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The neuronal effects of glucose deficiency on amino acid metabolism was studied on three-dimensional cultures of rat telencephalon neurones. Transient (6 h) exposure of differentiated cultures to low glucose (0.25 mm instead of 25 mm) caused irreversible damage, as judged by the marked decrease in the activities of two neurone-specific enzymes and lactate dehydrogenase, 1 week after the hypoglycemic insult. Quantification of amino acids and ammonia in the culture media supernatants indicated increased amino acid utilization and ammonia production during glucose-deficiency. Measurement of intracellular amino acids showed decreased levels of alanine, glutamine, glutamate and GABA, while aspartate was increased. Added lactate (11 mm) during glucose deficiency largely prevented the changes in amino acid metabolism and ammonia production, and attenuated irreversible damage. Higher media levels of glutamine (4 mm instead of 0.25 mm) during glucose deprivation prevented the decrease of intracellular glutamate and GABA, while it further increased intracellular aspartate, ammonia production and neuronal damage. Both lactate and glutamine were readily oxidized in these neuronal cultures. The present results suggest that in neurones, glucose deficiency enhances amino acid deamination at the expense of transamination reactions. This results in increased ammonia production and neuronal damage.
In simulated tests on rats of the 1st months of life set up for the purpose of educing causes accounting for a highly effective utilization of the milk proteins in the early post-natal perions subject to study were the amino acids metabolism rates. An investigation of the enzymes activity showed that a falling of the milk proteins utilization effectiveness proceeds against the background of an intensive inclusion of the catabolic route of the amino acids metabolism in the liver. The urea content in the urine correlated with a gradual inclusion of the enzymatic liver systems partaking in the urine formation. The amino acids metabolism with a ramified chain in the liver tissue of rats of the first days of life was found to stand low to a still greater degree than this was the case in adult animals. One of the causes responsible for a highly effective utilization of the milk proteins in the perinatal period may be due to an incomplete functioning of the catabolic route of the amino acids metabolism in the liver.
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In order to determine the nutritional effects of BCAA compositions in the treatment of cancerous hypoproteinemia, the appropriate ratio of I-leu: Leu: Val and the proportion of BCAA to Total Amino Acids were investigated. As for results, indices such as the serum albumin, the RBP and N-balance quickly recovered to normal levels when the ratio of I-leu: Leu: Val was 1.0:1.8:1.0 and the proportion o BCAA to TAA was 31%. These composition thus may be suitable for the treatment of cancerous hypoproteinemia.
We investigated amino acid metabolism in the Zucker diabetic fatty (ZDF Gmi fa/fa) rat during the prediabetic insulin-resistant stage and the frank type 2 diabetic stage. Amino acids were measured in plasma, liver, and skeletal muscle, and the ratios of plasma/liver and plasma/skeletal muscle were calculated. At the insulin-resistant stage, the plasma concentrations of the gluconeogenic amino acids aspartate, serine, glutamine, glycine, and histidine were decreased in the ZDF Gmi fa/fa rats, whereas taurine, alpha-aminoadipic acid, methionine, phenylalanine, tryptophan, and the 3 branched-chain amino acids were significantly increased. At the diabetic stage, a larger number of gluconeogenic amino acids had decreased plasma concentrations. The 3 branched-chain amino acids had elevated plasma concentrations. In the liver and the skeletal muscles, concentrations of many of the gluconeogenic amino acids were lower at both stages, whereas the levels of 1 or all of the branched-chain amino acids were elevated. These changes in amino acid concentrations are similar to changes seen in type 1 diabetes. It is evident that insulin resistance alone is capable of bringing about many of the changes in amino acid metabolism observed in type 2 diabetes.
Protein synthesis during germination of Bacillus megayerium spores can be divided into two stages. During the first 75 min of germination (Stage I) endogenous nitrogen reserves are sufficient to support protein synthesis, and most amino acids are generated by proteolysis of dormant spore protein. The amino acids produced are excreted initially from the spore, but then reabsorbed and partially utilized for protein synthesis. Significant amino acid metabolism also occurs during Stage I, utilizing enzymes already present in the dormant spore. The biosynthesis of a number of amino acids is low or absent during Stage I due to the absence of biosynthetic enzymes. Subsequently, at defined times in Stage I, these missing enzymes are synthesized and amino acid biosynthesis is initiated. By the beginning of Stage II (from 75 min on) the developing spore has regained the capacity for synthesis of all amino acids and requires an exogenous nitrogen source for rapid protein synthesis.
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Early diagnosis and treatment may prevent brain damage and mental retardation in young infants with inborn errors of amino acid metabolism. The abnormal blood and urinary amino acids and their metabolites are listed in two separate tables in association with each disorder to aid laboratories in making a diagnosis during screening. Because of recent developments and discoveries, more detailed descriptions and diagnostic approaches in phenylketonuria (PKU) variants and urea cycle deficiencies are also presented. The test procedures routinely used for screening inherited metabolic disorders are also described. These include five simple chemical tests to detect excessive metabolites and amino acids; a one dimensional thin layer chromatography (TLC) to screen urine for abnormal amino acid patterns; a two-dimensional TLC for semiquantitative identification of amino acids in both urine and blood; and a high performance liquid chromatographic (HPLC) method for quantitative identification of amino acids. In addition, both one- and two-dimensional chromatographies run on small thin layer cellulose plates, are introduced, modifications which save a great deal of time, labor, and reagents. A new automated HPLC system is introduced for the quantitation of both primary and secondary amino acids; the sensitivity and speed of this system is especially useful for screening large numbers of physiological fluids. It is recommended that both the urine and blood from the same patients be screened to ensure that a diagnosis is not overlooked.
We intended to elucidate an integrated mathematical model of amino acid metabolism and we propose a system for optimization treatment of disturbed metabolic states caused by congenital enzyme deficiencies. Our analysis focused on the metabolic pathway starting at asparaginic acid proceeding to isoleucine, methionine and lysine. The rate of change in the concentration of the biochemical species was expressed as 21 linear rate equations. We obtained the rate constants and the magnitude of feedback from reported experimental data. Linear systems analysis revealed that the metabolic system under study was stable but uncontrollable. These properties were insensitive to changes in the magnitude of feedback. To show the effect of optimizing the feedback so that it minimizes the square of the concentration of the species and the control input, we analyzed the impulse response of the species, transient response and the singular value of the system for four cases; (1) at the physiological state without optimizing the feedback, (2) at the physiological state attained after optimizing the feedback, (3) at the pathophysiological state attained with enzyme deficiency states for lysine and methionine metabolism without optimizing the feedback, and (4) at the pathophysiological state attained after optimizing the feedback for enzyme deficiencies. In the enzyme deficient model, the impulse response oscillated and lasted longer than that in the physiological state. These changes appeared even in the species on other branched pathways. The singular value was elevated in the enzyme deficient state. By optimizing the feedback, all the impulse responses in the enzyme deficient state recovered to nearly those in the normal physiological state. Similarly, the transient response and the singular value in the enzyme deficient state recovered to nearly the normal physiological values. We elucidated the numerical value of the feedback gain for this optimization. The present analysis is useful for the evaluation of the integrated properties of amino acid metabolism and the optimization technique is potentially of use for determining a treatment course for congenital metabolic enzyme deficiencies.
The influence of contractile activity on protein degradation and amino acid metabolism in skeletal muscle was investigated by utilizing an in-vitro electrical stimulation model with the rat epitrochlearis muscle preparation. Graded decreases in contraction force and in the muscle content of ATP and PCr, and increases in lactate were recorded with different rates of stimulation (1 h) and with both isometric twitches and tetanic contractions. 3-Methylhistidine and phenylalanine were chosen as indicators of myofibrillar and total protein degradation, respectively. The release of 3-methylhistidine was significantly stimulated by contractile activity, but a significant increase in the total amount of this amino acid (released amount + tissue content) occurred only at the most intense contraction rates. The release rate, tissue content and total amount of phenylalanine were not influenced by the contractions. Glutamate formation was generally inhibited, but its release was increased. Alanine synthesis was increased in moderately and intensely stimulated muscles. Glutamine and glycine were not influenced by the contractions, however. Inhibition of protein synthesis did not significantly influence protein degradation or amino acid release. The data suggest that in the absence of anabolic factors in the medium, myofibrillar protein degradation is increased in heavily activated muscle. This takes place without total protein breakdown being affected.
Analyses of free amino acids in poplar (Populus gelrica) were carried out throughout a year to see the effect of low temperature on a system regulating amino acid metabolism in the tree. The results indicated that during the wintering phase arginine was the major amino acid both in bark and xylem, particularly in xylem, and that at the time of budding and growing glutamine and glutamate became dominant. Changes in the relative levels of glutamine (plus glutamate) and arginine to the total amino acids of the alpha-ketoglutarate family indicated the presence of a regulatory system annually controlling the synthesis between glutamine (plus glutamate) and arginine. The system appeared to be governed and sensitized by low temperatures. Neither a transition of the synthesis from arginine to glutamine (plus glutamate) nor budding occurred in the poplars which spent the winter months in a greenhouse.
6-Azauridine triacetate (6-AzUrd-TA) administration causes changes in amino acid metabolism both in experimental animals and in man. This effect is dose-related. Amino acid changes caused by 6-AzUrd-TA resemble those in inborn homocystinuria, beta-alaninemia, and hyperhistidinemia. Inhibition of certain enzymes using pyridoxal phosphate as a coenzyme appears to be the common denominator for these changes. There is supportive evidence suggesting that homocystinemia and thrombotic episodes, both caused by 6-AzUrd-TA, are related. These results also reveal that anticancer drugs other than amino acid analogs and amino acid-depleting enzymes may cause significant changes in amino acid metabolism. Their detection and correlation with the therapeutic or adverse effects can be used as an alternative method for studying the relevance of amino acid changes to the treatment of cancer.
The present study evaluates the metabolism of glutamine and glutamate by normal rat kidney (NRK) cells. The major aim was to evaluate the effect of acute acidosis on the metabolism of amino acid and ammonia formation by cultured NRK cells. Experiments at either pH 7.0 or 7.4 were conducted with phosphate-buffered saline supplemented with either 1 mM [5-15N]glutamine, [2-15N]glutamine, or [15N]glutamate. Incubation with either glutamine or glutamate as a precursor showed that production of ammonia and glucose was increased significantly at pH 7.0 vs. 7.4. The disappearance [corrected] of glutamine and glutamate was linear during a 60-min incubation at either pH. In experiments with [5-15N]glutamine, we found that approximately 57 and 43% of ammonia N was derived from 5-N of glutamine at pH 7.4 and 7.0, respectively. Experiments with [2-15N]glutamine or [15N]glutamate indicated that approximately 43 and 47% of 2-N glutamine and glutamate N utilization, respectively, was accounted for by ammonia production at pH 7.0. Similarly, 28 and 29% of NH3 was derived from 2-N of glutamine or glutamate N by activity of glutamate dehydrogenase at pH 7.4. In addition to 15NH3 formation, three major metabolic pathways of [2-15N]glutamine or [15N]glutamate disposal were identified: 1) transamination reactions involving the pH-independent formation of [15N] aspartate and [15N]alanine; 2) the synthesis of [6-15NH2]adenine nucleotide, a process more active at pH 7.4 vs. 7.0; and 3) glutamine synthesis from [15N]glutamate, especially at pH 7.4. The data indicate that NRK cells in culture consume glutamine and glutamate and generate ammonia and various amino acids, depending on the H+ concentration in the media. The studies suggest that these cell lines may provide a useful model for studying various aspects of the effect of pH on rat renal ammoniagenesis.
Between the years 1974 and 1984, amino acid chromatography was performed from dried blood spots and partly from urine of 70 328 neonates. Six cases of phenylketonuria, one histidinaemia, one hyperglycinaemia and three cystinurias were found. Since all these could have been detected by other methods, the regional screening was discontinued in agreement with international recommendations.
Sulphonylureas lower blood glucose but other metabolic effects have been little studied. In an assessment of carbohydrate and amino acid metabolism in 9 patients with non-insulin-dependent diabetes mellitus (NIDDM) before and after 3 months' therapy with gliclazide, glycaemic control was improved (mean +/- S.D. glycosylated haemoglobin 13.8 +/- 1.9% before therapy, 10.2 +/- 2.1% after therapy (p less than 0.01], but fasting amino acid levels were not altered. In contrast, postprandial levels of branched chain amino acids (BCAA) were significantly reduced: total BCAA (valine, leucine, and isoleucine) 120 mins following a standard test meal fell from 717 +/- 71 mumol/l before therapy to 600 +/- 90 mumol/l after 3 months' therapy (p less than 0.01). This finding implies an increased action of endogenous insulin on skeletal muscle to promote uptake of BCAA postprandially and, in accord with this, peripheral insulin levels were significantly increased following drug treatment (peak insulin level 55.6 +/- 20.2 mU/l before therapy, 91.3 +/- 17.9 mU/l after therapy (p less than 0.01]. Sulphonylurea drugs therefore do not simply have a hypoglycaemic action but also affect amino acid metabolism in NIDDM patients.
The impact of diabetes on cyclic nucleotide-associated mechanisms regulating skeletal muscle protein and amino acid metabolism was assessed using epitrochlaris preparations from streptozotocin-induced diabetic rats. 1 nM epinephrine inhibited alanine and glutamine release from control preparations, but no inhibition was observed from diabetic preparations with <0.1 mM. 10 nM epinephrine stimulated lactate production from control muscle but stimulation in diabetic preparations was observed only at 0.1 mM. Serotonin inhibited amino acid release and stimulated lactate production equally in control and diabetic muscle. 0.1 mM epinephrine increased cyclic (c)AMP levels by 360% in control muscles, but these levels were increased only 83% in diabetic muscle. Basal-, fluoride-, and serotonin-stimulated adenylyl cyclase activities were equal in membrane preparations of diabetic and control muscle, but epinephrine-stimulated adenylyl cyclase was reduced by 60% in diabetic muscle. Carbamylcholine stimulation of alanine and glutamine release was blunted in diabetic preparations. Carbamylcholine increased cGMP levels in control but not in diabetic muscle. In diabetic muscle, guanylyl cyclase activity was 65% of control and the stimulation of cyclase activity by sodium azide was less in diabetic than control preparations. Added cGMP stimulated alanine and glutamine release from control, but not from diabetic muscle. These data suggest a loss of adrenergic and cholinergic responsiveness in diabetic muscle. Because amino acid release also showed a decreased responsiveness to added cAMP and cGMP, the presence of other derangements in the mechanism(s) of cyclic nucleotide regulation of muscle amino acid metabolism also seems likely.
The development of the multiorgan dysfunction syndrome, directly determining the severity of the septic process, is characterized by not only inverse ratio of the energy and plastic material, but by metabolic changes which are still unclear and cannot yet be explained. Our purpose was to detect some features of amino acid metabolism in patients with grave sepsis and septic shock. The concentrations of plasma free amino acids were measured on days 1, 3, and 5 in 37 patients with grave sepsis and septic shock. The diagnosis of grave sepsis, septic shock, and organ dysfunction was made proceeding from the criteria defined by R. Bone. The study revealed reliably increased (p < 0.05) levels of arginine, proline, alanine, and the arginine-ornithine index reflecting the direction of arginine transformation in patients with septic shock and grave organ dysfunction (for at least 3 systems). This may be explained by active degradation of endogenous proteins of skeletal muscles, which is characteristic of septic hypermetabolism. Strong correlations were revealed between arginine level and the APACHE-II score (r = 0.57), proline and the same score (r = 0.51), mean arterial pressure and the arginine-ornithine index (r = -0.72), APACHE-II score and the arginine-ornithine index (r = 0.79), arterial lactate and the arginine-ornithine index (r = 0.64). Hence, amino acid metabolism apparently mediates the effects of septic cascade mediators on the following cell.