Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:4.1.1.32 (phosphoenolpyruvate carboxykinase)
4,204 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have determined the crystal structure of Mn2+-bound Escherichia coli phosphoenolpyruvate carboxylase (PEPC) using X-ray diffraction at 2.6 A resolution, and specified the location of enzyme-bound Mn2+, which is essential for catalytic activity. The electron density map reveals that Mn2+ is bound to the side chain oxygens of Glu-506 and Asp-543, and located at the top of the alpha/beta barrel in PEPC. The coordination sphere of Mn2+ observed in E. coli PEPC is similar to that of Mn2+ found in the pyruvate kinase structure. The model study of Mn2+-bound PEPC complexed with phosphoenolpyruvate (PEP) reveals that the side chains of Arg-396, Arg-581 and Arg-713 could interact with PEP.
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PMID:Plausible phosphoenolpyruvate binding site revealed by 2.6 A structure of Mn2+-bound phosphoenolpyruvate carboxylase from Escherichia coli. 1048 Oct 43

Biotin causes improvements in disordered glucose metabolism by stimulating glucose-induced insulin secretion in pancreatic beta-cells and by accelerating glycolysis in liver and pancreas. Biotin is known to regulate hepatic and pancreatic glucokinase expression at both transcriptional and translational levels, and to regulate hepatic phosphoenolpyruvate carboxykinase expression at the transcriptional level. The effects of biotin on glucose-induced insulin secretion were investigated using the method of isolated pancreas perfusion. The pancreas of the biotin-deficient rat has an impaired insulin response to both glucose and arginine. In control rats as well as biotin-deficient rats, the insulin response to glucose stimulation was enhanced by the addition of 1 mM biotin to the perfusate. Biotin-induced enhancement of glucose-induced insulin release was evident within the first few minutes of perfusion. Since any effects on the glucokinase synthesis pathway would not be seen for at least 30 minutes, these results indicate that biotin may have the ability to act directly on the insulin secreting function of pancreatic beta-cells. Biotin perfusion was not found to cause enhancement of the arginine-induced insulin response, suggesting that biotin has no significant effects on the distal portion of the signaling pathway involved in insulin secretion. These results indicate that the administration of a high concentrations of biotin may improve the metabolism and/or utilization of glucose in patients with non-insulin-dependent diabetes mellitus.
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PMID:[Enhancement of glucose-induced insulin secretion and modification of glucose metabolism by biotin]. 1054 Aug 72

Arginine (Arg), injected intraperitoneally into rainbow trout (Oncorhynchus mykiss), increases plasma concentrations of glucagon, glucagon-like peptide-1 (GLP-1), and insulin by three- to 10-fold. Resulting ratios of glucagon and GLP-1 over insulin are unchanged in 20-d food-deprived fish (saline, 1.28 vs. Arg, 0.93; not significant) while slightly increased in feeding trout (saline, 0.70 vs. Arg, 0.92; P<0.05). In food-deprived juveniles, Arg injection leads to significant decreases in plasma fatty acids (saline, 1.65 mM L(-1) vs. Arg, 1.09 mM L(-1); P<0.05) and increases in glycogen phosphorylase total activity (saline, 3.7 units g(-1) vs. Arg, 4.6 units g(-1); P<0.05) and degree of phosphorylation (saline, 1.7 units g(-1) vs. Arg, 2.33 units g(-1); P<0.05). Plasma and liver glucose and liver enzymes (glucose-6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase, pyruvate kinase, phosphoenolpyruvate carboxykinase, lactate dehydrogenase, and malic enzyme) are unaffected. Otherwise, fish show the changes in plasma metabolites expected with food deprivation. Arg injection into feeding fish results in decreases in plasma fatty acids, liver glycogen, and glucose, while liver glucose 6-phosphate concentrations increase. Hepatocytes isolated from feeding fish injected with Arg 2 h previously show significantly lower rates of lactate oxidation than controls (85% of control), while rates of gluconeogenesis and hormonal responses to mammalian glucagon and GLP-1 remain unchanged. Rates of lactate oxidation and gluconeogenesis are significantly decreased by 5%-10% on treatment with porcine insulin. Complete immunoneutralization of insulin with rabbit antisalmon insulin serum decreases hepatic glucose 6-phosphate concentrations and abolishes the Arg-dependent effects on glycogen phosphorylase. It appears that short-term increases in pancreatic hormones cause only minor metabolic readjustments in the relatively short time frame covered in these experiments. Surprisingly, complete removal of insulin does not have immediate altering or detrimental effects on key metabolites and metabolic pathways, even if glucagon and GLP-1 concentrations are concurrently several-fold higher than usual. Our data clearly show the dual role of Arg in fish metabolism.
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PMID:Effects of arginine on pancreatic hormones and hepatic metabolism in rainbow trout. 1151 52

In Methanothermobacter thermautotrophicus, oxaloacetate synthesis is a major and essential CO(2)-fixation reaction. This methanogenic archaeon possesses two oxaloacetate-synthesizing enzymes, pyruvate carboxylase and phosphoenolpyruvate carboxylase. The phosphoenolpyruvate carboxylase from this organism was purified to homogeneity. The subunit size of this homotetrameric protein was 55 kDa, which is about half that of all known bacterial and eukaryotic phosphoenolpyruvate carboxylases (PPCs). The NH(2)-terminal sequence identified this enzyme as the product of MTH943, an open reading frame with no assigned function in the genome sequence. A BLAST search did not show an obvious sequence similarity between MTH943 and known PPCs, which are generally well conserved. This is the first report of a new type of phosphoenolpyruvate carboxylase that we call PpcA ("A" for "archaeal"). Homologs to PpcA were present in most archaeal genomic sequences, but only in three bacterial (Clostridium perfringens, Oenococcus oeni, and Leuconostoc mesenteroides) and no eukaryotic genomes. PpcA was the only recognizable oxaloacetate-producing enzyme in Methanopyrus kandleri, a hydrothermal vent organism. Each PpcA-containing organism lacked a PPC homolog. The activity of M. thermautotrophicus PpcA was not influenced by acetyl coenzyme A and was about 50 times less sensitive to aspartate than the Escherichia coli PPC. The catalytic core (including His(138), Arg(587), and Gly(883)) of the E. coli PPC was partly conserved in PpcA, but three of four aspartate-binding residues (Lys(773), Arg(832), and Asn(881)) were not. PPCs probably evolved from PpcA through a process that added allosteric sites to the enzyme. The reverse is also equally possible.
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PMID:The phosphoenolpyruvate carboxylase from Methanothermobacter thermautotrophicus has a novel structure. 1526 49

The regulatory properties of maize phosphoenolpyruvate carboxylase were significantly altered by site-directed mutagenesis of residues 226 through 232. This conserved sequence element, RTDEIRR, is part of a surface loop at the dimer interface. Mutation of individual residues in this sequence caused various kinetic changes, including desensitization of the enzyme to key allosteric effectors or alteration of the K(0.5 PEP) for the substrate phosphoenolpyruvate. R231A, and especially R232Q, displayed decreased apparent affinity for the activator glucose-6-phosphate. Apparent affinity for the activator glycine was reduced in D228N and R232Q, while the maximum activation caused by glycine was greatly reduced in R226Q and E229A. R226Q and E229A also showed significantly lower sensitivity to the inhibitors malate and aspartate. E229A exhibited a low K(0.5 PEP), while the K(0.5 PEP )of R232Q was significantly higher than that of wild type. Thus these seven residues are critical determinants of the enzyme's kinetic responses to activators, inhibitors and substrate. The present results support an earlier suggestion that Arg 231 contributes to the binding site of the allosteric activator glucose-6-phosphate, and are consistent with other proposals that the substrate phosphoenolpyruvate allosterically activates the enzyme by binding at or near the glucose-6-phosphate site. The results also suggest that the glycine binding site may be contiguous with the glucose-6-phosphate binding site. Glu 229, which extends from this interface region through the interior of the protein and emerges near the aspartate binding site, may provide a physical link for propagating conformational changes between the allosteric activator and inhibitor binding regions.
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PMID:The regulatory role of residues 226-232 in phosphoenolpyruvate carboxylase from maize. 1645 61

To study the importance of arginine provision and phosphate limitation for synthesis and accumulation of cyanophycin (CGP) in Acinetobacter sp. strain ADP1, genes encoding the putative arginine regulatory protein (argR) and the arginine succinyltransferase (astA) were inactivated, and the effects of these mutations on CGP synthesis were analyzed. The inactivation of these genes resulted in a 3.5- or 7-fold increase in CGP content, respectively, when the cells were grown on glutamate. Knockout mutations in both genes led to a better understanding of the effect of the addition of other substrates to arginine on CGP synthesis during growth of the cells of Acinetobacter sp. strain ADP1. Overexpression of ArgF (ornithine carbamoyltransferase), CarA-CarB (small and large subunits of carbamoylphosphate synthetase), and PepC (phosphoenolpyruvate carboxylase) triggered synthesis of CGP if amino acids were used as a carbon source whereas it was not triggered by gluconate or other sugars. Cells of Acinetobacter sp. strain ADP1, which is largely lacking genes for carbohydrate metabolism, showed a significant increase in CGP contents when grown on mineral medium supplemented with glutamate, aspartate, or arginine. The Acinetobacter sp. DeltaastA(pYargF) strain is unable to utilize arginine but synthesizes more arginine, resulting in CGP contents as high as 30% and 25% of cell dry matter when grown on protamylasse or Luria-Bertani medium, respectively. This recombinant strain overcame the bottleneck of the costly arginine provision where it produces about 75% of the CGP obtained from the parent cells grown on mineral medium containing pure arginine as the sole source of carbon. Phosphate starvation is the only known trigger for CGP synthesis in this bacterium, which possesses the PhoB/PhoR phosphate regulon system. Overexpression of phoB caused an 8.6-fold increase in CGP content in comparison to the parent strain at a nonlimiting phosphate concentration.
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PMID:Engineering the genotype of Acinetobacter sp. strain ADP1 to enhance biosynthesis of cyanophycin. 1646 94

Nitric oxide (NO) is synthesized from L-arginine by NO synthase in virtually all cell types. Emerging evidence shows that NO regulates the metabolism of glucose, fatty acids and amino acids in mammals. As an oxidant, pathological levels of NO inhibit nearly all enzyme-catalyzed reactions through protein oxidation. However, as a signaling molecule, physiological levels of NO stimulate glucose uptake as well as glucose and fatty acid oxidation in skeletal muscle, heart, liver and adipose tissue; inhibit the synthesis of glucose, glycogen, and fat in target tissues (e.g., liver and adipose); and enhance lipolysis in adipocytes. Thus, an inhibition of NO synthesis causes hyperlipidemia and fat accretion in rats, whereas dietary arginine supplementation reduces fat mass in diabetic fatty rats. The putative underlying mechanisms may involve multiple cyclic guanosine-3',5'-monophosphate-dependent pathways. First, NO stimulates the phosphorylation of adenosine-3',5'-monophosphate-activated protein kinase, resulting in (1) a decreased level of malonyl-CoA via inhibition of acetyl-CoA carboxylase and activation of malonyl-CoA decarboxylase and (2) a decreased expression of genes related to lipogenesis and gluconeogenesis (glycerol-3-phosphate acyltransferase, sterol regulatory element binding protein-1c and phosphoenolpyruvate carboxykinase). Second, NO increases the phosphorylation of hormone-sensitive lipase and perilipins, leading to the translocation of the lipase to the neutral lipid droplets and, hence, the stimulation of lipolysis. Third, NO activates expression of peroxisome proliferator-activated receptor-gamma coactivator-1alpha, thereby enhancing mitochondrial biogenesis and oxidative phosphorylation. Fourth, NO increases blood flow to insulin-sensitive tissues, promoting substrate uptake and product removal via the circulation. Modulation of the arginine-NO pathway through dietary supplementation with L-arginine or L-citrulline may aid in the prevention and treatment of the metabolic syndrome in obese humans and companion animals, and in reducing unfavorable fat mass in animals of agricultural importance.
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PMID:Regulatory role for the arginine-nitric oxide pathway in metabolism of energy substrates. 1652 13

Isolated cells from leaves of Spinacia oleracea have been maintained in a state capable of high rates of photosynthetic CO(2) fixation for more than 60 hours. The incorporation of (14)CO(2) under saturating CO(2) conditions into carbohydrates, carboxylic acids, and amino acids, and the effect of ammonia on this incorporation have been studied. Total incorporation, specific radioactivity, and pool size have been determined as a function of time for most of the protein amino acids and for gamma-aminobutyric acid. The measurements of specific radio-activities and of the approaches to (14)C "saturation" of some amino acids indicate the presence and relative sizes of metabolically active and passive pools of these amino acids.Added ammonia decreased carbon fixation into carbohydrates and increased fixation into carboxylic acids and amino acids. Different amino acids were, however, affected in different and highly specific ways. Ammonia caused large stimulatory effects in incorporation of (14)C into glutamine (a factor of 21), aspartate, asparagine, valine, alanine, arginine, and histidine. No effect or slight decreases were seen in glycine, serine, phenylalanine, and tyrosine labeling. In the case of glutamate, (14)C labeling decreased, but specific radioactivity increased. The production of labeled gamma-aminobutyric acid was virtually stopped by ammonia.The results indicate that added ammonia stimulates the reactions mediated by pyruvate kinase and phosphoenolpyruvate carboxylase, as seen with other plant systems. The data on the effects of added ammonia on total labeling, pool sizes, and specific radioactivities of several amino acids provides a number of indications about the intracellular sites of principal synthesis from carbon skeletons of these amino acids and the selective nature of effects of increased intracellular ammonia concentration on such synthesis.
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PMID:Amino Acid Synthesis in Photosynthesizing Spinach Cells : EFFECTS OF AMMONIA ON POOL SIZES AND RATES OF LABELING FROM CO(2). 1666 4

Phosphenolpyruvate (PEP) carboxylase from leaves of Crassula argentea displays varying levels of sensitivity to inactivation by various proteolytic enzymes. In general, the native enzyme is sensitive to proteinases known to attack at the carbonyl end of lysine or arginine (trypsin, papain, or bromelain). The ineffective proteolytic enzymes are those which have low specificity or which attack at the N-terminal end of hydrophobic amino acids, or which cannot attack lysine. The lack of an effect of endoproteinase arginine C, which is specific for arginine, probably indicates that lysine is the critical residue. When the native enzyme, which is comprised of an equilibrium of dimers with tetramers in approximately equal quantities, is treated by preincubation with 5 millimolar PEP, the enzyme becomes much more resistant to proteolytic inactivation. When the preincubation is with 5 millimolar malate rather than buffer alone, the effect is to slightly increase (ca. 15%) the sensitivity of the enzyme to inactivation by trypsin as measured by estimates of the pseudo-first order rate constant for inactivation. PEP carboxylase from corn leaves appears to be relatively susceptible to inactivation by trypsin, but is unaffected by preincubation with malate or PEP. The sensitivity of this C(4) enzyme to inhibition by malate is also unaffected by preincubation with these ligands.
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PMID:Oligomerization and the sensitivity of phosphoenolpyruvate carboxylase to inactivation by proteinases. 1666 31

This work demonstrates a novel computational approach combining flux balance modeling with statistical methods to identify correlations among fluxes in a metabolic network, providing insight as to how the fluxes should be redirected to achieve maximum product yield. The procedure is demonstrated using the example of amino acid production from an industrial Escherichia coli production strain and a hypothetical engineered strain overexpressing two heterologous genes. Regression analysis based on a random sampling of 5,000 points within the feasible solution space of the E. coli stoichiometric network suggested that increased activity of the glyoxylate cycle or PEP carboxylase and elimination of malic enzyme will improve lysine and arginine synthesis.
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PMID:Theoretical analysis of amino acid-producing Escherichia coli using a stoichiometric model and multivariate linear regression. 1695 34


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