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At least 757 records · Page 42Linked to original sources
PubMed1983

Insulin release : the fuel concept.

Insulin release evoked by nutrient secretagogues invariably coincides with an increase in the catabolism of exogenous and/or endogenous nutrients in pancreatic islet cells, resulting in an increased generation rate of reducing equivalents and ATP, and an increase in O2 consumption. This situation was documented in response to a number of carbohydrates, including the anomers of D-glucose and D-mannose, various 2-keto acids, including pyruvate and its poorly oxidized phenylated analog 3-phenylpyruvate, and selected amino acids, including the nonmetabolized analog of L-leucine 2-aminobicyclo[2, 2, 1]heptane-2-carboxylic acid. These convergent observations indicate that the B-cell should be considered as a fuel-sensor organ. Further progress in this field requires both the identification of those circulating nutrients used by the B-cell whether in the resting or stimulated state, and a better understanding of the coupling between the generation of second messengers (H+, NAD(P)H, ATP) and more distal events in the secretory sequence, such as the remodelling of ionic fluxes across the plasma membrane and within the pancreatic B-cell.

Amino Acids↗
PubMed1976

Inhibition of pyruvate oxidation by skeletal muscle mitochondria by phenylpyruvate.

1. Phenylpyruvate inhibits pyruvate plus malate oxidation in human and rat skeletal muscle mitochondria in state 3 and in the uncoupled state, it has, however, no effect in state 4. 2. Inhibition by phenylpyruvate of pyruvate oxidation by intact uncoupled rat muscle mitochondria was competitive, with the Ki value about 0.18 mM. 3. It is suggested that the inhibition of pyruvate oxidation is due to the action of phenylpyruvate on muscle pyruvate dehydrogenase, and is the principal cause of the elevated concentration of pyruvate and lactate in blood plasma of phenylketonuric patients.

Animals↗
PubMedDate not supplied

Influence of amino acids upon insulin release evoked by 3-phenylpyruvate.

Insulin release induced by 3-phenylpyruvate in rat pancreatic islets was unaffected by L-norleucine, L-valine, L-alanine and L-asparagine, but potentiated by L-glutamine, glycine and L-serine. The latter two amino acids also enhanced insulin secretion evoked by the combination of 3-phenylpyruvate and L-glutamine. Since 3-phenylpyruvate is known to stimulate insulin release by acting as a transamination partner and facilitating the catabolism of endogenous amino acids, the present findings suggest that the secretory efficiency of such a biochemical sequence depends upon the subcellular location of the transamination reaction and upon the interference of 3-phenylpyruvate with the transport of 2-keto acids into mitochondria.

Amino Acids↗
PubMed1973

Effect of phenylpyruvate on enzymes involved in fatty acid synthesis in rat brain.

1. The effects of azaserine and nicotinamide, agents which inhibit and stimulate hepatic NAD synthesis respectively, on the content of NAD(+) and NADH in isolated rat islets of Langerhans incubated in vitro were studied. The effects of these compounds on the rates of insulin release, from isolated islets incubated in vitro, in response to various secretagogues were also measured. 2. Preincubation of islets in the presence of azaserine (0.3mm) caused a marked depletion of the normal islet-cell content of both NAD(+) and NADH and prevented the secretion of insulin in response to stimulatory concentrations of d-glucose, xylitol, d-xylulose, l-arginine hydrochloride and l-leucine. 3. Preincubation of islets in the presence of nicotinamide (2mm) increased the islet content of NAD(+) and enhanced the rate of release of insulin in response to d-glucose. Also when nicotinamide was present the inhibitory effect of azaserine on insulin release and the azaserine-induced depletion of the islet content of NAD(+) and NADH was prevented. 4. Preincubation with azaserine was without effect on the stimulation of insulin release caused by theophylline or dibutyryl cyclic AMP. 5. It is suggested that insulin release caused by sugars and amino acids is dependent on the maintenance of NAD concentrations, though this may not be the case for release due to theophylline and dibutyryl cyclic AMP.

Journal Article↗
PubMed1985

Glutamine metabolism in isolated perfused rat liver. The transamination pathway.

In isolated perfused rat liver, added 4-methyl-thio-2-oxobutyrate and phenylpyruvate are rapidly transaminated to the corresponding amino acids with glutamine, the latter being supplied via the portal vein or by endogenous synthesis. With portal glutamine concentrations below 5mM and in the presence of a oxo-acid acceptor, the flux through glutamine transaminases exceeded the ammonium ion-stimulated glutaminase flux. 4-Methylthio-2-oxobutyrate-induced extra glutamine uptake was not dependent on the perfusate pH in the range of pH 7 to 8. During glutamine/4-methylthio-2-oxobutyrate transamination, the amide nitrogen of glutamine is fully recovered as glutamate, ammonia, urea and alanine. Oxoglutarate formed by omega-amidase activity is released as glutamate or oxidized by oxoglutarate dehydrogenase. alpha-Cyanocinnamate, the inhibitor of the monocarboxylate translocator in the mitochondrial membrane inhibited 4-methylthio-2-oxobutyrate-induced glutamine uptake and methionine release by about 30%. This might indicate that about 2/3 of glutamine transaminase flux is cytosolic. alpha-Cyanocinnamate inhibited 4-methylthio-2-oxobutyrate-induced glutamate efflux by about 90%. Stimulation of flux through glutamine transaminases is accompanied by a 70-80% inhibition of glutaminase flux. This is not explained by a direct inhibition of glutaminase by 4-methylthio-2-oxobutyrate but by a substrate competition between glutaminase and glutamine transaminases. 4-Methylthio-2-oxobutyrate decreases glutamine release by the liver due to withdrawal by transamination. The oxo acid itself is without effect on glutamine synthetase flux. With respect to hepatocyte heterogeneity there is no evidence for a zonal distribution of glutamine transaminase activities, as it has been shown for glutamine synthetase and glutaminase activities.

Alanine↗
PubMed1992

[Phenylalanine metabolites in hyperphenylalaninemic children].

Phenylalanine and its organic acid derivatives, phenylacetate, mandelic, o-hydroxy-phenylacetate, phenyllactate and phenylpyruvate are increased due to the enzymatic block in the normal pathway of phenylalanine metabolism in phenylketonuric and hyperphenylalaninemic patients. These organic acids are neurotoxic and whether they are responsible for behavior and learning problems in hyperphenylalaninemic children remains to be seen. The purpose of the present study was to evaluate: 1) variations of the organic acid derivatives of phenylalanine during dietary treatment and 2) the usefulness of its determination to further adjust the phenylketonuric diet. Twenty-eight children, ages 4 months to 16 years, were studied. On the same day, the level of phenylalanine in the plasma and phenylalanine metabolites in freshly collected urine samples were tested. Phenylalanine metabolites were detected in some patients with blood phenylalanine levels below 242 microM/L and they rose as levels of blood phenylalanine increased with the phenylpyruvic acid being the highest when blood phenylalanine levels were greater than 424 microM/L. These compounds are usually not detected in normal urine. However, we have or learning problems, thus we do not make further adjustments in the PKU diet on the basis of phenylalanine metabolites.

Adolescent↗
PubMed2005

Dual substrate recognition of aminotransferases.

Pyridoxal 5'-phosphate-dependent aminotransferases reversibly catalyzes the transamination reaction in which the alpha-amino group of amino acid 1 is transferred to the 2-oxo acid of amino acid 2 (usually 2-oxoglutarate) to produce the 2-oxo acid of amino acid 1 and amino acid 2 (glutamate). An aminotransferase must thus be able to recognize and bind two kinds of amino acids (amino acids 1 and 2), the side chains of which are different in shape and properties, from among many other small molecules. The dual substrate recognition mechanism has been discovered based on three-dimensional structures of aromatic amino acids, histidinol phosphate, glutamine:phenylpyruvate, acetylornithine, and branched-chain amino acid aminotransferases. There are two representative strategies for dual substrate recognition. An aromatic amino acid aminotransferase prepares charged and neutral pockets for acidic and aromatic side chains, respectively, at the same place by a large-scale rearrangement of the hydrogen-bond network caused by the induced fit. In a branched-chain aminotransferase, the same hydrophobic cavity implanted with hydrophilic sites accommodates both hydrophobic and acidic side chains without side-chain rearrangements of the active-site residues, which is reminiscent of the lock and key mechanism. Dual substrate recognition in other aminotransferases is attained by combining the two representative methods.

Amino Acids↗
PubMed1975

Permanent chemical phenylketonuria and a normal phenylalanine tolerance in two sisters with a normal mental development.

A positive ferric chloride reaction was found at routine examination of the urine of a 14 year old mentally normal girl, admitted for complaints of headache and other meningitis-like symptoms. It turned out that she excreted permanently increased amounts of phenylpyruvic, phenyllactic and o-hydroxyphenylacetic acids, but phenylacetic acid (free plus conjugated) was normal. Fasting serum phenylalanine was not increased nor was urinary phenylalanine. On loading with L-phenylalanine (100 mg/kg) a normal serum phenylalanine response followed, but urinary phenylpyruvic, phenyllactic and o-hydroxyphenylacetic acids increased further. Phenylacetic acid responded too, but remained in the normal range. In addition to the above-mentioned abnormalities the urine contained a still unidentified abnormal acid, which also increased after loading with phenylalanine. Her 12 year old healthy sister showed the same chemical abnormality. Two older brothers and the parents had normal excretions. The enzyme defect has not been identified. As a possibility the defective decarboxylation of phenylpyruvic acid is proposed.

Adolescent↗
PubMedDate not supplied

Enhanced conversion rate of L-phenylalanine by coupling reactions of aminotransferases and phosphoenolpyruvate carboxykinase in Escherichia coli K-12.

In Escherichia coli, aspartate aminotransferase (encoded by aspC) and aromatic amino acid aminotransferase (encoded by tyrB) share overlapping substrate specificity in the syntheses of aromatic amino acids. Through the transamination reactions catalyzed by AspC or TyrB, L-phenylalanine (L-Phe) can be produced from phenylpyruvate with aspartic acid as the amino donor. To modulate and enhance the production levels of proteins, both aspC and tyrB were subcloned into a runaway-replication vector. As a result, the specific activities of AspC and TyrB obtained showed 65-fold and 50-fold increases, respectively, compared with the wild-type level. Employing resting cells of AspC- and TyrB-overproducing E. coli K-12 strains for L-Phe productions resulted in molar conversion yields of 70% and 55%, respectively. With an additional introduction of phosphoenolpyruvate carboxykinase (encoded by pck) into the transamination reactions, the conversion yields were improved to 93% from 70% and to 75% from 55% in a relatively short time. These results account for more than an 8-fold increase in productivity, as compared to the previous report (Calton et al., 1985). In addition, a four-run reuse of the recombinant cells for L-Phe production gave a total yield of 91 g/L with a 93% conversion.

Aspartate Carbamoyltransferase↗