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PubMed2006

Is pyruvate an endogenous anti-inflammatory molecule?

Pyruvic acid is an effective scavenger of reactive oxygen species. Ethyl pyruvate has demonstrated anti-inflammatory actions and improved hyperpermeability and bacterial translocation due to endotoxemia and is of benefit in animal models of sepsis and septic shock. Ethyl pyruvate specifically inhibits tumor necrosis factor-alpha production and decreases circulating levels of high-mobility group box-1 and nuclear factor-kappaB signaling pathways by specifically targeting its p65 subunit in animals with established endotoxemia or sepsis and in macrophage cultures. Ethyl pyruvate also decreases cyclo-oxygenase-2, inducible nitric oxide synthase, and interleukin-6 mRNA expression in the liver, ileal mucosa, and colonic mucosa in animal models with hemorrhagic shock. Similar beneficial actions have been seen in endotoxemia. These and other studies suggest that ethyl pyruvate could be of significant benefit in the treatment of patients who are critically ill and have sepsis/septic shock.

Animals↗
PubMed1981

Exercise training fails to increase skeletal muscle enzymes in patients with chronic obstructive pulmonary disease.

We examined the effect of a 6-wk exercise training program on several skeletal enzymes in patients with chronic obstructive pulmonary disease. Eight trained their arms and 7 trained their legs. In all patients, muscle biopsy specimens were taken from the trained limbs, and in 7 patients, additional biopsy specimens were taken from the untrained limbs. The enzymes examined were citrate synthase, 3-beta-hydroxyacyl coenzyme A dehydrogenase, and pyruvate kinase. Also examined were cardiac frequency responses to incremental and endurance cycle ergometry; these responses were evaluated for arm and leg exercise, respectively. Despite the patient's increased exercise endurance, we were unable to document a significant increase in the enzyme concentrations in the trained limbs. Similarly, analyses of the cardiac frequency failed to show the evolution of the typical cardiovascular training response. This pattern is in marked contrast to that seen in normal subjects after endurance training. We conclude that patients with chronic obstructive pulmonary disease are incapable of exercising at an intensity high enough to induce the classic training response and associated changes in muscle enzymes. Therefore, other mechanisms must be important in explaining the increased endurance for submaximal exercise.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed1985

Postnatal growth and differentiation in three hindlimb muscles of the rat. Characterization with biochemical and enzyme-histochemical methods.

The postnatal development, between 0 and 90 days, of three hindlimb muscles and diaphragm of the rat was investigated with respect to fiber types and diameter (histochemistry) and substrate oxidation rates and enzyme activities (biochemistry). The process of muscle fiber differentiation into mature patterns was evaluated by visual classification into 3 or 4 groups having different staining intensities for 3 enzyme-histochemical reactions, enabling 26 fiber types to be distinguished. These exhibited specific sizes and growth rates that varied among the muscles. One of the hindleg muscles (flexor digitorum brevis) remained much more immature than soleus and extensor digitorum longus. The histochemical and biochemical findings correlated well. The capacity for pyruvate and palmitate oxidation, and the activities of cytochrome c oxidase and citrate synthase, increased markedly between 9 and 37 days in soleus and extensor digitorum longus (except citrate synthase in the latter) but not in flexor digitorum brevis. Creatine kinase activity increased in all hindlimb muscles. Both the capacity and the activity of pyruvate oxidation (determined in homogenates and intact isolated muscles, respectively), were in accordance with the fiber type composition. In contrast to oxidation capacity, the activity of pyruvate oxidation decreased after birth until the mature stage, when a value of 18-42% of that of early postnatal muscles was recorded.

Adenosine Triphosphatases↗
PubMed1991

[Uncoupling expression of genes coding for the synthesis of proteins involved in transport and utilization of fructose in Escherichia coli K-12].

A novel mutation fruS localised in the fru operon has been obtained. The mutation uncouples expression of genes determining fructose specific uptake and utilization. In the fruS bacteria fruA and fruF genes (coding for enzyme II and FPr, respectively) become constitutive, while the fruK gene (responsible for fructose-1-phosphate kinase synthesis) remains inducible. In contrast to the already known mutations making the whole fru operon constitutive, the fruS mutation: 1) does not lead to xylitol sensitivity; 2) does not depress growth on lactate, pyruvate and alanine; 3) does not decrease PEP-synthase activity.

Alanine↗
PubMed2002

Crystallization of the FAD-independent acetolactate synthase of Klebsiella pneumoniae.

Leucine and valine are formed in a common pathway from pyruvate in which the first intermediate is 2-acetolactate. In some bacteria, this compound also has a catabolic fate as the starting point for the butanediol fermentation. The enzyme (EC 4.1.3.18) that forms 2-acetolactate is known as either acetohydroxyacid synthase (AHAS) or acetolactate synthase (ALS), with the latter name preferred for the catabolic enzyme. A significant difference between AHAS and ALS is that the former requires FAD for catalytic activity, although the reason for this requirement is not well understood. Both enzymes require the cofactor thiamine diphosphate. Here, the crystallization and preliminary X-ray diffraction analysis of the Klebsiella pneumoniae ALS is reported. Data to 2.6 A resolution have been collected at 100 K using a rotating-anode generator and an R-AXIS IV++ detector. Crystals have unit-cell parameters a = 137.4, b = 143.9, c = 134.4 A, alpha = 90, beta = 108.4, gamma = 90 degrees and belong to space group C2. Preliminary analysis indicates that there are four monomers located in each asymmetric unit.

Acetolactate Synthase↗
PubMed1998

Myocardial aerobic metabolism is impaired in a cell culture model of cyanotic heart disease.

A human pediatric cardiomyocyte cell culture model of chronic cyanosis was used to assess the effects of low oxygen tension on mitochondrial enzyme activity to address the postoperative increase in lactate and decreased ATP in the myocardium and the high incidence of low-output failure with restoration of normal oxygen tension, after technically successful corrective cardiac surgery. Chronically hypoxic cells (PO2 = 40 mmHg for 7 days) exhibited significantly reduced activities for pyruvate dehydrogenase, cytochrome-c oxidase, succinate cytochrome c reductase, succinate dehydrogenase, and citrate synthase. The activity of NADH-cytochrome c reductase was unaffected. Lactate production and the lactate-to-pyruvate ratio were significantly greater in hypoxic cardiomyocytes. Western and Northern analysis demonstrated a decrease in the levels of various mRNA and corresponding polypeptides in hypoxic cells. Thus hypoxia influences mitochondrial metabolism through acute and chronic adaptive mechanisms, reflecting allosteric (posttranscriptional) and transcriptional modulation. Transcriptional downregulation of key mitochondrial enzyme systems can explain the insufficient myocardial aerobic metabolism and low-output failure in children with cyanotic heart disease after cardiac surgery.

Adenosine Triphosphate↗
PubMed1979

Pyruvate carboxylase and phosphoenolpyruvate carboxykinase activity in leukocytes and fibroblasts from a patient with pyruvate carboxylase deficiency.

Normal values are given for the activities of pyruvate carboxylase (E.C.6.4.1.1), mitochondrial phosphoenolpyruvate carboxykinase (E.C. 4.1.1.32, PEPCK), and citrate synthase (E.C. 4.1.3.7) in fibroblasts, lymphocytes, and leukocytes. Also given are values for these enzymes in the leukocytes and fibroblasts from a severely mentally and developmentally retarded patient with proximal renal tubular acidosis and hepatic, cerebral, and renal cortical pyruvate carboxylase deficiency. In normals, virtually all of the mitochondrial PEPCK and pyruvate carboxylase activity was present in the mononuclear leukocyte fraction of whole venous blood. Cellular fractionation studies with human lymphocytes and fibroblasts demonstrated that all of the PEPCK activity in these cells is mitochondrial. Normal values for pyruvate carboxylase in leukocytes were 0.092 (0.070--0.208) mU/mg protein (n=5), in lymphocytes 0.154 (0.092--0.262) mU/mg protein (n=5), and in fibroblasts 1.36 (0.778--2.19) mU/mg protein (n=5). The patient with hepatic, renal, and cerebral pyruvate carboxylase deficiency had no detectable activity (less than 0.009 mU/mg protein) in his leukocytes and 0.018 mU/mg protein in his fibroblasts. Data from an assay for pyruvate carboxylase activity in the patient's fibroblasts show that the activity observed is significant but very close to the lower limits of the assay. Values for PEPCK in normal lymphocytes were 1.42 (0.824--1.88) mU/mg protein (n=5), in leukocytes 1.68 (1.64--1.72) mU/mg protein (n=2), and in fibroblasts 5.49 (3.94--6.33) mU/mg protein (n=6).

Acidosis, Renal Tubular↗
PubMed1996

Effect of polyunsaturated fatty acids in obese mice.

Genetically obese (ob/ob) mice display a variety of metabolic differences from lean litter mates. In the obese state, fatty acid desaturation-elongation in brown adipose tissue mitochondria is apparently altered, resulting in differences in membrane fatty acid composition. This change in membrane lipid environment appears to influence GDP binding and therefore the activity of the proton conductance pathway associated with regulation of energy expenditure in these animals. In liver, binding of insulin to the nuclear membrane is increased by feeding a high polyunsaturated/saturated (P/S) diet fat. Consumption of a high P/S diet decreased mRNA levels for fatty acid synthase, acetyl-CoA carboxylase, malic enzyme, and pyruvate kinase in obese and lean animals. Expression of mRNA for these lipogenic enzymes was higher in obese animals and suggests that obese mice may be resistant to polyunsaturated fatty acid feedback control of gene expression.

Adipose Tissue, Brown↗
PubMed1989

Effect of Ca2+-homopantothenate and mild hypoxia on some enzyme activities evaluated in subcellular fractions from different rat brain regions.

The effect of Ca2+-homopantothenate (HOPA) treatment (250 mg/kg for 5 d) has been studied by evaluating the specific activity of enzymes related to: glycolytic pathway (hexokinase, phosphofructokinase, pyruvate kinase, lactate dehydrogenase), tricarboxylic acid cycle (citrate synthase, malate dehydrogenase), mitochondrial electron transfer chain (succinate dehydrogenase, cytochrome oxidase), NADH redox state (NADH cytochrome c reductase), acetylcholine metabolism (acetylcholinesterase), and glutamate metabolism (glutamate dehydrogenase). The enzymatic activity assays were performed on homogenate in toto, nonsynaptic mitochondria and synaptosomes isolated from: cerebral cortex, hippocampus, striatum, hypothalamus, medulla oblongata, and cerebellum of normoxic rats and rats submitted to intermittent normobaric hypoxia (90:10, N2:O2). In normoxic rats, HOPA was unable to induce any modification. Hypoxia per se induced a decrease in the activity of synaptosomal cytochrome oxidase in cerebral cortex, hippocampus, and cerebellum.

Acetylcholinesterase↗
PubMed2005

Flight muscle enzyme activities do not differ between pelagic and near-shore foraging seabird species.

Common terns (Sterna hirundo), sooty terns (S. fuscata) and brown noddies (Anous stolidus) are phylogenetically related seabirds that differ in field activity levels and daily energy expenditure. To test whether muscle metabolic capacities co-evolve with activity levels and energy expenditure, we collected pectoral muscle biopsies from members of each species, and measured the activities of key enzymes in oxidative metabolism (citrate synthase, CS), anaerobic metabolism (lactate dehydrogenase, LDH), glycolysis (pyruvate kinase, PK), fatty acid oxidation (3-hydroxyacyl CoA dehydrogenase) and phosphocreatine hydrolysis (creatine phosphokinase, CPK). We hypothesized that temperate-breeding common terns would have higher enzyme activities than the two tropical species (sooty terns and brown noddies); consistent with the higher activity level of common terns. There were no differences in enzyme activities among adults of the three species. Common tern chicks within 2-3 days of flight had two-fold higher pyruvate kinase activity than adults, suggesting an increased glycolytic capacity in the chicks. Given the lack of difference among species at the enzymatic level, our results support the notion that behavior and whole organism performance can evolve considerably before there are detectable changes in underlying lower-level physiological/biochemical traits.

Animals↗
PubMed1997

Dihydrodipicolinate synthase from Escherichia coli: pH dependent changes in the kinetic mechanism and kinetic mechanism of allosteric inhibition by L-lysine.

Dihydrodipicolinate synthase (DHDPS) catalyzes the formation of dihydrodipicolinate from pyruvate and L-aspartate beta-semialdehyde (ASA). A parallel initial velocity pattern that displays competitive substrate inhibition by ASA and dead-end inhibition patterns obtained at pH 8 are consistent with a ping pong kinetic mechanism for DHDPS. The results suggest that pyruvate binds to free enzyme with subsequent formation of a Schiff base with an enzymic lysine residue followed by binding of ASA to the F enzyme form to initiate the second half-reaction. At low pH (5.7) the initial velocity and dead-end inhibition patterns are consistent with a sequential steady state ordered kinetic mechanism with pyruvate binding to enzyme prior to ASA. The irreversible step in the reaction, leading to the ping pong kinetic mechanism at high pH, is proposed to be loss of a proton from the methyl group of pyruvate in Schiff base with enzyme to form an enamine intermediate. Consistent with this proposal is the change to a sequential steady state ordered kinetic mechanism at low pH at or below the pK of the enamine intermediate. L-Lysine is an allosteric inhibitor of the DHDPS reaction that causes partial inhibition (approximately 90%) at saturating concentrations. Inhibition patterns for L-lysine vs pyruvate and ASA suggest that lysine binds to the F enzyme form at pH 8 with a Ki value of about 0.3 mM. An examination of the effects of different L-lysine concentrations on the kinetic parameters V/Kpyruvate, V/KASA, and V indicate that L-lysine decreases only the values of V/KASA and Vmax, which is consistent with the inhibitory effects of lysine manifested on the second half-reaction. In contrast at low pH the data suggest L-lysine binds to free enzyme with an inhibition constant of about 5 mM.

Allosteric Regulation↗
PubMed2002

The impact of oxidative stress on Arabidopsis mitochondria.

Treatment of Arabidopsis cell culture for 16 h with H2O2, menadione or antimycin A induced an oxidative stress decreasing growth rate and increasing DCF fluorescence and lipid peroxidation products. Treated cells remained viable and maintained significant respiratory rates. Mitochondrial integrity was maintained, but accumulation of alternative oxidase and decreased abundance of lipoic acid-containing components during several of the treatments indicated oxidative stress. Analysis of the treatments was undertaken by IEF/SDS-PAGE, comparison of protein spot abundances and tandem mass spectrometry. A set of 25 protein spots increased >3-fold in H2O2/menadione treatments, a subset of these increased in antimycin A-treated samples. A set of 10 protein spots decreased significantly during stress treatments. A specific set of mitochondrial proteins were degraded by stress treatments. These damaged components included subunits of ATP synthase, complex I, succinyl CoA ligase, aconitase, and pyruvate and 2-oxoglutarate dehydrogenase complexes. Nine increased proteins represented products of different genes not found in control mitochondria. One is directly involved in antioxidant defense, a mitochondrial thioredoxin-dependent peroxidase, while another, a thioredoxin reductase-dependent protein disulphide isomerase, is required for protein disulfide redox homeostasis. Several others are generally considered to be extramitochondrial but are clearly present in a highly purified mitochondrial fraction used in this study and are known to play roles in stress response. Using H2O2 as a model stress, further work revealed that this treatment induced a protease activity in isolated mitochondria, putatively responsible for the degradation of oxidatively damaged mitochondrial proteins and that O2 consumption by mitochondria was significantly decreased by H2O2 treatment.

Antimycin A↗
PubMed2000

The activating component of the anaerobic ribonucleotide reductase from Escherichia coli. An iron-sulfur center with only three cysteines.

Class III anaerobic ribonucleotide reductase small component, named protein beta, contains a (4Fe-4S) center. Its function is to mediate electron transfer from reduced flavodoxin to S-adenosylmethionine, required for the introduction of a glycyl radical in the large component, named protein alpha, which then becomes active for the reduction of ribonucleotides. By site-directed mutagenesis we demonstrate that the three cysteines of the conserved CXXXCXXC sequence are involved in iron chelation. Such a sequence is also present in the activase of the pyruvate formate-lyase and in the biotin synthase, both carrying an iron-sulfur center involved in reductive activation of S-adenosylmethionine. Even though they are able to bind iron in the (4Fe-4S) form, as shown by Mössbauer spectroscopy, the corresponding Cys to Ala mutants are catalytically inactive. Mutation of the two other cysteines of the protein did not result in inactivation. We thus conclude that the (4Fe-4S) cluster has, in the wild type protein, only three cysteine ligands and a fourth still unidentified ligand.

Amino Acid Sequence↗
PubMed2001

Acute inhibition of hepatic glucose-6-phosphatase does not affect gluconeogenesis but directs gluconeogenic flux toward glycogen in fasted rats. A pharmacological study with the chlorogenic acid derivative S4048.

Effects of acute inhibition of glucose-6-phosphatase activity by the chlorogenic acid derivative S4048 on hepatic carbohydrate fluxes were examined in isolated rat hepatocytes and in vivo in rats. Fluxes were calculated using tracer dilution techniques and mass isotopomer distribution analysis in plasma glucose and urinary paracetamol-glucuronide after infusion of [U-(13)C]glucose, [2-(13)C]glycerol, [1-(2)H]galactose, and paracetamol. In hepatocytes, glucose-6-phosphate (Glc-6-P) content, net glycogen synthesis, and lactate production from glucose and dihydroxyacetone increased strongly in the presence of S4048 (10 microm). In livers of S4048-treated rats (0.5 mg kg(-1)min(-)); 8 h) Glc-6-P content increased strongly (+440%), and massive glycogen accumulation (+1260%) was observed in periportal areas. Total glucose production was diminished by 50%. The gluconeogenic flux to Glc-6-P was unaffected (i.e. 33.3 +/- 2.0 versus 33.2 +/- 2.9 micromol kg(-1)min(-1)in control and S4048-treated rats, respectively). Newly synthesized Glc-6-P was redistributed from glucose production (62 +/- 1 versus 38 +/- 1%; p < 0.001) to glycogen synthesis (35 +/- 5% versus 65 +/- 5%; p < 0.005) by S4048. This was associated with a strong inhibition (-82%) of the flux through glucokinase and an increase (+83%) of the flux through glycogen synthase, while the flux through glycogen phosphorylase remained unaffected. In livers from S4048-treated rats, mRNA levels of genes encoding Glc-6-P hydrolase (approximately 9-fold), Glc-6-P translocase (approximately 4-fold), glycogen synthase (approximately 7-fold) and L-type pyruvate kinase (approximately 4-fold) were increased, whereas glucokinase expression was almost abolished. In accordance with unaltered gluconeogenic flux, expression of the gene encoding phosphoenolpyruvate carboxykinase was unaffected in the S4048-treated rats. Thus, acute inhibition of glucose-6-phosphatase activity by S4048 elicited 1) a repartitioning of newly synthesized Glc-6-P from glucose production into glycogen synthesis without affecting the gluconeogenic flux to Glc-6-P and 2) a cellular response aimed at maintaining cellular Glc-6-P homeostasis.

Animals↗
PubMed1997

Growth of Escherichia coli in acetate as a sole carbon source is inhibited by ankyrin-like repeats present in the 2',5'-linked oligoadenylate-dependent human RNase L enzyme.

Expression of low levels of the 2',5'-linked oligoadenylate-dependent human RNase L, an enzyme induced by interferons, is highly toxic in Escherichia coli. This protein contains an ankyrin domain responsible for RNase L toxicity. The only known ORF in E. coli containing ankyrin repeats is yjaC in the acetate metabolic cluster. We have investigated if expression of mutant forms of RNase L interfere with metabolism of acetate in E. coli. Our findings demonstrate that E. coli expressing RNase L ankyrin repeats is unable to grow in medium containing acetate as the sole carbon source, while it can grow when expressing other domains of the protein. This defect correlates with a severe decrease in the levels of induction of enzymes in the glyoxylate bypass.

Acetates↗
PubMed1982

Effect of vasoactive intestinal polypeptide on glycogen metabolism in rat hepatocytes.

The effects of vasoactive intestinal polypeptide (VIP) on several enzymes of glycogen metabolism in rat hepatocytes were compared with those of glucagon and of vasopressin (ADH). VIP caused phosphorylase activation and glycogenolysis in hepatocytes from fed rats. In hepatocytes from fasted rats incubated with glucose, lactate, and pyruvate, VIP inhibited net glycogen deposition, inactivated glycogen synthase, and activated phosphorylase. VIP was about 100-fold less potent than glucagon and 1,000-fold less potent than ADH in causing activation of phosphorylase. The ability of VIP to activate phosphorylase was not altered by chelation of the calcium in the medium. The half maximal effective doses of VIP for both phosphorylase activation and stimulation of glycogenolysis were 10-30 nM. Treatment with VIP, ADH, or glucagon did not decrease phosphorylase phosphatase activity. Each of these hormones, however, lengthened the lag time before synthase phosphatase activity was expressed in vitro. Other gut hormones tested did not affect hepatocyte glycogen metabolism. These results do not support the concept of physiologic control of hepatic glycogen metabolism by VIP or by other gut hormones.

Animals↗