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PubMed1979

Mechanism of activation of glycogen phosphorylase by fructose in the liver. Stimulation of phosphorylase kinase related to the consumption of adenosine triphosphate.

1. A dose-dependent activation of phosphorylase and consumption of ATP was observed in isolated hepatocytes incubated in the presence of fructose; histone kinase and phosphorylase kinase activities were unchanged at doses of this sugar that were fully effective on phosphorylase. The activation of phosphorylase by fructose was also observed in cells incubated in a Ca2+-free medium as well as in the livers of rats in vivo. 2. In a liver high-speed supernatant, fructose, tagatose and sorbose stimulated the activity of phosphorylase kinase; this effect was dependent on the presence of K+ ions, which are required for the activity of fructokinase; it was accompanied by the transformation of ATP into ADP. In the presence of hexokinase, glucose also stimulated phosphorylase kinase, both in an Na+ or a K+ medium. 3. The activities of partially purified muscle or liver phosphorylase kinase were unchanged in the presence of fructose. 4. Some properties of liver phosphorylase kinase are described, including a high molecular weight and an inhibition at ATP/Mg ratios above 0.5, as well as an effect of ATP concentration on the hysteretic behaviour of this enzyme. 5. The effect of fructose on the activation of phosphorylase is discussed in relation to the comsumption of ATP.

Adenosine Triphosphate↗
PubMed1979

Histidine mutants requiring adenine: selection of mutants with reduced hisG expression in Salmonella typhimurium.

A method is described for the selection of Salmonella typhimurium mutants with reduced levels of hisG enzyme activity. This method is based on the fact that the hisG enzyme catalyzes the consumption of ATP in the first step of histidine biosynthesis. Normally, this reaction is closely regulated, both by feedback inhibition and by repression of the operon. However, conditions can be set up that result in the uncontrolled use of adenine in histidine biosynthesis. Cells grown under these conditions become phenotypic adenine auxotrophs. Some revertant clones that no longer require adenine contain mutations in hisG, hisE, or the his-control region. The hisG mutations are of all types (nonsense, frameshift, missense, deletion and leady types), and they map throughout the hisG gene.

ATP Phosphoribosyltransferase↗
PubMed2026

Beyond NAD Depletion: SARM1-Induced ATP Collapse Involves Direct ATP Degradation and Mitochondrial Dysfunction and Is Pharmacologically Reversible.

Sterile alpha and Toll/interleukin-1 receptor motif-containing protein 1 (SARM1) is an inducible NAD-consuming enzyme and execution factor in axon degeneration. Rapid ATP collapse after SARM1 activation, however, is not fully explained by NAD depletion alone. We used SARM1-overexpressing HEK293 cells and the cell-permeant activator CZ-48 to examine SARM1-induced non-apoptotic cell death, termed sarmoptosis. CZ-48 induced cell death that was suppressed by HSP90/70-annotated ATP-competitive compounds, especially geldanamycin and VER-155008 (VER), without reducing SARM1 abundance. VER preserved NAD and ATP during SARM1 activation but failed to rescue FK866-mediated NAD starvation, thereby distinguishing CZ-48/SARM1-driven cytotoxicity from generic NAD depletion. In cell-free assays, purified SARM1 reduced ATP levels; this effect was enhanced by SARM1's activator NMN and attenuated by its pharmacological inhibitors, although the in vitro activity was modest and the reaction products remain to be identified. ATPase-related perturbations, including thapsigargin and bafilomycin A1, also protected cells from CZ-48-induced death, further supporting a central role for ATP collapse in sarmoptosis. iTRAQ proteomics, MitoSOX Red staining, and DiOC6(3) staining revealed that CZ-48 treatment was associated with mitochondrial and metabolic remodeling, mitochondrial ROS accumulation, and mitochondrial depolarization, all of which were mitigated by VER. Collectively, these findings support a convergent ATP-collapse model in which SARM1 activation promotes NAD depletion, directly consumes ATP, and is associated with mitochondrial dysfunction that may amplify ATP-production failure.

ATP collapse↗
PubMed1977

Effects of ventricular fibrillation on coronary blood flow and myocardial metabolism.

Ventricular fibrillation is frequently induced during cardiac surgery to quiet the operative field. The reported effects of fibrillation on the myocardium vary considerably. In an attempt to better define these effects, we subjected 28 dogs to one hour of total normothermic bypass. Myocardial blood flow, lactate, adenosine triphosphate (ATP), oxygen consumption, and left ventricular fibrillation was induced in 5 dogs and continuous electrical fibrillation in 7 dogs. These groups were compared to two respective control groups with beating hearts of 8 animals each. Coronary sinus flow, total coronary blood flow, left ventricular flow, myocardial oxygen consumption, and myocardial tissue lactate increased significantly in the fibrillating hearts. Left ventricular dp/dt decreased with fibrillation, but not significantly. It is concluded that the metabolic demands of ventricular fibrillation exceed the increase in coronary blood flow, when compared to demands of the beating heart, and that decreased left ventricular performance may result.

Adenosine Triphosphate↗
PubMed1975

Incubation studies on human red cells utilizing glucose or inosine under various conditions.

Human red cells were incubated at pH 8.2 and 30 mM phosphate concentration with glucose, glucose plus methylene blue, or inosine. In 16 normal subjects, the lactate production rate (LPR) from glucose alone was 92.2 +/- 7.5 mumoles per minute per liter red blood cell. With methylene blue added, the mean LPR was 118.5 +/- 7.4 per cent of control glucose values. With inosine as substrate the mean LPR was 68.5 +/- 6.0 per cent of that from glucose. Lactate/glucose ratios averaged 1.36, presumably because of accumulation of intermediates under conditions of high pH and Pi. Patients with various kinds of anemias had LPR's from glucose that were usually markedly higher than normal, but the LPR's from inosine were generally about 2/3 of those from glucose. The LPR's of the anemic patients correlated with their degree of reticulocytosis and several patients with pyruvate kinase (PK) deficiency showed normal LPR if the red cell population age was ignored, byt marked depression when compared to expected LPR for degree of reticulocytosis. The LPR from glucose of red cells of G6PD-deficient subjects was decreased (not increased) by methylene blue. Methylene blue, while stimulating the pentose phosphate pathway, also mediated some oxidation of NADH, thus complicating the stoichiometry of the overall system. In addition, the results suggested that the dye may have attacked -SH groups on some enzymes. In normal red cells, the lower LPR from inosine than from glucose was explained as due to consumption of ATP for hexose utilization (thus generating more ADP for the triose reactions). In confirmation, when red cells were incubated without substrate to deplete their ATP-, and enhance their ADP-, levels, the LPR from inosine exceeded that from glucose. Fluoride and iodoacetate affected LPR from glucose more than from inosine, suggesting the necessity of adequate ATP levels in hexose utilization. Overall glycolysis in the red cell is seen as the resultant of a network of metabolic reactions in which ADP and ATP levels are important control parameters.

Adenosine Diphosphate↗
PubMed1975

The effects of ATP on platelets: evidence against the central role of released ADP in primary aggregation.

The influence of freshly purified ATP on the effects of aggregating agents on human platelets was studied. ATP inhibited aggregation induced by ADP competitively (Ki = 20 muM) and immediately without need for prior incubation. ATP had no effect on primary aggregation induced by adrenaline, thrombin, vasopressin, or 5-hydroxytryptamine (5HT). ATP inhibited the shape change and the consumption of metabolic ATP induced by ADP but did not inhibit these effects when induced by thrombin, vasopressin, or 5HT. ATP counteracted the inhibition by ADP of PGE1-stimulated cyclic AMP production in platelets but did not reduce inhibition by adrenaline. It is concluded that adrenaline, thrombin, 5HT, and vasopressin each can induce primary aggregation of human platelets by a mechanism independent of extracellular ADP.

Adenine↗
PubMed1979

A requirement for ATP for beta-galactoside transport by Bacillus alcalophilus.

Lactose-grown cells of Bacillus alcalophilus actively transported methylthio-beta, D-galactoside (TMG) in a range of pH values from 7.5 to 10.5 with a pH optimum at 8.5. The TMG was accumulated in a chemically unmodified form, and cell extracts failed to catalyze either ATP or P-enolpyruvate-dependent phosphorylation of TMG. At pH 8.5, the lactose-grown cells exhibited a transmembrane proton gradient (deltapH) of 1.38 units, interior acid, and a transmembrane electrical potential (delta psi) of -132 mV. Accordingly, the total protonmotive force at this pH was very low, -51mV. Several lines of evidence indicate that the protonmotive force or delta psi did not directly energize TMG transport but, rather, that ATP was directly required: (a) in cells treated with arsenate so that the delta psi was unaffected and cellular ATP levels were markedly lowered, TMG transport was inhibited in proportion to the reduction of cellular ATP, while electrogenic alpha-aminoisobutyric acid transport was not; (b) when a valinomycin-induced potassium diffusion potential was established in starved cells, alpha-aminoisobutyric acid transport, but not TMG transport, was stimulated; and (c) in a series of experiments in which the delta psi was rapidly abolished by treatment with gramicidin, ATP levels declined slowly and the rate of TMG transport correlated directly with ATP levels rather than with the delta psi. Consumption of cellular ATP concomitant with TMG transport could be demonstrated.

Adenosine Triphosphate↗
PubMed1975

Mathematical analysis of multienzyme systems. I. Modelling of the glycolysis of human erythrocytes.

A mathematical model for the glycolysis of human erythrocytes is presented which takes into account ATP-synthesis and -consumption. A set of three differential equations describes the steady states and the time-dependent changes of the metabolite concentrations under blood storage conditions. For a given parameter combination there are in general three stationary points of the system, one of which is unstable. At a low ATP-need the ATP-level is relatively constant for variations in the rate constant of the ATP-consuming processes. Above a critical level of the energy consumption the system breaks down. An important role of the 2.3P2G-bypass of the erythrocytes is its action as an "energy buffer", wasting ATP in case of ATP-overproduction and producing ATP in case of underproduction. A parameter combination consistent with the data on the isolated enzymes was found which gives a good agreement of theoretical predictions with the measured metabolite concentrations. Under blood preservation conditions the difference of the rates of ATP-production and -consumption is the most important factor for a high ATP-level over long periods.

Adenosine Triphosphatases↗
PubMed1976

Adenine nucleotide changes at initiation of bull sperm motility.

Testicular and cauda epididymal sperm were obtained via catheters previously implanted in the rete testis and proximal vas deferens of bulls and were used to examine the relationships among sperm motility, cyclic adenosine 3':5'-monophosphate (cAMP) level, adenine nucleotide levels, and rates of glucose and oxygen consumption. Testicular, cauda epididymal, and ejaculated sperm contain cAMP-stimulated protein kinase, adenylate cyclase, and nucleotide phosphodiesterase. Treatment of the nonmotile testicular sperm with phosphodiesterase inhibitors resulted in a doubling of cellular cAMP concentration and a 25% increase in their glucose consumption. No change in motility, ATP level, or rate of oxygen consumption was observed. Sperm in neat cauda epididymal semen had flagellating tails but no progressive motility. Dilution of these sperm into glucose-containing buffer resulted in an increase in intracellular cAMP concentration and a decrease in ATP level with concomitant increases in ADP and AMP levels. These biochemical changes occurred within 30 s after dilution and apparently preceded the initiation of progressive motility by most cells. Since sperm in neat cauda epididymal semen became progressively motile when diluted with neat cauda epididymal plasma as well as accessory sex gland fluid or buffer, composition of the fluid surrounding the sperm is not responsible for the initiation of progressive motility upon dilution nor does cauda epididymal plasma contain an inhibitory factor. Perhaps release from contact immobilization provides the stimulation for the initial acquisition of progressive motility by cauda epididymal sperm. We conclude that during epididymal passage sperm develop from a cell physically unresponsive to changes in cAMP concentration to a form which initiates progressive motility upon changes in cAMP concentration.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1978

Adenine nucleotides in foetal rat liver cells. Compartmentation and variation with age.

The digitonin method for the separation of cytosolic and mitochondrial fractions was applied to liver cells isolated from foetal rats. The cytosolic [ATP]/[ADP] ratio approximately doubles during the last 4 days of gestation, whereas the mitochondrial ratio remains constant. In the presence of oligomycin and added glucose, the cytosolic [ATP]/[ADP] ratio does not increase with age, but is still considerably higher than the mitochondrial ratio. Without added glucose, and when the glycogen content of foetal liver is still very low (more than 3 days before birth), the cytosolic [ATP]/[ADP] ratio in the presence of oligomycin becomes very low and equal to the mitochondrial ratio. It is concluded that the increasein the cytosolic [ATP]/[ADP] ratio during the last 4 days of gestation is solely due to enhanced mitochondrial activity in this period. Atractyloside and bongkrekic acid do not influence the O2 consumption, nor the [ATP]/[ADP] ratios in either compartment of foetal liver cells. Respiration of isolated foetal mitochondria, however, is strongly inhibited by both compounds. The implications of these findings are discussed.

Adenosine Diphosphate↗
PubMed1979

An acid transporting enzyme in human gastric mucosa.

Isolation of a microsomal fraction from human gastric mucosa followed by density gradient centrifugation yielded a vesicular membrane preparation free of mitochondrial markers, containing a K+-activated, ouabain-insensitive ATPase with an activity of 20.7 mumol P1 released/mg protein per h. Sodium dodecyl sulfate gel electrophoresis showed that the human gastric membrane vesicles contained a major polypeptide of 110,000 daltons, which accounted for approximately or equal to 30% of the total protein stained and was phosphorylated by [gamma-32P]ATP and dephosphorylated in the presence of K+. Electron microscopy revealed the presence of vesicles with an average size of 0.13 micrometer in diameter. Addition of 0.65 microM ATP to this vesicular preparation resulted in the uptake of 17 nmol H+/mg protein which was dependent on the presence of K+. The gradient was dissipated by a combination of valinomycin and protonophore after consumption of the ATP. Incubation of fixed human fundic sections or human gastric biopsy with monospecific hog gastric membrane antibody followed by fluorescein-conjugated goat anti-rabbit gamma-globulin, showed fluorescent staining in the middle portion of the gastric glands. These data indicate that human stomach contains a H+ transport ATPase with characteristics similar to those established for lower species.

Adenosine Triphosphatases↗
PubMed1976

Contribution of tissue acidosis to ischemic injury in the perfused rat heart.

The isolated perfused working rat heart preparation has been used to study the effects of respiratory acidosis on myocardial metabolism and contractilly. Hearts were perfused with 5 mM glucose and 10(-2) U/ml of insulin in order to enhance metabolsim of glucose relative to that of fatty acids. After perfusion with Krebs bicarbonate medium at pH 6.6, hearts rapidly ceased performing external work and peak left ventricular pressure fell by 75% after 5 minutes. Oxygen consumption, rate of ATP generation and overall glycolytic flux also declined rapidly. After about 2 minutes of perfusion, the fall of glycolytic flux showed a partial reversal, which was largely accounted for by increased lactate production, so that glucose oxidation decreased further. The reversal of glycoltic flux could be accounted for by partial release of H+ inhibition of phospho-fructokinase by increased tissue levels of adenosine 5'-diphosphate (ADP), adenosine monophosphate (AMP) and P1 and decreased levels of adenosine triphosphate (ATP) and creatine phosphate. The increased proportion of glucose uptake converted to lactate together with an increase of the tissue lactate/pyruvate ratio could be accounted for by inhibition of the malate-aspartate cycle combined with tissue hypoxia. Lactate accumulated in the tissue as a result of a decreased permeability of the plasma membrane to lactate. Decreased oxygen delivery to the myocardium was caused by secondary constriction of the coronary vessels. In further experiments, the coronary flow was regulated by an external pump which delivered fluid at a controlled rate into the aortic cannula above the coronary arteries, and the degree of tissue hypoxia was monitored by measuring changes of pyridine nucleotide reduction state by surface fluorescence techniques. The effects of acidosis uncomplicated by possible hypoxia were compared directly with those produced by ischemic hypoxia. The effects of acidosis under these conditions were similar to those described above, and to those produced by ischemia. From these and other data it is concluded that the effects of ischemia are caused by a lowering of the intracellular pH, which decreases the rate of energy production relative to the rate of energy demand. However, it is suggested that the primary cause of the decreased peak systolic pressure with either acidosis or ischemia is not a result of a defect of energy metabolism, but is due to alteration of the calcium cycle of the heart. Possible causes of irreversible heart failure after prolonged ischemia are discussed.

Acidosis, Respiratory↗
PubMed2026

ARL6IP1 Inhibits Breast Cancer Tumor Progression by Targeting OLFM4 to Regulate Glycolysis.

INTRODUCTION: ARL6IP1 has been linked to cancer progression, but its precise role in BC, particularly in metabolism and its interaction with an OLFM4, remains unclear. AIMS: This study aimed to investigate the role of ADP-ribosylation factor-like 6 interacting protein 1 (ARL6IP1) in breast cancer (BC) cell behavior and metabolism and explore its interaction with an olfactomedin-4 (OLFM4) as a potential therapeutic target. OBJECTIVE: The objective of this study was to determine the effects of ARL6IP1 knockdown on BC cell proliferation, invasion, migration, apoptosis, oxidative stress, and glycolysis. Additionally, this study also explored the interaction between ARL6IP1 and OLFM4 and their combined role in BC progression and metabolism. METHODS: Key gene modules in the GSE73540 dataset were identified through weighted gene co-expression network analysis (WGCNA). Three BC-related datasets (GSE73540, GSE22820, and GSE36295) and The Cancer Genome Atlas (TCGA) were applied for additional examination of differentially expressed genes (DEGs). Intersection analysis selected ARL6IP1 as a hub gene for prognostic analysis. In vitro experiments investigated how ARL6IP1 knockdown influences BC cell proliferation, invasion, migration, apoptosis, epithelial-mesenchymal transition (EMT), oxidative stress, and glycolysis. The connection between ARL6IP1 and an OLFM4 was confirmed using Co-immunoprecipitation (Co-IP), and their roles in BC tumor progression and glycolysis were evaluated. RESULTS: ARL6IP1 was elevated in BC datasets and linked with poor BC prognosis. Experiments demonstrated that knockdown of ARL6IP1 significantly reduced BC cell growth while promoting apoptosis and oxidative stress. Besides, ARL6IP1 knockdown reduced glycolysis, as manifested by decreased extracellular acidification rate (ECAR), glucose consumption, adenosine triphosphate (ATP) levels, and lactate production while increasing mitochondrial respiration (OCR). Co-IP validated the connection between ARL6IP1 and OLFM4, and OLFM4 overexpression partially counteracted the suppression of glycolysis and cell behavior resulting from ARL6IP1 knockdown. CONCLUSION: ARL6IP1 is a critical regulator of BC progression, influencing glycolysis, mitochondrial function, and key cellular behaviors. Targeting the ARL6IP1-OLFM4 axis offers a promising therapeutic strategy for managing BC.

Humans↗
PubMed1978

Is the adenine nucleotide translocator rate-limiting for oxidative phosphorylation?

1. The effects of atractyloside and carboxyatractyloside (between 5 and 40mum) on O(2) uptake, glucose synthesis, urea synthesis, the adenine nucleotide content and the intracellular K(+) concentration were measured in isolated hepatocytes. 2. Urea synthesis was much less inhibited than glucose synthesis by both atractylosides. Measurements of intermediary metabolites of carbohydrate metabolism in freeze-clamped liver after injection of atractyloside into rats indicate that inhibition of gluconeogenesis is due to interference at the cytosolic reactions requiring ATP (phosphoenolpyruvate carboxykinase and 3-phosphoglycerate kinase). 3. The decrease in [ATP]/[ADP]x[P(i)] after addition of atractyloside or carboxyatractyloside was restricted to the cytosol. 4. Dihydroxyacetone can be converted either into glucose with the consumption of 2mol of ATP (per mol of glucose) or into lactate with the production of 2mol of ATP. In the presence of high concentrations of atractyloside and carboxyatractyloside more ATP was produced than was used for the synthesis of glucose from dihydroxyacetone, probably for the maintenance of intracellular [K(+)]. 5. When the rates of respiration were altered by changing substrates, the degrees of inhibition of respiration and translocation by a given concentration of the atractylosides were the same, whereas at a given concentration of HCN the degree of inhibition was high at higher initial rates, and low at lower initial rates. 6. Inhibition of a complex series of reactions by atractyloside does not necessarily indicate that the translocator is a rate-limiting step in that sequence as Th. P. M. Akerboom, H. Bookelman & J. M. Tager [(1977) FEBS. Lett.74, 50-54] assume. This point is discussed.

Adenine Nucleotides↗
PubMed1979

Effect of adenosine triphosphate and some derivatives on cerebral blood flow and metabolism.

1. Responses of cerebral blood vessels to peri- and intravascular doses of ATP (adenosine triphosphate) and some derivatives were studied in cat and baboon. 2. Perivascular application of ATP to cat pial arterioles gave a threshold dilatory effect at a concentration of 10(-11) M. This figure is comparable to the amount of ATP calculated to be released from electrically stimulated brain slices. 3. It is concluded that adenine nucleotides have a major role to play in the local control of cerebral blood flow. 4. Intracarotid injection of ATP showed a calculated threshold effect at 4 x 10(8) M in the cat and 4 x 10(-9) M in the baboon. 5. The threshold response of the vasculature to intracarotid adenosine lay between 4 x 10(-7) M and 4 x 10(-6) M in the baboon. Little effect was produced with AMP, pyrophosphate and inorganic phosphate. 6. Intracarotid ATP increased the oxygen consumption of the baboon brain parenchyma. This effect was attributed in part to an elevation of the cellular cyclic AMP levels. 7. Osmotic disruption of the blood-brain barrier in baboon did not affect the vasodilatory or metabolic effect of intracarotid ATP. 8. It is postulated that circulating purine compounds mediate a form of metabolic communication inthe body. Also, release of purine compounds from active local nerves might influence cerebral blood flow.

Adenosine Triphosphate↗
PubMed1976

Cross bridge ATP utilization in arterial smooth muscle.

Measurements of oxygen consumption and lactate production were used to estimate the ATP production in porcine carotid arteries. Changes in the total energy metabolism were correlated with changes in force which was altered by changing the muscle length under maximum stimulation. This tension-dependent metabolism could be used to distinguish between cross bridge and other ATP utilization. The tension-dependent metabolism was equal under K+ -depolarization or histamine stimulation. Tension cost was 300x smaller than skeletal muscle while the cross bridge cycle duration 30x longer.

Actomyosin↗
PubMed1979

The relationship of regional coronary blood flow to mitochondrial function during reperfusion of the ischemic myocardium.

The relationship of changes in regional coronary flow to the nature and degree of biochemical disturbances during occlusion of branches of the left anterior descending coronary artery and following reestablishment of flow was investigated in two groups of dogs: group I, moderate ischemia before reflow, and group II, severe ischemia prior to reflow. Regional coronary blood flow was determined before ligation, after 60 min of ischemia and after 15 min of reflow using labelled microspheres. Hearts made ischemic for 60 min but not reperfused served as controls. Groups I and II were distinguished by the following features. Group II showed a marked exacerbation of biochemical damage on reperfusion of the ischemic region (reduced levels of ATP, impairment of mitochondrial oxygen consumption and mitochondrial calcium binding). This was accompanied by significant subendocaridial hyperemia. Reperfusion in group I, on the otherhand, partially reversed these changes (increased level of ATP in the ischemic-reperfused region, improved mitochondrial oxygen consumption and calcium binding). Mitochondrial calcium uptake and oxidative phosphorylation (ADP/O ratio) were not affected in any group. These data illustrate that the degree of biochemical damage following reperfusion of the ischemic myocardium is determined by the degree of ischemia, and suggest that interference with ATP production by the mitochondria is not responsible for the damage.

Animals↗
PubMedDate not supplied

[Quantitative model of human erythrocyte glycolysis. II. Effect of arsenate on glycolysis. Experimental study of the relationship between the rate of glycolysis and the ATP concentration].

The effect of arsenate on human erythrocyte glycolysis was studied. The stationary rate of glucose consumption rises and then drops with a gradual increase of arsenate concentration while ATP and glucose-6-phosphate concentrations drop monotonically. A plot of glucose consumption rate against ATP concentration gives a bell-like curve. This curve is the same for different donors if it is plotted in relative units with values at zero arsenate concentration taking for 100%, while the absolute values obtained for separate donors are very different. The normal (physiological) point is situated on the steeply descending part of the curve.

Adenosine Triphosphate↗