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PubMed1994

A biochemical study of the intermediary carbon metabolism of Shewanella putrefaciens.

Cell extracts were used to determine the enzymes involved in the intermediary carbon metabolism of several strains of Shewanella putrefaciens. Enzymes of the Entner-Doudoroff pathway (6-phosphogluconate dehydratase and 2-keto-3-deoxy-6-phosphogluconate aldolase) were detected, but those of the Embden-Meyerhof-Parnas pathway were not. While several tricarboxylic acid cycle enzymes were present under both aerobic and anaerobic conditions, two key enzymes (2-oxoglutarate dehydrogenase and pyruvate dehydrogenase) were greatly diminished under anaerobic conditions. Extracts of cell grown anaerobically on formate as the sole source of carbon and energy were positive for hydroxypyruvate reductase, the key enzyme of the serine pathway in other methylotrophs, while no hexulose synthase activity was seen.

Aerobiosis↗
PubMed1998

A pathogenic role of IL-12 in blood-stage murine malaria lethal strain Plasmodium berghei NK65 infection.

We studied whether the infection with a blood-stage murine malaria lethal Plasmodium berghei NK65 induces IL-12 production, and if so, how the IL-12 production is involved in the protection or pathogenesis. The infection of C57BL/6 mice enhanced mRNA expression of IL-12 p40 and also IFN-gamma, IL-4, and IL-10 in both spleen and liver during the early course of the infection. It also enhanced the mRNA expression of TNF-alpha, Fas ligand, and cytokine-inducible nitric oxide synthase. Increased IL-12 p40 production was also observed in the culture supernatant of spleen cells and in sera of infected mice. In addition, the infection caused massive liver injury with elevated serum glutamic-oxaloacetic transaminase and serum glutamic-pyruvic transaminase activities and body weight loss. Treatment of these infected mice with neutralizing mAb against IL-12 prolonged the survival and diminished the liver injury with reduced elevation of serum serum glutamic-oxaloacetic transaminase and serum glutamic-pyruvic transaminase activities and decreased body weight loss. However, the anti-IL-12 treatment did not affect parasitemia, and all these mice eventually died. Similar results were obtained when infected mice were treated with neutralizing mAb against IFN-gamma. Moreover, anti-IL-12 treatment greatly reduced the secretion and mRNA expression of IFN-gamma in both spleen and liver. These results suggest that the lethal P. berghei NK65 infection induces IL-12 production and that the IL-12 is involved in the pathogenesis of liver injury via IFN-gamma production rather than the protection.

Animals↗
PubMed2006

Temperature- and exercise-induced gene expression and metabolic enzyme changes in skeletal muscle of adult zebrafish (Danio rerio).

Both exercise training and cold acclimatization induce muscle remodelling in vertebrates, producing a more aerobic phenotype. In ectothermic species exercise training and cold-acclimatization represent distinct stimuli. It is currently unclear if these stimuli act through a common mechanism or if different mechanisms lead to a common phenotype. The goal of this study was to survey responses that represent potential mechanisms responsible for contraction- and temperature-induced muscle remodelling, using an ectothermic vertebrate. Separate groups of adult zebrafish (Danio rerio) were either swim trained or cold acclimatized for 4 weeks. We found that the mitochondrial marker enzyme citrate synthase (CS) was increased by 1.5x in cold and by 1.3x with exercise (P<0.05). Cytochrome c oxidase (COx) was increased by 1.2x following exercise training (P<0.05) and 1.2x (P=0.07) with cold acclimatization. However, only cold acclimatization increased beta-hydroxyacyl-CoA dehydrogenase (HOAD) compared to exercise-trained (by 1.3x) and pyruvate kinase (PK) relative to control zebrafish. We assessed the whole-animal performance outcomes of these treatments. Maximum absolute sustained swimming speed (Ucrit) was increased in the exercise trained group but not in the cold acclimatized group. Real-time PCR analysis indicated that increases in CS are primarily transcriptionally regulated with exercise but not with cold treatments. Both treatments showed increases in nuclear respiratory factor (NRF)-1 mRNA which was increased by 2.3x in cold-acclimatized and 4x in exercise-trained zebrafish above controls. In contrast, peroxisome proliferator-activated receptor (PPAR)-alpha mRNA levels were decreased in both experimental groups while PPAR-beta1 declined in exercise training only. Moreover, PPAR-gamma coactivator (PGC)-1alpha mRNA was not changed by either treatment. In zebrafish, both temperature and exercise produce a more aerobic phenotype, but there are stimulus-dependent responses (i.e. HOAD and PK activities). While similar changes in NRF-1 mRNA suggest that common responses might underlie aerobic muscle remodelling there are distinct changes (i.e. CS and PPAR-beta1 mRNA) that contribute to specific temperature- and exercise-induced phenotypes.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed1976

Inactivation of pyridoxal phosphate dependent enzymes by mono- and polyhaloalanines.

beta,beta-Dichloro- and beta,beta,beta-trifluoroalanine irreversibly inactivate a number of pyridoxal phosphate dependent enzymes which catalyze beta- or gamma-elimination reactions. The inactivation is time dependent and the rate of inactivation is first order in enzyme concentration. This suggests that inactivation is due to covalent modification of the enzyme by a species generated at the active site from the polyhaloalanine (i.e., suicide inactivation). Monohaloalanines are substrates and do not inactivate. For gamma-cystathionase, covalent and stoichiometric attachment of [1-14C]beta,beta,beta-trifluoroalanine was shown. It is proposed that the mechanism of inactivation involves Schiff base formation between inactivator and enzyme-bound pyridoxal and subsequent elimination of HC1 from dichloroalanine or HF from trifluoroalanine. This results in the formation of a beta-halo-alpha,beta unsaturated imine, an activated Michael acceptor. Michael addition of a nucleophile at the active site leads to covalent labeling of the enzyme and inactivation. Alanine racemase is also inactivated by the two polyhaloalanines. Glutamate-pyruvate and gultamate-oxaloacetate transaminase are inactivated by monohaloalanines but not by polyhaloalanines.

Alanine↗
PubMed2004

Dihydrodipicolinate synthase is not inhibited by its substrate, (S)-aspartate beta-semialdehyde.

DHDPS (dihydrodipicolinate synthase; EC 4.2.1.52) is the enzyme that catalyses the first unique step of lysine biosynthesis in plants and micro-organisms. As such, it has attracted much attention as a target for herbicide and anti-microbial action. DHDPS has two substrates: pyruvate and ( S )-aspartate beta-semialdehyde [( S )-ASA]. There are various literature reports that suggest that high levels of ( S )-ASA inhibit the enzyme [Karsten (1997) Biochemistry 36, 1730-1739; Stahly (1969) Biochim. Biophys. Acta 191, 439-451], whereas others have not observed this phenomenon. We have resolved this long-running literature debate and shown unequivocally that this difference in reported behaviour can be attributed to differences in the preparation of ( S )-ASA used by each researcher. DHDPS is not inhibited by its substrate; rather, the inhibition is due to an, as yet, unidentified inhibitor in preparations of the substrate generated by ozonolysis. Furthermore, we demonstrate that ( R )-ASA is neither an inhibitor nor a substrate of DHDPS from Escherichia coli.

Aspartic Acid↗
PubMed1993

Stimulation of rat liver glycogen synthesis by the adenosine kinase inhibitor 5-iodotubercidin.

The adenosine kinase inhibitor 5-iodotubercidin (Itu) was found to have the following effects on glycogen metabolism in hepatocytes of fasted rats. (1) Itu strongly stimulated glycogen synthesis from different substrates (glucose, lactate plus pyruvate, dihydroxyacetone, glycerol and fructose). In cells incubated with these substrates, the well-known stimulating effect of amino acids and that of Itu was more than additive. (2) In parallel with the increase in glycogen deposition, there was an increase in synthase a and a decrease in phosphorylase a concentrations after administration of Itu. Synthase a was increased by Itu and amino acids in an additive manner, whereas the observed activation of phosphorylase after addition of amino acids was antagonized by Itu. (3) In contrast with amino acids, Itu increased neither the cell volume nor the aspartate and glutamate concentrations. (4) Itu enhanced the levels of cyclic AMP. The stimulation of glycogen deposition in the presence of Itu persisted when the cyclic AMP concentration was further increased by adenosine or 2-chloroadenosine. (5) Itu decreased the concentration of ATP, but its effects on glycogen synthesis, synthase a and phosphorylase a concentrations persisted when the ATP catabolism was prevented by adenosine. (6) The effect of Itu on glycogen synthesis was not the result of inhibition of adenosine kinase, since 5'-amino-5'-deoxyadenosine, another inhibitor of this enzyme, had no effect on glycogen deposition.

2-Chloroadenosine↗
PubMed1988

Dehydroepiandrosterone induced alterations in rat liver carbohydrate metabolism.

Long-term dietary administration of the adrenal hormone dehydroepiandrosterone (DHEA) to male Sprague-Dawley rats induced significant alterations in the activities of enzymes involved in liver carbohydrate metabolism. Although glycogen synthase activity was increased and phosphorylase decreased, glycogen stores were reduced. This was presumably related to lysosomal glycogen degradation, since alpha-glucosidase was increased. All rate-limiting enzymes of glucose metabolism which were studied (glucose-6-phosphate dehydrogenase, total hexokinases, pyruvate kinase, fructose-1,6-bisphosphatase) revealed markedly reduced activity, only glucose-6-phosphatase activity was increased. These enzymatic changes point to a far-reaching metabolic shift towards energy loss via decreased glucose consumption and increased glucose output. The enzyme pattern induced by DHEA is in many respects opposite to that induced in preneoplastic and neoplastic liver lesions by chemical hepatocarcinogens.

Animals↗
PubMed1991

Herbicide Resistance in Datura innoxia: Kinetic Characterization of Acetolactate Synthase from Wild-Type and Sulfonylurea-Resistant Cell Variants.

Acetolactate synthase (ALS, EC 4. 1.3. 18), the first enzyme in the biosynthesis of branched-chain amino acids, was isolated from wild-type and sulfonylurea-resistant Datura innoxia cell variants and characterized. Apparent K(m) values of the ALS for pyruvate from three sulfonylurea-resistant variants (CSR2, CSR6, and CSR10) were manyfold greater than that of the wild type. The inhibition of wild-type and herbicide-resistant ALS activity by chlorsulfuron (CS), a sulfonylurea herbicide, and l-leucine (l-Leu), one of the feedback inhibitors of the enzyme, was examined. ALS from two CS-resistant variants exhibited severalfold greater resistance to CS than did the wild-type enzyme. Inhibition of ALS by l-Leu fitted a partially competitive pattern most closely. It is proposed that the herbicide resistance mutation accentuated the partial inhibition characteristics of ALS by l-Leu. ALS from one of the two CS-resistant variants (CSR6) had a K(i) for l-Leu an order of magnitude greater than that of the wild-type enzyme. The alterations in kinetic properties observed in the ALS from sulfonylurea-resistant variants are discussed in relation to the possible evolutionary significance of the herbicide binding site of this enzyme, the physiological effects of such biochemical alterations, and their practical utility in genetic studies.

Journal Article↗
PubMed2003

Impaired oxidative phosphorylation in skeletal muscle of intrauterine growth-retarded rats.

Intrauterine growth retardation (IUGR) has been linked to the development of type 2 diabetes in later life. We have developed a model of uteroplacental insufficiency, a common cause of intrauterine growth retardation, in the rat. Early in life, the animals are insulin resistant and by 6 mo of age they develop diabetes. Glycogen content and insulin-stimulated 2-deoxyglucose uptake were significantly decreased in muscle from IUGR rats. IUGR muscle mitochondria exhibited significantly decreased rates of state 3 oxygen consumption with pyruvate, glutamate, alpha-ketoglutarate, and succinate. Decreased pyruvate oxidation in IUGR mitochondria was associated with decreased ATP production, decreased pyruvate dehydrogenase activity, and increased expression of pyruvate dehydrogenase kinase 4. Such a defect in IUGR mitochondria leads to a chronic reduction in the supply of ATP available from oxidative phosphorylation. Impaired ATP synthesis in muscle compromises energy-dependent GLUT4 recruitment to the cell surface, glucose transport, and glycogen synthesis, which contribute to insulin resistance and hyperglycemia of type 2 diabetes.

Aconitate Hydratase↗
PubMed1972

Protein kinases.

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Binding Sites↗
PubMed2001

The physiological effects and metabolic alterations caused by the expression of Rhizobium etli pyruvate carboxylase in Escherichia coli.

Oxaloacetate (OAA) plays an important role in the tricarboxylic acid cycle and for the biosynthesis of a variety of cellular compounds. Some microorganisms, such as Rhizobium etli and Corynebacterium glutamicum, are able to synthesize OAA during growth on glucose via either of the enzymes pyruvate carboxylase (PYC) or phosphoenolpyruvate carboxylase (PPC). Other microorganisms, including Escherichia coli, synthesize OAA during growth on glucose only via PPC because they lack PYC. In this study we have examined the effect that the R. etli PYC has on the physiology of E. coli. The expressed R. etli PYC was biotinylated by the native biotin holoenzyme synthase of E. coli and displayed kinetic properties similar to those reported for alpha4 PYC enzymes from other sources. R. etli PYC was able to restore the growth of an E. coli ppc null mutant in minimal glucose medium, and PYC expression caused increased carbon flow towards OAA in wild-type E. coli cells without affecting the glucose uptake rate or the growth rate. During aerobic glucose metabolism, expression of PYC resulted in a 56% increase in biomass yield and a 43% decrease in acetate yield. During anaerobic glucose metabolism, expression of PYC caused a 2.7-fold increase in succinate concentration, making it the major product by mass. The increase in succinate came mainly at the expense of lactate formation. However, in a mutant lacking lactate dehydrogenase activity, expression of PYC resulted in only a 1.7-fold increase in succinate concentration. The decreased enhancement of succinate formation in the /dh mutant was hypothesized to be due to accumulation of pyruvate and NADH, metabolites that affect the interconversion of the active and inactive form of the enzyme pyruvate formate-lyase.

Acetates↗
PubMed1996

Effects of short-chain acyl-CoA dehydrogenase deficiency on development expression of metabolic enzyme genes in the mouse.

Patients with an acyl-CoA dehydrogenase deficiency share the disease features of hypoglycemia, hyperammonemia, tissue fatty change, hypoketonemia, carnitine deficiency, and organic acidemia due to apparent disruption of normal fatty acid, glucose, and urea metabolism. Most of the acute clinical episodes occur in young children. These episodes are precipitated by fasting and are often fatal, with the in vivo mechanisms essentially unknown. Since the genes of the rate controlling enzymes of these pathways are tissue and developmentally regulated at the transcriptional level, we measured, throughout neonatal development, the steady-state mRNA levels of long-chain, medium-chain, and short-chain (SCAD) acyl-CoA dehydrogenases, pyruvate carboxylase (PC), phosphoenolpyruvate carboxykinase (PEPCK), carbamyl phosphate synthetase I (CPS), ornithine transcarbamylase (OTC), and argininosuccinate synthetase (AS) in fed or fasted SCAD-deficient BALB/ByJ mice compared to BALB/cBy controls. Overall, our results showed no major effects on expression of acyl-CoA dehydrogenases due to SCAD deficiency, regardless of age or fasting. In SCAD-deficient mice we found depressed mRNA expression and enzyme activity for the urea cycle enzymes CPS and AS at 6 days of age, and found no apparent effects on expression of gluconeogenic enzymes PC or PEPCK. There was a period of overall lower gene expression for most genes at 6 and 15 days, which appears to be in parallel with the developmental period when children with these diseases are most severely affected.

Acyl-CoA Dehydrogenase↗
PubMed1997

Physiology and pathology of tau protein kinases in relation to Alzheimer's disease.

Alzheimer's disease (AD) is characterized by neuronal cell death and two kinds of deposits, neurofibrillary tangles (NFT) and senile plaques. The main component of NFT is paired helical filaments (PHF), which mainly consist of hyperphosphorylated tau protein. Tau protein kinases I and II were found as candidate enzymes responsible for hyperphosphorylation of tau to induce the formation of PHF. Since prior phosphorylation of tau by TPKII strongly enhanced the action of TPKI, it was thought that TPKII was involved in the formation of PHF-tau in concert with TPKI. After cloning, TPKI was found to be identical with glycogen synthase kinase 3 beta (GSK3 beta), while TPKII consists of a novel 23 kDa protein activator and a catalytic subunit that is identical with cyclin-dependent kinase 5 (CDK5). The phosphorylation sites on tau by TPKI and TPKII could account for the most, but not all, of the major phosphorylation sites of fetal tau and PHF-tau. An antibody for a site specifically phosphorylated by TPKI (Ser413) could identify all three neurofibrillary lesions in the AD brain, and double staining for either TPKI or TPKII and NFT in the brain of Down's syndrome patients clearly demonstrated that TPKI and TPKII are both associated with NFT in vivo, suggesting that the level of TPKI or TPKII is elevated in AD brain by some mechanism. On the other hand, the levels of both TPKs change developmentally, being high in the neonatal period when the phosphorylation of fetal tau proceeds actively, suggesting that the TPKI/TPKII cooperative system has an important physiological role in the formation of neural networks. In AD brain, aberrant accumulation of amyloid-beta protein (A beta) occurs ahead of the accumulation of PHF in NFT. When a primary culture of embryonic rat hippocampus was treated with 20 microM A beta, induction of TPKI, extensive phosphorylation of tau and then programmed cell death were observed, indicating that TPKI induced by A beta phosphorylates tau, followed by disruption of axonal transportation and finally cell death. By using a yeast two hybrid system, TPKI was found to interact with pyruvate dehydrogenase (PDH), which is a key enzyme in the glycolytic pathway. PDH was phosphorylated in vitro by TPKI to reduce the activity converting pyruvate into acetyl-CoA, which is required for acetylcholine synthesis. In a primary culture of rat hippocampal cells treated with A beta, PDH was inactivated in inverse relation to the activation of TPKI, resulting in accumulation of pyruvate or lactate, energy failure induced by the disturbance of glucose metabolism, and a shortage of acetylcholine owing to deficiency of acetyl-CoA, all of which are characteristic of AD brain. In cholinergic neurons such as those of the septum, non-aggregated A beta, specifically A beta (1-42), not A beta (1-40), caused a shortage of acetylcholine by activation of TPKI and inactivation of PDH without cell death.

Alzheimer Disease↗
PubMed2006

Redirection of the NADH oxidation pathway in Torulopsis glabrata leads to an enhanced pyruvate production.

This study aimed at increasing the pyruvate productivity of a multi-vitamin auxotrophic yeast Torulopsis glabrata by redirecting NADH oxidation from adenosine triphosphate (ATP)-production pathway (oxidative phosphorylation pathway) to non-ATP production pathway (fermentative pathway). Two respiratory-deficient mutants, RD-17 and RD-18, were screened and selected after ethidium bromide (EtBr) mutagenesis of the parent strain T. glabrata CCTCC M202019. Compared with the parent strain, cytochrome aa (3) and b in electron transfer chain (ETC) of RD-18 and cytochrome b in RD-17 were disrupted. As a consequence, the activities of key ETC enzymes of the mutant RD-18, including F(0)F(1)-ATP synthase, complex I, complex I + III, complex II + III, and complex IV, decreased by 22.2, 41.6, 53.1, 23.6, and 84.7%, respectively. With the deficiency of cytochromes in ETC, a large amount of excessive cytosolic NADH was accumulated, which hampered the further increase of the glycolytic flux. An exogenous electron acceptor, acetaldehyde, was added to the strain RD-18 culture to oxidize the excessive NADH. Compared with the parent strain, the concentration of pyruvate and the glucose consumption rate of strain RD-18 were increased by 26.5 and 17.6%, respectively, upon addition of 2.1 mM of acetaldehyde. The strategy for increasing the glycolytic flux in T. glabrata by redirecting the NADH oxidation pathway may provide an alternative approach to enhance the glycolytic flux in yeast.

Adenosine Triphosphate↗
PubMed2000

Theoretical indicators of enzyme reaction specificity from conserved information in amino acid sidechains.

Amino acid sequences for 11 acetohydroxy acid synthase (EC 4.1.3.18; AHS) polypeptides with experimentally established activity were chosen for computational comparisons to detect conserved local information associated with reaction specificity for each sequence. Windowed analysis by Pearson product moment cross-correlation of six amino acid sidechain properties revealed locally conserved segments common to all proteins with AHS activity. Seven information segments were detected in the same arrangement in sequences for the large subunit polypeptides of prokaryotes, and in the sequences for single polypeptides of eukaryotic AHS. The information segments were numbered 1-7 according to sequential position, and sequence features such as cofactor binding sites were defined for specific segments. Extension of the information segment analysis to seven other proteins of the pyruvate decarboxylase superfamily permitted use of the content and organization of information segments to recognize four classes of enzyme reaction specificity. Estimates of information entropy, based upon a state space defined by reaction specificity, directly reflected the known reaction complexity for all but one enzyme examined. Our data suggest that development of information-segment models for enzyme superfamilies may improve the accuracy of inferring protein activity from sequence.

Acetolactate Synthase↗