (p<0.05) in KPD patients compared to controls. Since KIC can be converted to acetoacetate and then reduced to β-hydroxybutyrate (BHOB), and KIC and KMV can be metabolized to acetyl CoA, the ratios of KIC+KMV/C2 and KIC/BHOB were calculated as indicators of their relative conversion to acetyl CoA and acetoacetate respectively. KIC+KMV/C2 was significantly lower (p<0.001) in KPD than T2D and control and KIC/BOHB was lower (p<0.001) in KPD than T2D. Acetyl carnitine was markedly elevated in the KPD group, indicating accelerated production of acetyl CoA from free fatty acids. During acute DKA, KPD patients have higher serum BCAAs because their catabolism is decreased, due to slower rate of transamination in the cytosol by BCAA transaminase 1 (BCAT1) and slower rate of entry into mitochondria and metabolism to acetyl CoA and acetoacetate by BCAT2, BCKA dehydrogenase and other catabolic enzymes. This is diametrically opposite to their profile in the stable, near-normoglycemic state, when BCAA catabolism is accelerated. We propose that during acute DKA, accelerated flux of fatty acids to acetyl CoA diminishes carnitine and NAD+ availability for mitochondrial transport and metabolism of BCAA catabolites in KPD patients, whereas in the near-normoglycemic state they have heightened dependence on BCAA catabolism for energy production through acetyl CoA and ketogenesis.
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De Sain-Van Der Velden, M. G., D. J. Reijngoud, G. A. Kaysen, M. M. Gadellaa, H. Voorbij, F. Stellaard, H. A. Koomans i T. J. Rabelink. "Evidence for increased synthesis of lipoprotein(a) in the nephrotic syndrome." Journal of the American Society of Nephrology 9, nr 8 (sierpień 1998): 1474–81. http://dx.doi.org/10.1681/asn.v981474.
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In patients with the nephrotic syndrome, markedly increased levels of lipoprotein(a) (Lp(a)) concentration have been frequently reported, and it has been suggested that this may contribute to the increased cardiovascular risk in these patients. The mechanism, however, is not clear. In the present study, in vivo fractional synthesis rate of Lp(a) was measured using incorporation of the stable isotope 13C valine. Under steady-state conditions, fractional synthesis rate equals fractional catabolic rate (FCR). FCR of Lp(a) was estimated in five patients with the nephrotic syndrome and compared with five control subjects. The mean plasma Lp(a) concentration in the patients (1749+/-612 mg/L) was higher than in control subjects (553+/-96 mg/L). Two patients were heterozygous for apolipoprotein(a) (range, 19 to 30 kringle IV domains), whereas all control subjects were each homozygous with regard to apolipoprotein(a) phenotype (range, 18 to 28 kringle IV domains). The FCR of Lp(a) was comparable between control subjects (0.072+/-0.032 pools/d) and patients (0.064+/-0.029 pools/d) despite the wide variance in plasma concentration. This suggests that differences in Lp(a) levels are caused by differences in synthesis rate. Indeed, the absolute synthetic rate of Lp(a) correlated directly with plasma Lp(a) concentration (P < 0.0001) in all subjects. The present results demonstrate that increased synthesis, rather than decreased catabolism, causes elevated plasma Lp(a) concentrations in the nephrotic syndrome.
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Curic, Mirjana, Birgitte Stuer-Lauridsen, Pierre Renault i Dan Nilsson. "A General Method for Selection of α-Acetolactate Decarboxylase-Deficient Lactococcus lactis Mutants To Improve Diacetyl Formation". Applied and Environmental Microbiology 65, nr 3 (1.03.1999): 1202–6. http://dx.doi.org/10.1128/aem.65.3.1202-1206.1999.
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ABSTRACT The enzyme acetolactate decarboxylase (Ald) plays a key role in the regulation of the α-acetolactate pool in both pyruvate catabolism and the biosynthesis of the branched-chain amino acids, isoleucine, leucine, and valine (ILV). This dual role of Ald, due to allosteric activation by leucine, was used as a strategy for the isolation of Ald-deficient mutants of Lactococcus lactis subsp.lactis biovar diacetylactis. Such mutants can be selected as leucine-resistant mutants in ILV- or IV-prototrophic strains. Most dairy lactococcus strains are auxotrophic for the three amino acids. Therefore, the plasmid pMC004 containing the ilv genes (encoding the enzymes involved in the biosynthesis of IV) of L. lactis NCDO2118 was constructed. Introduction of pMC004 into ILV-auxotrophic dairy strains resulted in an isoleucine-prototrophic phenotype. By plating the strains on a chemically defined medium supplemented with leucine but not valine and isoleucine, spontaneous leucine-resistant mutants were obtained. These mutants were screened by Western blotting with Ald-specific antibodies for the presence of Ald. Selected mutants lacking Ald were subsequently cured of pMC004. Except for a defect in the expression of Ald, the resulting strain, MC010, was identical to the wild-type strain, as shown by Southern blotting and DNA fingerprinting. The mutation resulting in the lack of Ald in MC010 occurred spontaneously, and the strain does not contain foreign DNA; thus, it can be regarded as food grade. Nevertheless, its application in dairy products depends on the regulation of genetically modified organisms. These results establish a strategy to select spontaneous Ald-deficient mutants from transformable L. lactis strains.
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Maggio-Hall, Lori A., Paul Lyne, Jon A. Wolff i Nancy P. Keller. "A single acyl-CoA dehydrogenase is required for catabolism of isoleucine, valine and short-chain fatty acids in Aspergillus nidulans". Fungal Genetics and Biology 45, nr 3 (marzec 2008): 180–89. http://dx.doi.org/10.1016/j.fgb.2007.06.004.
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Tang, L., Y. X. Zhang i C. R. Hutchinson. "Amino acid catabolism and antibiotic synthesis: valine is a source of precursors for macrolide biosynthesis in Streptomyces ambofaciens and Streptomyces fradiae." Journal of Bacteriology 176, nr 19 (1994): 6107–19. http://dx.doi.org/10.1128/jb.176.19.6107-6119.1994.
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Teasley, Kathleen M., i Renee L. Buss. "Do Parenteral Nutrition Solutions with High Concentrations of Branched-Chain Amino Acids Offer Significant Benefits to Stressed Patients?" DICP 23, nr 5 (maj 1989): 411–16. http://dx.doi.org/10.1177/106002808902300510.
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The critically ill, stressed patient has been characterized as having altered cellular metabolism. Altered protein metabolism is manifested as negative nitrogen balance, reduced whole-body protein synthesis, and increased proteolysis. An increased oxidation of the branched-chain amino acids (BCAA) leucine, isoleucine, and valine has also been observed. Exogenous administration of BCAA as part of a total parenteral nutrition (TPN) regimen has been proposed to compensate for the altered protein metabolism in the stressed patient by sparing endogenous sources of BCAA, thereby reducing skeletal muscle catabolism and increasing protein synthesis. Numerous clinical studies have been performed investigating this theory. The results are controversial. Differences in study outcomes appear to be related to study design, especially patient selection. Our review of those studies which were randomized, prospective, and controlled indicates that an improvement in nitrogen retention and visceral protein status can be achieved in stress-stratified patients who receive a TPN regimen containing a BCAA-enriched formula. The significance of these outcomes on morbidity, length of hospital stay, and mortality has not been evaluated.
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Daniels, Craig, Patricia Godoy, Estrella Duque, M. Antonia Molina-Henares, Jesús de la Torre, José María del Arco, Carmen Herrera i in. "Global Regulation of Food Supply by Pseudomonas putida DOT-T1E". Journal of Bacteriology 192, nr 8 (5.02.2010): 2169–81. http://dx.doi.org/10.1128/jb.01129-09.
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ABSTRACT Pseudomonas putida DOT-T1E was used as a model to develop a “phenomics” platform to investigate the ability of P. putida to grow using different carbon, nitrogen, and sulfur sources and in the presence of stress molecules. Results for growth of wild-type DOT-T1E on 90 different carbon sources revealed the existence of a number of previously uncharted catabolic pathways for compounds such as salicylate, quinate, phenylethanol, gallate, and hexanoate, among others. Subsequent screening on the subset of compounds on which wild-type DOT-TIE could grow with four knockout strains in the global regulatory genes Δcrc, Δcrp, ΔcyoB, and ΔptsN allowed analysis of the global response to nutrient supply and stress. The data revealed that most global regulator mutants could grow in a wide variety of substrates, indicating that metabolic fluxes are physiologically balanced. It was found that the Crc mutant did not differ much from the wild-type regarding the use of carbon sources. However, certain pathways are under the preferential control of one global regulator, i.e., metabolism of succinate and d-fructose is influenced by CyoB, and l -arginine is influenced by PtsN. Other pathways can be influenced by more than one global regulator; i.e., l-valine catabolism can be influenced by CyoB and Crp (cyclic AMP receptor protein) while phenylethylamine is affected by Crp, CyoB, and PtsN. These results emphasize the cross talk required in order to ensure proper growth and survival. With respect to N sources, DOT-T1E can use a wide variety of inorganic and organic nitrogen sources. As with the carbon sources, more than one global regulator affected growth with some nitrogen sources; for instance, growth with nucleotides, dipeptides, d-amino acids, and ethanolamine is influenced by Crp, CyoB, and PtsN. A surprising finding was that the Crp mutant was unable to flourish on ammonium. Results for assayed sulfur sources revealed that CyoB controls multiple points in methionine/cysteine catabolism while PtsN and Crc are needed for N-acetyl-l-cysteamine utilization. Growth of global regulator mutants was also influenced by stressors of different types (antibiotics, oxidative agents, and metals). Overall and in combination with results for growth in the presence of various stressors, these phenomics assays provide multifaceted insights into the complex decision-making process involved in nutrient supply, optimization, and survival.
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Do Carmo, A., D. da Silva, M. De Oliveira, A. Borges, A. De Carvalho i C. De Moraes. "Genes involved in protein metabolism of the probiotic lactic acid bacterium Lactobacillus delbrueckii UFV H2b20". Beneficial Microbes 2, nr 3 (1.09.2011): 209–20. http://dx.doi.org/10.3920/bm2011.0025.
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A basic requirement for the prediction of the potential use of lactic acid bacteria (LAB) in the dairy industry is the identification of specific genes involved in flavour-forming pathways. The probiotic Lactobacillus delbrueckii UFV H2b20 was submitted to a genetic characterisation and phylogenetic analysis of genes involved in protein catabolism. Eight genes belonging to this system were identified, which possess a closely phylogenetic relationship to NCFM strains representative, as it was demonstrated for oppC and oppBII, encoding oligopeptide transport system components. PepC, PepN, and PepX might be essential for growth of LAB, probiotic or not, since the correspondent genes are always present, including in L. delbrueckii UFV H2b20 genome. For pepX gene, a probable link between carbohydrate catabolism and PepX expression may exists, where it is regulated by PepR1/CcpA-like, a common feature between Lactobacillus strains and also in L. delbrueckii UFV H2b20. The well conserved evolutionary history of the ilvE gene is evidence that the pathways leading to branched-chain amino acid degradation, such as isoleucine and valine, are similar among L. delbrueckii subsp. bulgaricus strains and L. delbrueckii UFV H2b20. Thus, the involvement of succinate in flavour formation can be attributed to IlvE activity. The presence of aminopeptidase G in L. delbrueckii UFV H2b20 genome, which is absent in several strains, might improve the proteolytic activity and effectiveness. The nucleotide sequence encoding PepG revealed that it is a cysteine endopeptidase, belonging to Peptidase C1 superfamily; sequence analysis showed 99% identity with L. delbrueckii subsp. bulgaricus ATCC 11842 pepG, whereas protein sequence analysis revealed 100% similarity with PepG from the same organism. The present study proposes a schematic model to explain how the proteolytic system of the probiotic L. delbrueckii UFV H2b20 works, based on the components identified so far.
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Sonnabend, Robin, Lucas Seiler i Markus Gressler. "Regulation of the Leucine Metabolism in Mortierella alpina". Journal of Fungi 8, nr 2 (18.02.2022): 196. http://dx.doi.org/10.3390/jof8020196.
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The oleaginous fungus Mortierella alpina is a safe source of polyunsaturated fatty acids (PUFA) in industrial food and feed production. Besides PUFA production, pharmaceutically relevant surface-active and antimicrobial oligopeptides were isolated from this basal fungus. Both production of fatty acids and oligopeptides rely on the biosynthesis and high turnover of branched-chain-amino acids (BCAA), especially l-leucine. However, the regulation of BCAA biosynthesis in basal fungi is largely unknown. Here, we report on the regulation of the leucine, isoleucine, and valine metabolism in M. alpina. In contrast to higher fungi, the biosynthetic genes for BCAA are hardly transcriptionally regulated, as shown by qRT-PCR analysis, which suggests a constant production of BCAAs. However, the enzymes of the leucine metabolism are tightly metabolically regulated. Three enzymes of the leucine metabolism were heterologously produced in Escherichia coli, one of which is inhibited by allosteric feedback loops: The key regulator is the α-isopropylmalate synthase LeuA1, which is strongly disabled by l-leucine, α-ketoisocaproate, and propionyl-CoA, the precursor of the odd-chain fatty acid catabolism. Its gene is not related to homologs from higher fungi, but it has been inherited from a phototrophic ancestor by horizontal gene transfer.
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Chambellon, Emilie, Liesbeth Rijnen, Frédérique Lorquet, Christophe Gitton, Johan E. T. van Hylckama Vlieg, Jeroen A. Wouters i Mireille Yvon. "The d-2-Hydroxyacid Dehydrogenase Incorrectly Annotated PanE Is the Sole Reduction System for Branched-Chain 2-Keto Acids in Lactococcus lactis". Journal of Bacteriology 191, nr 3 (1.12.2008): 873–81. http://dx.doi.org/10.1128/jb.01114-08.
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ABSTRACT Hydroxyacid dehydrogenases of lactic acid bacteria, which catalyze the stereospecific reduction of branched-chain 2-keto acids to 2-hydroxyacids, are of interest in a variety of fields, including cheese flavor formation via amino acid catabolism. In this study, we used both targeted and random mutagenesis to identify the genes responsible for the reduction of 2-keto acids derived from amino acids in Lactococcus lactis. The gene panE, whose inactivation suppressed hydroxyisocaproate dehydrogenase activity, was cloned and overexpressed in Escherichia coli, and the recombinant His-tagged fusion protein was purified and characterized. The gene annotated panE was the sole gene responsible for the reduction of the 2-keto acids derived from leucine, isoleucine, and valine, while ldh, encoding l-lactate dehydrogenase, was responsible for the reduction of the 2-keto acids derived from phenylalanine and methionine. The kinetic parameters of the His-tagged PanE showed the highest catalytic efficiencies with 2-ketoisocaproate, 2-ketomethylvalerate, 2-ketoisovalerate, and benzoylformate (V max/Km ratios of 6,640, 4,180, 3,300, and 2,050 U/mg/mM, respectively), with NADH as the exclusive coenzyme. For the reverse reaction, the enzyme accepted d-2-hydroxyacids but not l-2-hydroxyacids. Although PanE showed the highest degrees of identity to putative NADP-dependent 2-ketopantoate reductases (KPRs), it did not exhibit KPR activity. Sequence homology analysis revealed that, together with the d-mandelate dehydrogenase of Enterococcus faecium and probably other putative KPRs, PanE belongs to a new family of d-2-hydroxyacid dehydrogenases which is unrelated to the well-described d-2-hydroxyisocaproate dehydrogenase family. Its probable physiological role is to regenerate the NAD+ necessary to catabolize branched-chain amino acids, leading to the production of ATP and aroma compounds.
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Upadhyaya, Bikram, Kaustav Majumder i Regis Moreau. "γ-Glutamyl Valine, Found in Dry Edible Beans, Is Anti-diabetic in db/db Mice". Current Developments in Nutrition 6, Supplement_1 (czerwiec 2022): 339. http://dx.doi.org/10.1093/cdn/nzac053.080.
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Abstract Objectives Dietary γ-glutamyl peptides (γ-GPs) found in dry edible beans exhibit biological activities (antioxidant, anti-inflammatory) with potential benefits against chronic metabolic disorders. γ-GPs are responsible for the desirable Kokumi flavor through allosteric activation of the Calcium Sensing Receptor (CaSR) present in multiple mammalian tissues. In this study, we investigated the metabolic effects of γ-glutamyl valine (γ-EV) in diabetic obese mice. Methods Four-weeks old male db/db mice (BKS.Cg-Dock7m +/+ Leprdb/J) were fed AIN-93G diet ad libitum and given water with or without γ-EV (500 mg/kg body weight) for 3 weeks. After 3 weeks of intervention, blood, intestine and liver were collected to determine blood glucose, blood plasma γ-EV concentrations (LC-MS/MS), alanine aminotransferase (ALT) activity, jejunum and liver transcriptomes (RNA-Seq), liver protein expression (Western blot), and liver glycogen content. Results Mice given γ-EV had higher weight gain (45%, p < 0.001, n = 8), lower food intake (21%, p < 0.0001), and better food efficiency (79%, p < 0.0001) than their control counterparts. γ-EV blood concentrations reached 2.07 ± 0.56 μM. Blood glucose levels decreased (29%, p < 0.01) and urination was markedly improved. The hepatosomatic index increased (66%, p < 0.0001); however, blood ALT activity was not significantly changed. RNA-Seq analysis revealed 147 jejunal genes and 1308 liver genes were differentially expressed due to γ-EV intake, 26 of these genes were common to these tissues. The top 3 GO categories affected by γ-EV in jejunum were fatty acid metabolic process (17/193 genes), lipid metabolic process (22/545 genes), and peroxisome (11/136 genes); and in liver, the top 3 GO categories were oxidoreductase activity (104/686 genes), lipid metabolic process (79/545 genes), and iron ion binding (43/185 genes). Hepatic AMP-activated protein kinase (p-AMPKα, Thr172) abundance, a major cellular regulator of lipid and glucose metabolism, increased (86%, p < 0.05), and liver glycogen decreased (79%, p < 0.0001) in the treatment group suggesting γ-EV induced catabolism. Conclusions γ-EV improved the diabetic condition of db/db mice via modulation of glucose and lipid metabolism. Funding Sources Funding was provided by the University of Nebraska-Lincoln Collaboration Initiative and the Nebraska Dry Bean Commission.
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Mantuano, Paola, Gianluca Bianchini, Ornella Cappellari, Brigida Boccanegra, Elena Conte, Francesca Sanarica, Antonietta Mele i in. "Ergogenic Effect of BCAAs and L-Alanine Supplementation: Proof-of-Concept Study in a Murine Model of Physiological Exercise". Nutrients 12, nr 8 (30.07.2020): 2295. http://dx.doi.org/10.3390/nu12082295.
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Background: Branched-chain amino acids (BCAAs: leucine, isoleucine, valine) account for 35% of skeletal muscle essential amino acids (AAs). As such, they must be provided in the diet to support peptide synthesis and inhibit protein breakdown. Although substantial evidence has been collected about the potential usefulness of BCAAs in supporting muscle function and structure, dietary supplements containing BCAAs alone may not be effective in controlling muscle protein turnover, due to the rate-limiting bioavailability of other AAs involved in BCAAs metabolism. Methods: We aimed to evaluate the in vivo/ex vivo effects of a 4-week treatment with an oral formulation containing BCAAs alone (2:1:1) on muscle function, structure, and metabolism in a murine model of physiological exercise, which was compared to three modified formulations combining BCAAs with increasing concentrations of L-Alanine (ALA), an AA controlling BCAAs catabolism. Results: A preliminary pharmacokinetic study confirmed the ability of ALA to boost up BCAAs bioavailability. After 4 weeks, mix 2 (BCAAs + 2ALA) had the best protective effect on mice force and fatigability, as well as on muscle morphology and metabolic indices. Conclusion: Our study corroborates the use of BCAAs + ALA to support muscle health during physiological exercise, underlining how the relative BCAAs/ALA ratio is important to control BCAAs distribution.
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Banerjee, Priyanka, Victor Adriano Okstoft Carmelo i Haja N. Kadarmideen. "Integrative Analysis of Metabolomic and Transcriptomic Profiles Uncovers Biological Pathways of Feed Efficiency in Pigs". Metabolites 10, nr 7 (6.07.2020): 275. http://dx.doi.org/10.3390/metabo10070275.
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Feed efficiency (FE) is an economically important trait. Thus, reliable predictors would help to reduce the production cost and provide sustainability to the pig industry. We carried out metabolome-transcriptome integration analysis on 40 purebred Duroc and Landrace uncastrated male pigs to identify potential gene-metabolite interactions and explore the molecular mechanisms underlying FE. To this end, we applied untargeted metabolomics and RNA-seq approaches to the same animals. After data quality control, we used a linear model approach to integrate the data and find significant differently correlated gene-metabolite pairs separately for the breeds (Duroc and Landrace) and FE groups (low and high FE) followed by a pathway over-representation analysis. We identified 21 and 12 significant gene-metabolite pairs for each group. The valine-leucine-isoleucine biosynthesis/degradation and arginine-proline metabolism pathways were associated with unique metabolites. The unique genes obtained from significant metabolite-gene pairs were associated with sphingolipid catabolism, multicellular organismal process, cGMP, and purine metabolic processes. While some of the genes and metabolites identified were known for their association with FE, others are novel and provide new avenues for further research. Further validation of genes, metabolites, and gene-metabolite interactions in larger cohorts will elucidate the regulatory mechanisms and pathways underlying FE.
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Holeček, Milan. "Branched-Chain Amino Acids and Branched-Chain Keto Acids in Hyperammonemic States: Metabolism and as Supplements". Metabolites 10, nr 8 (9.08.2020): 324. http://dx.doi.org/10.3390/metabo10080324.
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In hyperammonemic states, such as liver cirrhosis, urea cycle disorders, and strenuous exercise, the catabolism of branched-chain amino acids (BCAAs; leucine, isoleucine, and valine) is activated and BCAA concentrations decrease. In these conditions, BCAAs are recommended to improve mental functions, protein balance, and muscle performance. However, clinical trials have not demonstrated significant benefits of BCAA-containing supplements. It is hypothesized that, under hyperammonemic conditions, enhanced glutamine availability and decreased BCAA levels facilitate the amination of branched-chain keto acids (BCKAs; α-ketoisocaproate, α-keto-β-methylvalerate, and α-ketoisovalerate) to the corresponding BCAAs, and that BCKA supplementation may offer advantages over BCAAs. Studies examining the effects of ketoanalogues of amino acids have provided proof that subjects with hyperammonemia can effectively synthesize BCAAs from BCKAs. Unfortunately, the benefits of BCKA administration have not been clearly confirmed. The shortcoming of most reports is the use of mixtures intended for patients with renal insufficiency, which might be detrimental for patients with liver injury. It is concluded that (i) BCKA administration may decrease ammonia production, attenuate cataplerosis, correct amino acid imbalance, and improve protein balance and (ii) studies specifically investigating the effects of BCKA, without the interference of other ketoanalogues, are needed to complete the information essential for decisions regarding their suitability in hyperammonemic conditions.
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Holeček, Milan, Melita Vodeničarovová i Radana Fingrová. "Dual Effects of Beta-Hydroxy-Beta-Methylbutyrate (HMB) on Amino Acid, Energy, and Protein Metabolism in the Liver and Muscles of Rats with Streptozotocin-Induced Type 1 Diabetes". Biomolecules 10, nr 11 (23.10.2020): 1475. http://dx.doi.org/10.3390/biom10111475.
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Beta-hydroxy-beta-methyl butyrate (HMB) is a unique product of leucine catabolism with positive effects on protein balance. We have examined the effects of HMB (200 mg/kg/day via osmotic pump for 7 days) on rats with diabetes induced by streptozotocin (STZ, 100 mg/kg intraperitoneally). STZ induced severe diabetes associated with muscle wasting, decreased ATP in the liver, and increased α-ketoglutarate in muscles. In plasma, liver, and muscles increased branched-chain amino acids (BCAAs; valine, isoleucine, and leucine) and decreased serine. The decreases in mass and protein content of muscles and increases in BCAA concentration were more pronounced in extensor digitorum longus (fast-twitch muscle) than in soleus muscle (slow-twitch muscle). HMB infusion to STZ-treated animals increased glycemia and serine in the liver, decreased BCAAs in plasma and muscles, and decreased ATP in the liver and muscles. The effects of HMB on the weight and protein content of tissues were nonsignificant. We concluded that fast-twitch muscles are more sensitive to STZ than slow-twitch muscles and that HMB administration to STZ-treated rats has dual effects. Adjustments of BCAA concentrations in plasma and muscles and serine in the liver can be considered beneficial, whereas the increased glycemia and decreased ATP concentrations in the liver and muscles are detrimental.
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Zhao, Xue, Qing Han, Yujia Liu, Chenglin Sun, Xiaokun Gang i Guixia Wang. "The Relationship between Branched-Chain Amino Acid Related Metabolomic Signature and Insulin Resistance: A Systematic Review". Journal of Diabetes Research 2016 (2016): 1–12. http://dx.doi.org/10.1155/2016/2794591.
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Recent studies have shown the positive association between increased circulating BCAAs (valine, leucine, and isoleucine) and insulin resistance (IR) in obese or diabetic patients. However, results seem to be controversial in different races, diets, and distinct tissues. Our aims were to evaluate the relationship between BCAA and IR as well as later diabetes risk and explore the phenotypic and genetic factors influencing BCAA level based on available studies. We performed systematic review, searching MEDLINE, EMASE, ClinicalTrials.gov, the Cochrane Library, and Web of Science from inception to March 2016. After selection, 23 studies including 20,091 participants were included. Based on current evidence, we found that BCAA is a useful biomarker for early detection of IR and later diabetic risk. Factors influencing BCAA level can be divided into four parts: race, gender, dietary patterns, and gene variants. These factors might not only contribute to the elevated BCAA level but also show obvious associations with insulin resistance. Genes related to BCAA catabolism might serve as potential targets for the treatment of IR associated metabolic disorders. Moreover, these factors should be controlled properly during study design and data analysis. In the future, more large-scale studies with elaborate design addressing BCAA and IR are required.
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Holeček, Milan. "Role of Impaired Glycolysis in Perturbations of Amino Acid Metabolism in Diabetes Mellitus". International Journal of Molecular Sciences 24, nr 2 (15.01.2023): 1724. http://dx.doi.org/10.3390/ijms24021724.
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The most frequent alterations in plasma amino acid concentrations in type 1 and type 2 diabetes are decreased L-serine and increased branched-chain amino acid (BCAA; valine, leucine, and isoleucine) levels. The likely cause of L-serine deficiency is decreased synthesis of 3-phosphoglycerate, the main endogenous precursor of L-serine, due to impaired glycolysis. The BCAA levels increase due to decreased supply of pyruvate and oxaloacetate from glycolysis, enhanced supply of NADH + H+ from beta-oxidation, and subsequent decrease in the flux through the citric acid cycle in muscles. These alterations decrease the supply of α-ketoglutarate for BCAA transamination and the activity of branched-chain keto acid dehydrogenase, the rate-limiting enzyme in BCAA catabolism. L-serine deficiency contributes to decreased synthesis of phospholipids and increased synthesis of deoxysphinganines, which play a role in diabetic neuropathy, impaired homocysteine disposal, and glycine deficiency. Enhanced BCAA levels contribute to increased levels of aromatic amino acids (phenylalanine, tyrosine, and tryptophan), insulin resistance, and accumulation of various metabolites, whose influence on diabetes progression is not clear. It is concluded that amino acid concentrations should be monitored in patients with diabetes, and systematic investigation is needed to examine the effects of L-serine and glycine supplementation on diabetes progression when these amino acids are decreased.
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Zouaoui, Maroua, Aude Simongiovanni i Marie-Pierre Létourneau-Montminy. "206 Meta-analysis of the response of piglets to dietary valine: impact of other branched chain amino acids". Journal of Animal Science 98, Supplement_3 (2.11.2020): 18. http://dx.doi.org/10.1093/jas/skaa054.030.
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Abstract Branched chain amino acids (BCAA), valine (Val), isoleucine (Ile) and leucine (Leu) share the same metabolic pathways. An excess of Leu stimulates the catabolism of Val and Ile that may lead to a decrease in piglet growth performance. The objective of this study is to quantify the response of piglets to dietary Val and the influence of Leu and Ile on this response through a meta-analysis approach. A total of 16 articles published between 2001 and 2018, including 23 experiments and 126 treatments were used. Multiple regression models were fitted with the MIXED procedure of Minitab software with the random effect of the experiment. The Y variables were Average Daily Gain (ADG), Average Daily Feed Intake (ADFI) and Feed Conversion Ratio (FCR). The main X variable was the Standardized Ileal Digestible Val (ValSID) and the other ones were Leu (LeuSID) and Ile (IleSID). The response of ADG, ADFI and FCR to ValSID was curvilinear (P< 0.001: ADG, R2 = 0.93%; ADFI, R2= 0.97%; FCR, R2=0.93%). Results showed that increasing dietary LeuSID reduced ADG and ADFI (P< 0.05) but also that the response of piglets to ValSID was stronger in high LeuSID diet (P < 0.05; Interaction ValSIDxLeuSID; ADG and ADFI). Based on these models, increasing dietary ValSID from 7 to 8.5g/kg generates in wheat-based diets (10 g /kg of LeuSID) an improvement of ADG of 4.7% and ADFI of 2.5% compared to 7.4% for ADG and 5.2% for ADFI in corn-based diets (14 g/ kg of LeuSID). The response of ADG, ADFI and FCR to ValSID was not modified by IleSID. This study showed that ADG, ADFI and FCR are improved with increasing dietary Val and this effect was modulated by dietary Leu content except for FCR. Results can help piglet nutritionists to optimize dietary Val levels based on other BCAA content.