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PubMed2000

Liver hyperplasia and paradoxical regulation of glycogen metabolism and glucose-sensitive gene expression in GLUT2-null hepatocytes. Further evidence for the existence of a membrane-based glucose release pathway.

We investigated the impact of GLUT2 gene inactivation on the regulation of hepatic glucose metabolism during the fed to fast transition. In control and GLUT2-null mice, fasting was accompanied by a approximately 10-fold increase in plasma glucagon to insulin ratio, a similar activation of liver glycogen phosphorylase and inhibition of glycogen synthase and the same elevation in phosphoenolpyruvate carboxykinase and glucose-6-phosphatase mRNAs. In GLUT2-null mice, mobilization of glycogen stores was, however, strongly impaired. This was correlated with glucose-6-phosphate (G6P) levels, which remained at the fed values, indicating an important allosteric stimulation of glycogen synthase by G6P. These G6P levels were also accompanied by a paradoxical elevation of the mRNAs for L-pyruvate kinase. Re-expression of GLUT2 in liver corrected the abnormal regulation of glycogen and L-pyruvate kinase gene expression. Interestingly, GLUT2-null livers were hyperplasic, as revealed by a 40% increase in liver mass and 30% increase in liver DNA content. Together, these data indicate that in the absence of GLUT2, the G6P levels cannot decrease during a fasting period. This may be due to neosynthesized glucose entering the cytosol, being unable to diffuse into the extracellular space, and being phosphorylated back to G6P. Because hepatic glucose production is nevertheless quantitatively normal, glucose produced in the endoplasmic reticulum may also be exported out of the cell through an alternative, membrane traffic-based pathway, as previously reported (Guillam, M.-T., Burcelin, R., and Thorens, B. (1998) Proc. Natl. Acad. Sci. U. S. A. 95, 12317-12321). Therefore, in fasting, GLUT2 is not required for quantitative normal glucose output but is necessary to equilibrate cytosolic glucose with the extracellular space. In the absence of this equilibration, the control of hepatic glucose metabolism by G6P is dominant over that by plasma hormone concentrations.

Animals↗
PubMed1993

Control of gluconeogenic growth by pps and pck in Escherichia coli.

It is well-known that Escherichia coli grows more slowly on gluconeogenic carbon sources than on glucose. This phenomenon has been attributed to either energy or monomer limitation. To investigate this problem further, we varied the expression levels of pck, encoding phosphoenolpyruvate carboxykinase (Pck), and pps, encoding phosphoenolpyruvate synthase (Pps). We found that the growth rates of E. coli in minimal medium supplemented with succinate and with pyruvate are limited by the levels of Pck and Pps, respectively. Optimal overexpression of pck or pps increases the unrestricted growth rates on succinate and on pyruvate, respectively, to the same level attained by the wild-type growth rate on glycerol. Since Pps is needed to supply precursors for biosyntheses, we conclude that E. coli growing on pyruvate is limited by monomer supply. However, because pck is required both for biosyntheses and catabolism for cells growing on succinate, it is possible that growth on succinate is limited by both monomer and energy supplies. The growth yield with respect to oxygen remains approximately constant, even though the overproduction of these enzymes enhances gluconeogenic growth. It appears that the constant yield for oxygen is characteristic of efficient growth on a particular substrate and that the yield is already optimal for wild-type strains. Further increases in either Pck or Pps above the optimal levels become growth inhibitory, and the growth yield for oxygen is reduced, indicating less efficient growth.

Escherichia coli↗
PubMed1985

Metabolic characterization of three hamster melanoma variants.

Some enzyme activities and metabolic features of the black Ma melanotic, brown MI melanotic and Ab amelanotic melanomas of hamster were investigated. The activities of hexokinase and phosphofructokinase were similar in all three melanomas, the activity of NAD-dependent glycerol-3-phosphate dehydrogenase was higher in the amelanotic melanoma and that of pyruvate kinase and lactate dehydrogenase were slightly lower in MI than in the other tumors. The activities of citrate synthase, succinate dehydrogenase and malate dehydrogenase were higher in the Ma and MI melanotic melanomas than in the Ab amelanotic melanoma. The rate of labeled CO2 production from 6-14C-glucose, 1,5-14C-citric acid and U-14C-glutamine was about 2 times higher in melanotic melanomas than in amelanotic one, while no significant differences among the three melanomas were found in respect to 1-14C-glucose and U-14C-glycerol-3-phosphate. The production of 14CO2 was much higher from 1-14C-glucose than from 6-14C-glucose in all the melanomas studied. L-DOPA stimulated the production of 14CO2 from 1-14C-glucose much stronger in the Ma and MI melanomas than in the Ab melanoma. In none of the tumors the incorporation from 6-14C-glucose to CO2 was affected by L-DOPA. It is postulated that oxidation of glucose via the pentose phosphate cycle is involved in melanogenesis.

Animals↗
PubMed1999

Metabolic acidosis inhibits pyruvate oxidation in chick liver by decreasing activity of pyruvate dehydrogenase complex.

Replacement of drinking water with NH4Cl (1.5%) solution significantly reduced blood pH on the 2nd d in chicks and thereafter. Concomitant with this reduction, oxidation rate of state 3 with pyruvate in liver mitochondria was also decreased in acidotic animals when compared with control animals. No significant differences between the two groups were observed in the state 4 oxidation at any feeding period. The ADP/O ratio did not appear to be affected by the treatment. The successive experiments of gavage-feeding for 4 d were also employed to ensure an equivalent intake of diet and the amount of NH4Cl given. As a result, the higher the NH4Cl provided, the lower the oxidation rate of state 3 with pyruvate in liver mitochondria, and the actual activity of pyruvate dehydrogenase complex, as expressed as units of produced CO2 per g wet weight of liver, which were accompanied by the lower pH in blood. This study provides the first evidence for a critical role of pyruvate dehydrogenase complex in the regulation of pyruvate catabolism in the liver from acidotic chicks induced by NH4Cl.

Acidosis↗
PubMed1976

Does hyperinsulinemia in ob/ob mice cause an insulin-stimulated adipose tissue?

After a 1-h preincubation to remove endogenous insulin, adipose tissue of obese mice (C57BL/L4 ob/ob) had a lower rate of glucose metabolism than tissue which was not preincubated. In contrast, preincubation did not change the metabolism of adipose tissue from lean mice (C57B1/6J +/+). The preincubation effect was abolished in obese mice which had had their serum insulin levels lowered toward normal by streptozotocin treatment. Injection of anti-insulin serum to obese mice caused adipose tissue removed 15 min after the injection to display a rate of glucose metabolsim lower than that of tissue removed before the injection. No such effect was seen in lean mice. These data are consistent with the hypothesis that hyperinsulinemia in the obese mice causes a chronic state of insulin stimulation of their adipose tissue, possibly contributing to their high rates of lipogenesis and their obesity. Several lipogenic enzymes were measured in adipose tissue of both lean and obese mice, and no single enzymatic abnormality was detected which might explain the hyperlipogenesis. Pyruvate dehydrogenase and acetyl-CoA carboxylase were both insulin-sensitive enzymes in lean and obese mice.

ATP Citrate (pro-S)-Lyase↗
PubMed1977

Enzyme alteration in skeletal muscle of mice with muscular dystrophy.

1. Developmental enzyme alterations were investigated in skeletal muscle of the hereditary progressive muscular dystrophy (PMD) mice of C57BL/6J strain. 2. Enzymes examined were classified into three groups according to changes of activities in dystrophy muscle during ageing. Activities of creatine kinase (EC 2.7.3.2), pyruvate kinase (EC 2.7.1.40), glycogen phosphorylase (EC 2.4.1.1), and fructose-biphosphate aldolase (EC 4.1.2.13), each of which had the respective muscle specific isoenzyme of extremely high activity in normal adult skeletal muscle, decreased rapidly in dystrophy muscle from the early stage of the disease with ageing. Activities of glycogen synthase (EC 2.4.1.11) and hexokinase (EC 2.7.1.1) were higher in dystrophy muscle in the early stage but decreased gradually to lower levels than those in the control with ageing. Activities of glucose-6-phosphate dehydrogenase (EC 1.1.1.49) were always much higher in dystrophy muscle than in the control, with no relation to ageing. 3. Isoenzymes of creatine kinase, pyruvate kinase and phosphorylase in dystrophy muscle were mainly the muscle types, indicating that muscle differentiation was not blocked profoundly even in dystrophy muscle. In limited cases, especially in the early stage of the disease, very weak activities of the non-muscle fetal type isoenzymes of creatine kinase and phosphorylase were detected, apparently associated with partial muscle regeneration in dystrophy muscle.

Aging↗
PubMed2003

Phylogenomic analysis of the Giardia intestinalis transcarboxylase reveals multiple instances of domain fusion and fission in the evolution of biotin-dependent enzymes.

Sequencing of the gene encoding a pyruvate carboxylase-like protein from the amitochondrial eukaryote Giardia intestinalis revealed a 1,338 aa protein composed of acetyl-CoA carboxyltransferase (ACCT), pyruvate carboxyltransferase (PycB), and biotin carboxyl carrier protein (BCCP) domains, linked in a single polypeptide chain. This particular domain combination has been previously seen only in the methylmalonyl-CoA:pyruvate transcarboxylase from Propionibacterium freudenreichii, where each of these domains is encoded by an individual gene and forms a separate subunit. To get an insight into the evolutionary origin and biochemical function of the G. intestinalis enzyme, we compared its domain composition to those of other biotin-dependent enzymes and performed a phylogenetic analysis of each of its domains. The results obtained indicate that: (1) evolution of the BCCP domain included several domain fusion events, leading to the ACCT-BCCP and PycB-BCCP domain combinations; (2) fusions of the PycB and BCCP domains in pyruvate carboxylases and oxaloacetate decarboxylases occurred on several independent occasions in different prokaryotic lineages, probably due to selective pressure towards co-expression of these genes, and (3) because newly sequenced biotin-dependent enzymes are often misannotated in sequence databases, their annotation as either carboxylases, decarboxylases, or transcarboxylases has to rely on detailed analysis of their domain composition, operon organization of the corresponding genes, gene content in the particular genome, and phylogenetic analysis.

Acetyl-CoA Carboxylase↗
PubMed2005

Neuronal nitric oxide synthase controls enzyme activity pattern of mitochondria and lipid metabolism.

Mitochondria are affected by endogenous nitric oxide (NO). Besides effects of NO on mitochondrial enzymes and the stimulation of mitochondrial H2O2 production, a NO-dependent increase in mitochondrial biogenesis in several tissues has been reported. It is still obscure whether NO generated by one specific or different NO synthase (NOS) isoenzymes determine such effects. Therefore, we analyzed the amount of mitochondria, respiratory chain enzyme complexes, and citrate synthase in the brain, muscle, heart, kidney, and liver by comparing wild-type (WT) mice and mice lacking the neuronal nitric oxide synthase isoform (nNOS-KO). Our results show that the activities of NADH:cytochrome c oxidoreductase and succinate cytochrome c oxidoreductase differ between WT and nNOS-KO mice. However, similar quantities of mitochondria were found in the homogenates of tissues in WT and nNOS-KO animals. Most impressive, higher activities and protein of citrate synthase were found in the brain, muscle, heart, kidney, and liver of nNOS-KO mice. Additionally, higher contents of fatty acid synthase and lipids were determined in the livers of nNOS-KO mice but not in the heart and brain. Furthermore, liver mitochondria from nNOS-KO mice consumed pyruvate at a higher rate and released more citric acid. Our data document a previously unrecognized role of endogenous NO in the regulation of lipid metabolism.

Animals↗
PubMed1962

Glycolate metabolism in Escherichia coli.

Hansen, Robert W. (University of Illinois College of Medicine, Chicago) and James A. Hayashi. Glycolate metabolism in Escherichia coli. J. Bacteriol. 83:679-687. 1962.-This study of glycolate-adapted Escherichia coli indicates that the most probable route for utilization of the substrate includes glyceric acid, 3-phosphoglyceric acid, and the tricarboxylic acid cycle. A glyceric acid dehydrogenase, which reduces tartronic semialdehyde to glycerate in the presence of reduced diphosphopyridine nucleotide, and a kinase, which catalyzes the formation of 3-phosphoglycerate from glyceric acid and adenosine triphosphate, were shown to be present. Carbon recoveries in growing cultures and manometric data obtained with resting cells showed the complete oxidation of glycolate to carbon dioxide. Measurements of the oxidation of tricarboxylic acid cycle intermediates indicated that these compounds are oxidized without lag and at a rate commensurate with the rate of glycolate oxidation. Assays of the enzymes characteristic of known pathways of terminal oxidation, such as isocitratase, malate synthetase, isocitric dehydrogenase, and condensing enzyme, provided further evidence for an operating tricarboxylic acid cycle. A postulated pathway for the utilization of glycolic acid is as follows: glycolate --> glycerate --> 3-phosphoglycerate --> pyruvate --> tricarboxylic acid cycle.

Acetates↗
PubMed1985

Cerebral citric acid cycle enzymes in methionine sulfoximine toxicity.

The activity levels of pyruvate dehydrogenase, enzymes of the citric acid cycle, aspartate and alanine aminotransferases, and NADP+-isocitrate dehydrogenase were determined in the cerebral cortex, cerebellum, brain stem, corpus striatum, hippocampus, and midbrain regions of normal rats and rats injected with acute and subacute doses of methionine sulfoximine (MSI). In both conditions there was an elevation in the activities of pyruvate dehydrogenase and all the enzymes of the citric acid cycle except malate dehydrogenase, whereas the activities of aminotransferases and NADP+-isocitrate dehydrogenase were suppressed in all the cerebral regions. It is suggested that the operational rates of the citric acid cycle would be enhanced in MSI-induced hyperammonemia and that there might be a derangement in the transport of reducing equivalents across mitochondrial membranes. It has been suggested that the convulsant action of the drug is due to its effects on ionic gradients and may not be due to depletion of alpha-ketoglutarate from the citric acid cycle.

Animals↗
PubMed2006

Hypothalamic malonyl-CoA triggers mitochondrial biogenesis and oxidative gene expression in skeletal muscle: Role of PGC-1alpha.

Previous investigations show that intracerebroventricular administration of a potent inhibitor of fatty acid synthase, C75, increases the level of its substrate, malonyl-CoA, in the hypothalamus. The "malonyl-CoA signal" is rapidly transmitted to skeletal muscle by the sympathetic nervous system, increasing fatty acid oxidation, uncoupling protein-3 (UCP3) expression, and thus, energy expenditure. Here, we show that intracerebroventricular or intraperitoneal administration of C75 increases the number of mitochondria in white and red (soleus) skeletal muscle. Consistent with signal transmission from the hypothalamus by the sympathetic nervous system, centrally administered C75 rapidly (< or =2 h) up-regulated the expression (in skeletal muscle) of the beta-adrenergic signaling molecules, i.e., norepinephrine, beta3-adrenergic receptor, and cAMP; the transcriptional regulators peroxisomal proliferator activator regulator gamma coactivator 1alpha (PGC-1alpha) and estrogen receptor-related receptor alpha (ERRalpha); and the expression of key oxidative mitochondrial enzymes, including pyruvate dehydrogenase kinase, medium-chain length fatty acyl-CoA dehydrogenase, ubiquinone-cytochrome c reductase, cytochrome oxidase, as well as ATP synthase and UCP3. The role of PGC-1alpha in mediating these responses in muscle was assessed with C2C12 myocytes in cell culture. Consistent with the in vivo response, adenovirus-directed expression of PGC-1alpha in C2C12 muscle cells provoked the phosphorylation/inactivation and reduced expression of acetyl-CoA carboxylase 2, causing a reduction of the malonyl-CoA concentration. These effects, coupled with an increased carnitine palmitoyltransferase 1b, led to increased fatty acid oxidation. PGC-1alpha also increased the expression of ERRalpha, PPARalpha, and enzymes that support mitochondrial fatty acid oxidation, ATP synthesis, and thermogenesis, apparently mediated by an increased expression of UCP3.

4-Butyrolactone↗
PubMed1987

Interaction between insulin and thyroid hormones on the control of carbohydrate and lipid metabolism in rat adipose tissue.

Adipose tissue segments excised from normal rats and from rats rendered experimentally hypothyroid and hyperthyroid retained insulin responsiveness when studied in vitro. Basal rates of glucose oxidation to CO2, conversion into glyceride-glycerol, fatty acids, and total lipids, and the activities of pyruvate dehydrogenase and fatty acid synthetase were enhanced in fat pads from hyperthyroid rats when compared with values seen with tissue from euthyroid animals. The response of each of these parameters was further enhanced by treating tissue from hyperthyroid rats in vitro with insulin. Basal rates of glucose oxidation and the activities of pyruvate dehydrogenase and fatty acid synthetase were depressed as a result of hypothyroidism. However, all of these values could be restored to levels approaching the values seen in the basal state for euthyroid rats when tissue segments from hypothyroid rats were incubated in vitro with insulin. The basal rates for glucose conversion into glyceride-glycerol, fatty acids, and total lipids were not changed by hypothyroidism but retained insulin responsiveness. These data suggest that the insulin-effector system in adipose tissue is not altered by thyroid status and that thyroid hormones may act independently with insulin to regulate glucose and lipid metabolism in this tissue at multiple intracellular metabolic sites.

Adipose Tissue↗
PubMed2004

NADH augments blood flow in physiologically activated retina and visual cortex.

The mechanism(s) that increase retinal and visual cortex blood flows in response to visual stimulation are poorly understood. We tested the hypothesis that increased transfer of electrons and protons from glucose to cytosolic free NAD(+), reducing it to NADH, evoked by increased energy metabolism, fuels redox-signaling pathways that augment flow. The near-equilibrium between free cytosolic NADH/NAD(+) and lactate/pyruvate ratios established by lactate dehydrogenase predicts that transfer of additional electrons and protons from injected lactate to NAD(+) will augment the elevated blood flows in stimulated retina and cortex, whereas transfer of electrons and protons from NADH to injected pyruvate will attenuate the elevated flows. These predictions were tested and confirmed in rats. Increased flows evoked by stimulation also were prevented by inhibition of nitric oxide synthase. These findings support an important role for cytosolic free NADH in fueling a signaling cascade that increases *NO production, which augments blood flow in photostimulated retina and visual cortex.

Animals↗
PubMed1977

Properties of tyrosine-inhibitable 3-deoxy-d-arabinoheptulosonic acid-7-phosphate synthase from Salmonella.

Tyrosine-inhibitable 3-deoxy-D-arabinoheptulosonic acid-7-phosphate (DAHP) synthase was purified to homogeneity without significant loss of sensitivity to inhibition by tyrosine from an operator-constitutive strain (tyrOc) of Salmonella. The enzyme had an apparent molecular weight of 76,000 by gel filtration and a subunit molecular weight of 40,000 by sodium dodecyl sulfate-gel electrophoresis and by reaction with dimethyl suberimidate. It had an isoelectric point of 4.68. Inhibition by L-tyrosine showed a Hill coefficient of 1.8 at pH 7.0, suggesting cooperative interaction between tyrosine-binding sites, and was competitive with phosphoenol pyruvate and noncompetitive with erythrose-4-phosphate.

3-Deoxy-7-Phosphoheptulonate Synthase↗
PubMed1997

Biotin synthase, a new member of the family of enzymes which uses S-adenosylmethionine as a source of deoxyadenosyl radical.

The fact that biotin synthase, from Escherichia coli and Bacillus sphaericus, requires S-adenosylmethionine and a reducing system led us to postulate that this synthase could belong to the family of enzymes which use S-adenosylmethionine as a source of deoxyadenosyl radical, namely pyruvate formate-lyase, lysine 2,3-aminomutase, and anaerobic ribonucleotide reductase. We describe here experiments with S-[2,8-(3)H] adenosylmethionine and S-adenosyl-[methyl-3H]methionine which allowed the identification and quantification of the expected cleavage products, deoxyadenosine, and methionine. They are formed in equimolar amounts, in a ratio close to 3 with respect to the biotin produced. We postulate a mechanism involving the homolytic cleavage of two C-H bonds which should consume two equivalents of S-adenosylmethionine. The observed excess of S-adenosylmethionine consumption is attributed to abortive processes.

Bacillus↗