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Query: UNIPROT:P06889 (Mol)
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Rates of NADPH production via the pentose phosphate cycle were determined in perfused livers from phenobarbital-treated rats by measuring 14CO2 production from [1-14C]glucose infused in the presence and absence of p-nitroanisole (0.2 mM), a substrate for mixed-function oxidation. In the fed state, basal rates of NADPH generation were 34-44 mumol/g/hr. p-Nitroanisole, which was metabolized at rates of 8.9 mumol/g/hr, stimulated pentose cycle-dependent NADPH production by 21-24 mumol/g/hr. Fasting for 24 hr prior to perfusion diminished pentose cycle flux by 80% and largely abolished the stimulation of the pentose cycle by p-nitroanisole. In contrast, rates of p-nitroanisole O-demethylation were only diminished slightly, to 5.7 mumol/g/hr. Fasting decreased hepatic glucose, glucose 6-phosphate, and 6-phosphogluconate contents drastically as expected. Pretreatment of rats with 6-aminonicotinamide, which is metabolized to a potent inhibitor of 6-phosphogluconate dehydrogenase, decreased rates of NADPH generation via the pentose cycle to 6.9 mumol/g/hr but did not alter rates of p-nitroanisole metabolism (8.8 mumol/g/hr). Basal rates of NADPH generation decreased from 38 to 26 mumol/g/hr during infusion of potassium cyanide (2 mM), an inhibitor of mitochondrial energy metabolism. Cyanide also decreased rates of p-nitroanisole O-demethylation by over 60%; however, stimulation of NADPH generation via the pentose cycle by p-nitroanisole was as great in the presence (17-21 mumol/g/hr) as in the absence of cyanide. Since rates of mixed-function oxidation were unaffected after virtually complete inhibition of the pentose cycle with 6-amino-nicotinamide, it is concluded that reducing equivalents for the mixed-function oxidation of p-nitroanisole are not provided by the pentose cycle under these conditions.
Mol Pharmacol 1985 Oct
PMID:Rates of pentose cycle flux in perfused rat liver. Evaluation of the role of reducing equivalents from the pentose cycle for mixed-function oxidation. 405 19

The supply of NADPH for cytochrome P-450-dependent mixed function oxidation from the pentose cycle and mitochondria in periportal and pericentral regions of the liver lobule was evaluated in perfused rat liver. Rates of 7-ethoxycoumarin O-deethylation in livers from fed, normal rats monitored with micro-light guides placed on periportal and pericentral regions were 1.2 mumol/g/hr in both regions of the liver lobule. In livers from fed, phenobarbital-treated rats, rates were 3.6 and 7.0 mumol/g/hr in periportal and pericentral regions, respectively. Following treatment of rats with 6-aminonicotinamide, an inhibitor of the pentose cycle, rates of 7-hydroxycoumarin production were approximately 0.9 mumol/g/hr in both regions of the lobule in livers from normal rats and 2.1 and 3.4 mumol/g/hr in periportal and pericentral regions, respectively, in livers from phenobarbital-treated rats. Based on the difference in rates of 7-hydroxycoumarin production in the presence and absence of 6-aminonicotinamide, we conclude that the pentose cycle supplies NADPH for 7-ethoxycoumarin metabolism at rates around 0.3 mumol/g/hr in both regions of the liver lobule in livers from normal rats and 1.5 and 3.6 mumol/g/hr in periportal and pericentral regions, respectively, in livers from phenobarbital-treated rats. Potassium cyanide, an inhibitor of mitochondrial oxidation, reduced rates of 7-ethoxycoumarin O-deethylation to approximately 0.6 mumol/g/hr in both regions of the liver lobule in livers from fed, normal rats and to around 0.2 mumol/g/hr after fasting or treatment with 6-aminonicotinamide. In livers from fasted, phenobarbital-treated rats, 7-hydroxycoumarin was produced at rates of 0.3 and 0.7 mumol/g/hr in periportal and pericentral regions, respectively, in the presence of KCN. Decreases in rates of 7-hydroxycoumarin production during KCN infusion indicate that the mitochondria supply about 0.7 mumol of NADPH/g/hr for 7-ethoxycoumarin metabolism in both regions in livers from normal rats and 1.3 and 2.7 mumol/g/hr in periportal and pericentral regions in livers from phenobarbital-treated rats. The sum of KCN and 6-aminonicotinamide-sensitive rates of 7-ethoxycoumarin metabolism closely approximated rates measured in the absence of the inhibitors. These data indicate that mitochondria supply 50 to 70% of the reducing equivalents for mixed function oxidation of 7-ethoxycoumarin in both regions of the liver lobule in livers from fed rats.
Mol Pharmacol 1984 Nov
PMID:Reducing equivalents for mixed function oxidation in periportal and pericentral regions of the liver lobule in perfused livers from normal and phenobarbital-treated rats. 633 82

This study was undertaken in order to test the models of ATP and GTP binding to carp deoxyhaemoglobin proposed by Perutz & Brunori (1982) and to find out why GTP is a more potent allosteric effector than ATP. We have determined the conformations of both nucleoside triphosphates by nuclear magnetic resonance studies and found them to be the same. The purines are in anti conformation about the glycosidic bond that links them to the ribose; the pentose ring is 3'-endo; the P-O5'-C5'-C4' torsion angle lies in the trans domain (180 degrees +/- 20 degrees); the P alpha-O-P beta and P beta-O-P gamma angles are as in the free nucleotides, i.e. the trinucleotide chain is fully extended. Models having this conformation were fitted, first manually and then by energy refinement, to the effector site of an atomic model of human deoxyhaemoglobin in which the side-chains in the NA, EF and H segments had been replaced by those of carp. The results showed the location of the polar groups in carp haemoglobin to be such that (PO4) gamma can accept hydrogen bonds from Val NA1 beta 2 and from Arg H21 beta 1, while (PO4) beta and (PO4) alpha can accept hydrogen bonds from Lys EF6 beta 1 and beta 2. In ATP, the 6-amino group of the purine can donate a hydrogen bond to Glu NA2 beta 1. In GTP, the 2-amino group can donate a hydrogen bond to Glu NA2 beta 1; in addition, Val Na1 beta 1 can donate a hydrogen bond to O2' of the ribose. This additional hydrogen bond may explain why in carp haemoglobin GTP is a stronger allosteric effector than ATP. We have found the influence of the two allosteric effectors on the oxygen affinity of trout IV haemoglobin to be the same, even though the only difference in the lining of the allosteric effector sites lies in the replacement of Glu Na2 beta in carp by Asp in trout IV haemoglobin. Model building then showed that formation of a hydrogen bond between Asp Na2 beta and the 2-amino group of guanine precludes formation of a hydrogen bond between Val NA1 beta and O2' of the ribose or vice versa, which makes the number of hydrogen bonds formed between trout IV haemoglobin and GTP the same as those formed with ATP.
J Mol Biol 1984 Sep 25
PMID:Stereochemistry of ATP and GTP bound to fish haemoglobins. A transferred nuclear overhauser enhancement, 31P-nuclear magnetic resonance, oxygen equilibrium and molecular modelling study. 649 61

The lipid and carbohydrate metabolism of Giardia lamblia was studied using trophozoites isolated from a human and axenically grown in vitro in medium containing fetal bovine serum. The phospholipid, fatty acid and neutral lipid composition of the G. lamblia trophozoites was similar to that of the medium. Phosphatidylethanolamine, phosphatidylcholine and sphingomyelin were the major phospholipids detected; monoacyl-, diacyl-, triacylglycerides, sterols, and sterol esters were the major neutral lipids found. Several unidentified glycolipids were also detected. Glucose and threonine were readily incorporated by the trophozoites, but not into cellular phospholipids or sterols. However, approximately 86% of the glucose incorporated into the trophozoites was found in the nucleic acids, and 38% of the threonine incorporated was detected in the cellular proteins. Small amounts of the glucose and threonine were incorporated into glycolipid-containing fractions. Glycerol and acetate were not appreciably incorporated into trophozoites while glycerol 3-phosphate incorporation was not detected. Cholesterol was readily assimilated by the trophozoites; 98% of the incorporated was found in the sterol fraction. Radiorespirometric data suggest that the major routes of glucose metabolism in G. lamblia are via Embden- Meyerhof-Parnas and pentose phosphate pathways. However, endogenous acetate (as acetyl-CoA) formed during the metabolism of glucose is not used for lipid biosynthesis. These findings suggest that G. lamblia trophozoites are incapable of synthesizing cellular phospholipids or sterols de novo, but rather, utilize lipids already present in the medium.
Mol Biochem Parasitol 1981 Feb
PMID:Lipid and carbohydrate metabolism of Giardia lamblia. 678 99

The ability to carry out the initial reaction of the pentose phosphate pathway was investigated with extracts of mouse erythrocytes infected with Plasmodium chabaudi, purified merozoites of P. knowlesi, and schizonts of P. falciparum grown in vitro in human erythrocytes. Glucose-6-phosphate dehydrogenase activity (G-6pd) was detected in extracts of all the cells after electrophoresis on polyacrylamide gels. Separate host cell and parasite glucose-6-phosphate dehydrogenase activities were demonstrated with extracts of P. knowlesi and P. falciparum but not with P. chabaudi.
Mol Biochem Parasitol 1981 Feb
PMID:Detection of glucose-6-phosphate dehydrogenase in malarial parasites. 701 16

A glucose-negative mutant of Saccharomyces cerevisiae lacking 6-phosphogluconate dehydrogenase, the second enzyme of the pentose phosphate pathway, has been obtained by inositol starvation. Suppression of this mutant for growth on glucose takes place by the loss of glucose 6-phosphate dehydrogenase. A lesion in the latter enzyme alone leaves growth practically unaffected. The mutations define the respective structural genes.
Mol Gen Genet 1982
PMID:Pentose phosphate pathway mutants of yeast. 704 91

Catecholamines and thyroid hormones have a similar influence on heart function and metabolism, but this may occur in a differential manner and to a different extent. In this study, the effects of norepinephrine (NE) and of triiodothyronine (T3) were studied in regard to the function of the left (LV) and right ventricle (RV) and to the oxidative pentose phosphate pathway (PPP). NE was applied in rats as continuous i.v. infusion (0.2 mg/kg/h) for three days. T3 was given as daily s.c. injections (0.2 mg/kg) for the same period of time. LV and RV function was measured in the closed-chest trapanal-anesthetized animals using special Millar ultraminature catheter pressure transducers. NE induced an increase in heart rate, in mean arterial pressure, and in total peripheral resistance (TPR). The cardiac RNA/DNA and the left ventricular weight/body weight ratios were increased by about 40%. These effects were prevented by simultaneous alpha- and beta-receptor blockade with prazosin and metoprolol, respectively, but not by verapamil which abolished the hemodynamic effects. RVSP was significantly elevated by NE in a dose-dependent manner. The functional effects of T3 on the LV were not as pronounced as those induced by NE. Heart rate and LV dp/dtmax were increased by T3, and this increase was prevented by concomitant beta-receptor blockade with metoprolol. In contrast to NE, T3 induced an increase in cardiac output and a concomitant decrease in TPR. The RNA/DNA ratio was elevated and cardiac hypertrophy had developed after treatment for three days with T3. These changes were not affected by beta-receptor blockade with metoprolol. RVSP was increased by T3 to a lesser extent than with NE. In metabolic terms it turned out that only NE, but not T3 had a stimulating effect on the cardiac PPP. NE increased the mRNA and activity of glucose-6-phosphate dehydrogenase (G-6-PD), the first and regulating enzyme of this pathway. However, there was no effect of T3 on G-6-PD activity nor on 6-phosphogluconate dehydrogenase activity, one of the following enzymes in the pathway within the first 5 days of T3 treatment. These results demonstrate that the functional effects of T3 were not as pronounced as or even different from those of NE, and that T3 lacked a stimulating effect on the cardiac PPP.
Mol Cell Biochem
PMID:Response of the rat heart to catecholamines and thyroid hormones. 749 38

Enzymes and metabolic intermediates of glycolysis, pentose phosphate pathway and the tricarboxylic acid cycle were measured in immature rat uterus after treatment with oestradiol. The flux of glucose through alternative pathways was examined. Fructose-2,6-bis-phosphate, the well known regulator of glycolytic pathway, increased after the injection of oestradiol and remained elevated. This increase was accompanied by raised levels of most of glycolytic intermediates and by increase in glycolytic flux. The key enzymes of glycolysis and all the enzymes of pentose phosphate pathway showed a gradual increase in the activity with administration of oestradiol up to 48 hours. Phosphoribosyl pyrophosphate, the metabolite required in nucleotide synthesis, was also elevated. Marked changes in the levels of key metabolic intermediates and the enzyme activities are correlated with the increased nucleic acid, protein and lipid synthesis occurring following oestradiol treatment.
Biochem Mol Biol Int 1993 Nov
PMID:Effect of oestradiol on the carbohydrate metabolism of immature rat uterus: the role of fructose-2, 6-bis-phosphate and of phosphoribosyl pyrophosphate. 750 81

Cytokines can be produced within the nervous system by various cell types, including astrocytes, which secrete them in response to pathological processes such as viral infections. Astrocytes are known to play an important role in the homeostasis of the nervous system, in particular, by contributing to the regulation of local energy metabolism. We report that tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 alpha (IL-1 alpha) markedly stimulate glucose uptake and phosphorylation in primary cultures of neonatal murine astrocytes, as determined with [3H]-2-deoxyglucose ([3H]2DG). This effect is both concentration dependent, with observed EC50 values of 8 ng/ml for TNF-alpha and 30 pg/ml for IL-1 alpha, and time dependent, with a maximal response observed 24 hr after cytokine application. The effects of TNF-alpha and IL-1 alpha on glucose uptake and phosphorylation appear to be mediated by the phospholipase A2 signal transduction pathway. Evidence in support of this includes (i) inhibition by mepacrine, a phospholipase A2 inhibitor, of [3H]2DG uptake evoked by TNF-alpha and IL-1 alpha, and (ii) stimulation of [3H]arachidonic acid release by TNF-alpha and IL-1 alpha. Protein kinase C activation does not appear to be involved as the specific protein kinase C inhibitor Ro 31-7549 does not abolish TNF-alpha- or IL-1 alpha-induced increase in [3H]2DG uptake and phosphorylation. The additional glucose imported by astrocytes on exposure to TNF-alpha and IL-1 alpha is neither stored as glycogen nor released as glycolytically derived lactate, suggesting that it is processed through the tricarboxylic acid cycle or pentose phosphate pathway. These results demonstrate that TNF-alpha and IL-1 alpha can fundamentally perturb the energy metabolism of astrocytes, possibly impairing their ability to provide adequate energy substrates for neurons.
Mol Pharmacol 1995 Sep
PMID:Tumor necrosis factor-alpha and interleukin-1 alpha enhance glucose utilization by astrocytes: involvement of phospholipase A2. 756 37

6-Phosphogluconate dehydrogenase (6PGDH) from rat-liver and kidney-cortex cytosol has been partially purified and almost completely isolated (more than 95%) from glucose-6-phosphate dehydrogenase activity. The purification and isolation procedures included high-speed centrifugation, 60-75% ammonium-sulphate fractionation, by which both hexose-monophosphate dehydrogenases activities were separated, and finally the protein fraction was applied to a chromatographic column of Sephadex G-25 equilibrated with 10 mM Tris-EDTA-NADP buffer, pH 7.6, to eliminate any contaminating metabolites. The kinetic properties of the isolated partially purified liver and renal 6PGDH were examined. The saturation curves of this enzyme in both rat tissues showed a typical Michaelis-Menten kinetic, with no evidence of co-operativity. The optimum pH for both liver and kidney-cortex 6PGDH was 8.0. The Km values of liver 6PGDH for 6-phosphogluconate (6PG) and for NADP were 157 microM and 258 microM respectively, while the specific activity measured at optimum conditions (pH 8.0 and 37 degrees C) was 424.2 mU/mg of protein. NADPH caused a competitive inhibition against NADP with an inhibition constant (Ki) of 21 microM. The Km values for 6PG and NADP from kidney-cortex 6PGDH were 49 microM and 56 microM respectively. The specific activity at pH 8.0 and 37 degrees C was 120.7 mU/mg of protein. NADPH also competitively inhibited 6PGDH activity, with a Ki of 41 microM. This paper describes a quick, easy and reliable method for the separation of the two dehydrogenases present in the oxidative segment of the pentose-phosphate pathway in animal tissues, eliminating interference in the measurements of their activities.
Mol Cell Biochem 1995 Mar 23
PMID:Kinetic properties of hexose-monophosphate dehydrogenases. II. Isolation and partial purification of 6-phosphogluconate dehydrogenase from rat liver and kidney cortex. 762 92


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