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PubMed1989

Regulation of hexose transport in rat myoblasts during growth and differentiation.

We report here the effects of growth conditions and myogenic differentiation on rat myoblast hexose transport activities. We have previously shown that in undifferentiated myoblasts the preferred substrates for the high (HAHT)- and low (LAHT)-affinity hexose transport systems are 2-deoxyglucose (2-DG) and 3-O-methyl-D-glucose (3-OMG), respectively. The present study shows that at cell density higher than 4.4 x 10(4) cells/cm2, the activities of both transport processes decrease with increasing cell densities of the undifferentiated myoblasts. Since the transport affinities are not altered, the observed decrease is compatible with the notion that the number of functional hexose transporters may be decreased in the plasma membrane. Myogenic differentiation is found to alter the 2-DG, but not the 3-OMG, transport affinity. The Km values of 2-DG uptake are elevated upon the onset of fusion and are directly proportional to the extent of fusion. This relationship between myogenesis and hexose transport is further explored by using cultures impaired in myogenesis. Treatment of cells with 5-bromo-2'-deoxyuridine abolishes not only myogenesis but also the myogenesis-induced change in 2-DG transport affinity. Similarly, alteration in 2-DG transport affinity cannot be observed in a myogenesis-defective mutant, D1. However, under myogenesis-permissive condition, the myogenesis of this mutant is also accompanied by changes in its 2-DG transport affinity. The myotube 2-DG transport system also differs from its myoblast counterpart in its response to sulfhydryl reagents and in its turnover rate. It may be surmised from the above observations that myogenesis results in the alteration of the turnover rate or in the modification of the 2-DG transport system. Although glucose starvation has no effect on myogenesis, it is found to alter the substrate specificity and transport capacity of HAHT. In conclusion, the present study shows that hexose transport in rat myoblasts is very sensitive to the growth conditions and the stages of differentiation of the cultures. This may explain why different hexose transport properties have been observed with myoblasts grown under different conditions.

3-O-Methylglucose↗
PubMed1975

Kinetics of blood-brain transport of hexoses.

1. The kinetics of transport of glucose and four other hexoses through the blood-brain barrier were studied with a tritiated-water reference technique in the anesthetized rat. Brain clearance of [14-C]hexose was measured 15 s after a single injection of the hexose and 3-HOH reference into the common carotid artery. 2. Saturation of brain clearance of [14-C]hexose conformed to Michaelis-Menten kinetics. Linear transformation of the uptake data yielded the Km of carrier-mediated hexose transport: 2-deoxy-D-glucose 6 mM, D-glucose 9mM, 3-O-methyl-D-glucose and D-galactose 40 mM. A maximum transport velocity of 1.56 mumol/g per min was calculated and shown to be constant for all five hexoses. 3. The kinetics of 3-HOH and 3-0-methyl-D-[14-C]glucose efflux from brain to blood were studied with a modification of the water reference technique. An estimate of cerebral blood flow, 0.56 ml/g per min, was made from the efflux rate constant for 3-HOH, 0.61 min-1. The fractional extraction of 3-0-methyl-D-[14C]glucose uptake from blood was estimated from the efflux rate constant, 0.22 min-1, for this sugar and found to be 0.25. This value approximated the fractional extraction of 3-0-methyl-D-[14-C]glucose uptake that was determined from influx studies (0.24). These results indicated that the bidirectional movement of glucose across the blood brain barrier was symmetrical, which suggested that barrier sugar transport is equilibrative and not active. 4. Blood-brain barrier sugar transport was shown to be reversibly inhibited by phloretin, yet no modulation of transport was demonstrable after 2 or 8 days of starvation. Finally, regional analysis (olfactory bulb, caudate-putamen nucleus, thalamus-hypothalamus, and inferior-superior colliculi) demonstrated that, in addition to blood-brain barrier permeability, brain clearance of glucose was a function of cerebral blood flow.

Animals↗
PubMed1982

Hexose transport in L6 muscle cells. Kinetic properties and the number of [3H]cytochalasin B binding sites.

(1) Myoblasts in culture (L6 cell line) were used as an in vitro model system, to study the kinetic and pharmacological properties of hexose transport in skeletal muscle tissue. (2) Uptake of 2-deoxy-D-[3H]glucose into L6 cells grown in monolayer culture was judged rate limiting since: (2) The time course of sugar uptake extrapolated to zero, (b) a parallel inhibition of hexose uptake and phosphorylation was caused by cytochalasin B, and (c) very little backflow of the hexose was detected. (3) Uptake of 2-deoxy-D-[3H]glucose by cells in monolayers was linear for at least 20 min and it was stimulated by countertransport. The Kt value was 0.83 mM. Cytochalasin B inhibited uptake non-competitively, and half maximal inhibition was achieved at 0.3 microM. Cytochalasin E (up to 5 microM) did not affect 2-deoxy-D-[3H]glucose uptake. (4) L6 myoblasts, detached by trypsinization, retained the hexose transport activity. Kt in detached cells was 0.96 mM. V was 3.2 nmol/min per mg protein, and half maximal inhibition was observed with 0.25 microM cytochalasin B. (5) [3H]Cytochalasin B binding to detached cells showed saturable and non-saturable components. The former could be further separated into cytochalasin E-sensitive binding (probably associated to cytoskeletal proteins) and cytochalasin E-insensitive binding, a fraction of which was inhibited by D-glucose. The D-glucose sensitive sites amount to 16.3 pmol/mg protein, and showed a Kd of 0.49 microM, which is in close agreement with the Ki of cytochalasin B inhibition of hexose uptake. These sites probably are equivalent to the hexose carrier molecules, and are present at a density of 6.8 . 10(6) sites/cell.

3-O-Methylglucose↗
PubMed1995

Barbiturates inhibit hexose transport in cultured mammalian cells and human erythrocytes and interact directly with purified GLUT-1.

Barbiturates reduce cerebral blood flow, metabolism, and Glc transfer across the blood-brain barrier. The effect of barbiturates on hexose transport in cultured mammalian cell lines and human erythrocytes was studied. Pentobarbital inhibits [3H]-2-dGlc uptake in 3T3-C2 murine fibroblasts by approximately 95% and approximately 50% at 10 and 0.5 mM, respectively. Uptake of [3H]-2-dGlc is linear with time in the presence or absence of pentobarbital, and the percent inhibition is constant. This suggests that hexose transport, not phosphorylation, is inhibited by barbiturates. Inhibition by pentobarbital of hexose transport in 3T3-C2 cells is rapid (< 1 min), is not readily reversible, is not altered by the presence of albumin [1% (w/v)], and is independent of temperature (4-37 degrees C) and the level of cell surface GLUT-1. The IC50's for inhibition of hexose transport in 3T3-C2 cells by pentobarbital, thiobutabarbital, and barbital are 0.8, 1.0, and 4 mM, respectively. This is consistent with both the Meyer-Overton rule and the pharmacology of barbiturates. Neither halothane (< or = 10 mM) nor ethanol [< or = 0.4% (v/v)] significantly inhibits hexose transport. Inhibition by pentobarbital (0.5 mM) of [3H]-2-dGlc uptake by 3T3-C2 cells decreases the apparent Vmax (approximately 50%) but does not alter the apparent Km (approximately 0.5 mM). Inhibition of hexose transport by barbiturates, but not ethanol [< or = 0.4% (v/v)], is also observed in human erythrocytes and four other cultured mammalian cell lines. Pentobarbital quenches (Qmax approximately 75%) the intrinsic fluorescence of purified and reconstituted GLUT-1 (Kd approximately 3 mM). Quenching is independent of Glc occupancy, is unchanged by mild proteolytic inactivation, and does not appear to directly involve perturbations of the lipid bilayer. We propose that barbiturates can interact directly with GLUT-1 and inhibit the intrinsic activity of the carrier. Glc crosses the blood-brain barrier primarily via the GLUT-1 of the endothelial cells of cerebral capillaries. Partial inhibition of this process by barbiturates may be of significance to cerebral protection.

3T3 Cells↗
PubMed1997

Changes in the signalling status of the small GTP-binding proteins Rac and Rho do not influence insulin-stimulated hexose transport.

Post-receptor signalling molecules that convey the signal from the activated insulin receptor to the actual process of Glut4 translocation and hexose uptake are poorly understood. Various studies have suggested a requirement of the lipid kinase phosphatidylinositol-3 kinase (PI3-kinase) in this process. PI3kinase regulates the activation status of the small GTP-binding protein Rac which, in turn, is able to activate another G-protein Rho. Rac and Rho are known to regulate the structure of the membrane- and cytoplasmic actin-cytoskeleton. We have examined whether Rac and Rho transfer the signals generated by PI3kinase towards insulin-stimulated hexose uptake. For that purpose, we expressed in 3T3-L1 adipocytes the dominant-negative mutant of RacN17 using vaccinia virus-mediated gene transfer. The expression levels of the RacN17 protein were monitored by Western blotting. The abrogation of endogenous Rac signalling by expression of RacN17 was inferred from the observed loss of arachidonic acid release in response to insulin. Basal and insulin-stimulated hexose transport were not affected by expression of the RacN17 mutant. A possible contribution of Rho.GTP to stimulation of hexose uptake was examined by pre-incubation of adipocytes with lysophosphatidic acid (LPA). We observed a profound effect of LPA on the structure of the cytoskeleton and on the phosphorylation of Focal Adhesion Kinase (p125FAK), indicating that 3T3-L1 adipocytes respond to LPA and that Rho was activated by LPA. However, no effect was detected on the basal or on the insulin-stimulated hexose transport. We conclude that Rac and Rho are unlikely to be involved in insulin-stimulated hexose transport, suggesting a possible contribution of other signalling pathways, downstream of PI3kinase to this process.

3T3 Cells↗
PubMed1980

Effects of combined glutamine and serum deprivation on glucose control of hexose transport in mammalian fibroblast cultures.

Regulation of hexose transport in NIL hamster fibroblasts has been studied in confluent cultures preconditioned for 24 hr in media deprived of glutamine or of serum or of both. Cultures maintained in media containing dialyzed fetal calf serum and 4 mM glutamine accumulated up to 72 nmol of glutamine per mg of cell protein; in contrast, cells deprived of glutamine contained less than 1 nmol/mg of cell protein. Glutamine elicited a general enhancement of hexose transport compared with transport in glutamine-deprived cultures. This enhancement was particularly pronounced in glucose-fed cultures which in the absence of glutamine showed conspicuously low transport activity. When maintained in glucose media, cultures deprived of serum also showed a marked loss of hexose transport which, in this case, was not compensated for by addition of glutamine. However, regardless of the presence or absence of glutamine, these cultures were able to develop the usual transport enhancement response to glucose starvation. Moreover, 2,4-dinitrophenol was also able to elicit a pronounced enhancement of hexose transport in the glucose-fed cultures; this effect surpassed even the transport derepression observed in the glucose-starved cultures. In polyoma-transformed cultures maintained in serum-free media, hexose transport remained relatively high, even in the presence of glucose. However, addition of glutamine brought about an enhancement in both the presence and absence of serum. The various phenomena are discussed in regard to protein turnover in general and more specifically the turnover of hexose transport carriers.

Animals↗
PubMed1965

Fructose-1, 6-diphosphatase and acid hexose phosphatase of Escherichia coli.

Fraenkel, D. G. (Albert Einstein College of Medicine, New York, N.Y.), and B. L. Horecker. Fructose-1,6-diphosphatase and acid hexose phosphatase of Escherichia coli. J. Bacteriol. 90:837-842. 1965.-The conversion of fructose-1,6-diphosphate to fructose-6-phosphate (fructose-1,6-diphosphatase activity) is essential for growth of Escherichia coli on glycerol, acetate, or succinate, but is unnecessary for growth on hexoses or pentoses. It has sometimes been assumed that fructose-1,6-diphosphatase activity is due to a nonspecific acid hexose phosphatase. We have now obtained a number of one-step mutants which have lost the ability to grow on glycerol, succinate, or acetate, but which grow normally on hexoses; these mutants are deficient in a fructose-1,6-diphosphatase which can be assayed spectrophotometrically in the presence of Mg(++) and low concentrations of substrate. These mutants still possess the nonspecific acid hexose phosphatase, which does not require Mg(++) and is active only at much higher concentrations of fructose-1,6-diphosphate. Evidence is presented to support the hypothesis that the newly described activity is the physiological fructose-1,6-diphosphatase. The acid hexose phosphatase is a different enzyme whose function remains unknown.

Acid Phosphatase↗
PubMed1979

Serum protein-bound hexose in diabetes: the effect of glycemic control.

To determine whether the carbohydrate content of serum proteins is related to overall glycemic control, we studied serum protein-bound hexose and glycosylated hemoglobin [HbA1(a+b+c)] in 37 ambulant diabetic patients and 32 nondiabetic controls. Protein-bound hexose was correlated with HbA1(a+b+c) in the diabetic patients (r = 0.36, P less than 0.025). The mean protein-bound hexose level of the diabetic patients was greater than that of the controls (190.8 versus 174.7 mg/dl, P less than 0.01), but diabetic patients with HbA1(a+b+c) less than 12% had a mean protein-bound hexose similar to the controls. In nine of the diabetic patients, mean protein-bound hexose and HbA1(a+b+c) were significantly reduced during a period of intensive outpatient care, while two major serum glycoproteins, haptoglobins and alpha-1-antitrypsin, were unchanged. Our findings support the hypothesis that increased glycosylation of serum proteins may occur in diabetes mellitus; this abnormality in serum protein-bound hexose may be corrected by close attention to overall glycemic control.

Blood Proteins↗
PubMed1989

Effects of the anticancer agent VM-26 on hexose uptake in Ehrlich cells.

The chemotherapeutic agent VM-26 is a membrane-interactive drug which we have previously demonstrated to be a potent inhibitor of nucleoside transport. Since the carriers mediating nucleoside and hexose transport are structurally and functionally similar, we have further characterized the membrane related properties of this agent by examining its effect on the transport and phosphorylation of hexoses in Ehrlich ascites cells. Under conditions in which only the transport component of hexose uptake was measured, VM-26 had no effect on the influx of 2-deoxyglucose, 3-0-methylglucose, or D-glucose. Glucose-sensitive cytochalasin B binding was only weakly inhibited by the drug. However, VM-26 was an apparent non-competitive inhibitor of the net uptake of 2-deoxyglucose (transport and phosphorylation). Measurement of hexokinase activity in cell extracts failed to demonstrate any significant effect of VM-26 on enzyme activity. In summary, although VM-26 is a potent inhibitor of the transport of nucleosides, it has no apparent effect on the transmembrane flux of hexoses indicating a differential effect on nucleoside and hexose transporters. The ability of the drug to decrease the net accumulation of hexoses in the absence of any detectable effect on hexokinase activity warrants further investigation.

3-O-Methylglucose↗
PubMed1988

Inhibition of hexose transport by adenosine derivatives in human erythrocytes.

The human erythrocyte membrane carriers for hexoses and nucleosides have several structural features in common. In order to assess functional similarities, the effects of adenosine derivatives on hexose transport and cytochalasin B binding sites were studied. Adenosine inhibited zero-trans uptake of 3-O-methylglucose half-maximally at 5 mM, while more hydrophobic adenosine deaminase-resistant derivatives were ten- to 20-fold more potent transport inhibitors. However, degradation of adenosine accounted for very little of this difference in potency. Hexose transport was rapidly inhibited by N6-(L-2-phenylisopropyl)adenosine at 5 degrees C in a dose-dependent fashion (EC50 = 240 microM), to lower the transport Vmax without affecting the Km. A direct interaction with the carrier protein was further indicated by the finding that N6-(L-2-phenylisopropyl)adenosine competitively inhibited [3H]cytochalasin B binding to erythrocytes (Ki = 143 microM) and decreased [3H]cytochalasin B photolabeling of hexose carriers in erythrocyte ghosts. The cross-reactivity of adenosine and several of its derivatives with the hexose carrier suggests further homologies between the carriers for hexoses and nucleosides, possibly related to their ability to transport hydrophilic molecules through the lipid core of the plasma membrane.

3-O-Methylglucose↗
PubMed2001

Expression and activity of the Hxt7 high-affinity hexose transporter of Saccharomyces cerevisiae.

High-affinity hexose transport is required for efficient utilization of low hexose concentrations by the baker's yeast Saccharomyces cerevisiae. These low concentrations occur during the late exponential phase of batch growth on hexoses, during hexose-limited chemostat or fed-batch culture, or during growth on sugars such as sucrose and raffinose that are hydrolysed to hexoses outside the cell. The expression of the Hxt7 high-affinity glucose transporter of S. cerevisiae was examined during batch growth on glucose medium in a wild-type strain and a strain expressing only HXT7 (i.e. with null mutations in HXT1-HXT6). In the wild-type strain, HXT7 transcription was repressed at high glucose and was detected when the glucose in the culture approached depletion. In the HXT7-only strain, transcription of HXT7 was constitutive throughout the glucose growth phase and was increased further at low glucose concentrations. After glucose depletion, the levels of HXT7 mRNA declined rapidly in both strains. In contrast, the Hxt7 protein was relatively stable after glucose depletion. By monitoring the subcellular localization of an Hxt7::GFP fusion protein it was observed that Hxt7 was localized in the plasma membrane, even when expressed at high glucose concentrations in the HXT7-only strain. After glucose depletion Hxt7 was gradually endocytosed and targeted to the vacuole for degradation. The Hxt7::GFP fusion protein was a fully functional hexose transporter with a catalytic centre activity of approximately 200/sec. It is concluded that repression of HXT7 and degradation of Hxt7 at high glucose concentrations is dependent on a high glucose transport capacity.

Culture Media↗
PubMed1981

Role of Ca2+ and Mg2+ in neutrophil hexose transport.

The influence of extracellular Ca2+ and Mg2+ on the transport of 2-deoxy-[3H]glucose into human polymorphonuclear neutrophils was studied. Omission of these cations from the cell suspensions had little effect on resting hexose uptake. Furthermore, the addition of the bivalent cation chelator, EDTA, depressed uptake only slightly. Similarly, neither cation was essential for the enhanced 2-deoxy-D-[3H]glucose uptake stimulated by two chemotactic factors (C5a and N-formylmethionylleucylphenylalanine) and arachidonic acid: enhanced uptake was only partially depressed by the omission of Ca2+ and Mg2+ from the suspensions and was still prominent in the presence of EDTA. Two other neutrophil stimulants, the ionophores, A23187 and ionomycin, also enhanced hexose uptake but their actions were heavily dependent upon extracellular bivalent cations and were totally abrogated by EDTA. In all instances, extracellular Ca2+, but not Mg2+, supported optimal enhanced hexose transport induced by stimuli. Activation of 2-deoxy-D-[3H]glucose uptake by each of the five stimuli was totally blocked by cytochalasin B (a blocker of carrier-mediated hexose transport) and D-glucose but not by L-glucose. The data indicate, therefore, that a variety of neutrophil stimulants activate carrier-mediated hexose transport. Although this transport can be triggered by the movement of extracellular Ca2+ into the cell (as exemplified by the action of the two ionophores), such Ca2+ movement is not required for the actions of chemotactic factors or arachidonic acid. Other mechanisms, such as a rearrangement of intracellular Ca2+, may be involved in mediating the activation of hexose transport induced by the latter stimuli.

Biological Transport, Active↗
PubMed1988

Stress-induced increase of hexose transport as a novel index of cytopathic effects in virus-infected cells: role of the L protein in the action of vesicular stomatitis virus.

The VSV-specific increase in hexose transport by BHK cells has been measured by assay of the [3H]dGlc/[14C]AIB uptake ratio. The effect was abolished by uv-irradiation of the virus, indicating that viral gene expression is required. Cells infected with the T1026 R1 mutant of VSV, which causes only slight cytopathic changes, exhibited only a slight increase in hexose uptake. Cells infected with temperature-sensitive (ts) mutants of VSV that are defective in the function of the viral N, NS, G, or M proteins at the restrictive temperature (39.5 degrees) exhibited increased [3H]dGLC/[14C]AIB uptake ratios typical of wild-type virus at either restrictive (39.5 degrees) or permissive temperature (34 degrees). Cells infected with a mutant defective in the function of the viral L protein exhibited an increased [3H]dGlc/[14C]AIB uptake ratio at permissive temperature (34 degrees) only; at restrictive temperature (39.5 degrees) the uptake ratio was essentially the same as that of mock-infected cells. Temperature-shift experiments indicated that the effect on hexose transport persisted for at least 6 hr in cells which no longer expressed function L protein, and that when expression of L was restricted to the first 2 hr of infection, an almost complete stimulation of hexose transport was observed 4 hr later. These results indicate that expression of the L gene is a necessary factor for inducing an increased hexose uptake in VSV-infected BHK cells. They also suggest that the action of the L protein on hexose transport is indirect, and is presumably mediated by other cellular constituents. The studies support the concept that an increased dGlc uptake may be a useful index of the cytopathic consequences of virus infection.

Animals↗
PubMed1991

Influence of PMA and a low extracellular Ca2+ concentration on the development of the Na(+)-dependent hexose carrier in LLC-PK1 cells.

We have analyzed the development of Na(+)-dependent hexose transport during differentiation and during polarization of LLC-PK1, an established cell line with characteristics of the proximal tubule. When cell-cell contact was disturbed by a low extracellular Ca2+ concentration or by a phorbol myristate acetate (PMA) treatment, the development of Na(+)-dependent hexose transport was completely inhibited. The effect of PMA on the development of hexose transport could be uncoupled from its effect on the tight junctions. The PMA concentration needed for the latter effect was approx. 10-fold higher than for the former. As the primary cause of the PMA effect, an influence on the cytoskeleton is suggested. In contrast to PMA, the concentration dependence of both phenomena on the extracellular Ca2+ concentration was almost the same. Moreover, the incorporation of hexose carriers in the plasma membrane could be induced by changing the extracellular CA2+ concentration from low to normal. We conclude that there is a relation between the formation of tight junctions and the development of the Na(+)-dependent hexose carrier, possibly because Ca(2+)-dependent cell adhesion molecules play a role in both phenomena. However, a direct relation between Ca(2+)-dependent elements of the tight junctions and the insertion of the hexose carrier can not be excluded. The Ca(2+)-dependent development seems to be a common characteristic of apical membrane proteins in contrast to the development of the basolateral membrane protein, (Na(+)+K+)-ATPase.

Alkaline Phosphatase↗
PubMed1991

The hexose transporters at the plasma membrane and the tonoplast of transformed plant cells: kinetic characterization of two distinct carriers.

The plasma membrane hexose transporter and the tonoplast hexose transporter from heterotrophically grown transformed Nicotiana tabacum cells have been studied in vitro using membrane vesicles for trans-zero transport studies. In highly purified phase-partitioned outside-out plasma membrane vesicles (PMV) the hexose transporter showed an apparent Km value of 230 microM (substrate: 3-O-methyl-D-glucose (3-OMG); pHi 7.2/pHo 7.2), which was reduced to 120 microM when a pH gradient was imposed (pHo 5.7/pHi 7.2). However, the Vmax value was not affected indicating that no stable pH gradient was formed. Uptake experiments with 14C-labelled acetate supported this interpretation. Transport was insensitive to N-ethylmaleimide (NEM; up to 1 mM concentration) and p-chloromercuribenzene sulfonate (PCMBS; up to 500 microM), whereas the tonoplast hexose transporter (in mixed inside / out and outside / out vesicles) was inhibited by NEM in a substrate-protectable manner, and PCMBS was also inhibitory. Kinetically two components with apparent Km values of 6 and 20 mM could be distinguished for the tonoplast hexose transporter. Substrate specificities of both transporters were similar except for D-galactose and D-fructose. The results indicate structural differences between the tonoplast and plasma membrane hexose transporters in plants.

3-O-Methylglucose↗
PubMed1984

Further clues concerning the vectors essential to regulation of hexose transport, as studied in fibroblast cultures from a metabolic mutant.

A close study of the metabolic regulation of hexose transport in a hamster fibroblast mutant, highly defective in the enzyme phosphoglucose isomerase (PGI mutant), reveals the requirement for at least three vectors for transport regulation. The downward regulation of the hexose transport system, called the "transport curb," requires (i) a ligand for the transport system, (ii) oxidative energy metabolism, and (iii) some specific enzymes of the glucose-6-phosphate metabolism. Deprivation of glucose was shown to deprive the PGI mutant of UDP hexose, whereas the glucose-fed mutant contained high levels. The parental strain preserved the UDP hexose with or without glucose feeding. Cycloheximide added to the mutant showed two different types of effects. If added at the onset of glucose starvation, the up-regulation of the transport system was scarcely affected. If cycloheximide was added to the mutant at the onset of glucose refeeding, it prevented the development of the glucose-mediated transport curb. In the mutant, the glucose-mediated curb is not derived from energy metabolism but is solely dependent on certain enzymes of glucose-6-phosphate metabolism. The interference of this curb by cycloheximide requires evidently a reassessment, including that of the role of the UDP hexose pathway in regulation of the hexose transport system.

3-O-Methylglucose↗
PubMed1987

Metabolism of glucose into glutamate via the hexose monophosphate shunt and its inhibition by 6-aminonicotinamide in rat brain in vivo.

The treatment of rats for 4 h with 6-aminonicotinamide (60 mg kg-1) resulted in an 180-fold increase in the concentration of 6-phosphogluconate in their brains; glucose increased 2.6-fold and glucose 6-phosphate, 1.7-fold. Moreover, lactate decreased by 20%, glutamate by 8% and gamma-aminobutyrate by 12%, and aspartate increased by 10%. No significant changes were found in glutamine and citrate. In blood, 6-phosphogluconate increased 5-fold; glucose, 1.4-fold and glucose 6-phosphate, 1.8-fold. The metabolism of glucose in the rat brain, via both the Embden-Meyerhof pathway and the hexose monophosphate shunt, was investigated by injecting [U-14C]glucose or [2-14C]glucose, and that via the hexose monophosphate shunt alone by injecting [3,4-14C]glucose. The total radioactive yield of amino acids in the rat brain was 5.63 mumol at 20 min after injection of [U-14C]glucose, or 5.82 mumol after injection of [2-14C]glucose; by contrast, it was 0.62 mumol after injection of [3,4-14C]glucose. The treatment of rats with 6-aminonicotinamide showed significant decreases in these values, owing to decreases in the radioactive yields of glutamate, glutamine, aspartate, gamma-aminobutyrate, and alanine+glycine+serine. Glutamate isolated from the brain contained approximately 43% of its radioactivity in carbon 1 after injection of [3,4-14C]glucose, in contrast to 13% and 18% after injection of [U-14C]glucose and [2-14C]glucose, respectively, in both the control and treated rats. The calculations based on these findings showed that approximately 69% of the 14C-labelled glutamate was formed from [14C]acetyl coenzyme A (acetyl CoA) and the residual 31% by 14CO2 fixation of pyruvate after injection of [3,4-14C]glucose in both control and treated rats. The results gave direct evidence that glutamate and gamma-aminobutyrate in the brain were formed by metabolism of glucose via the hexose monophosphate shunt as well as via the Embden-Meyerhof pathway. From the radioactive yields of glutamate formed via [14C]acetyl CoA it was estimated that approximately 7.8% of the total glucose utilized was channelled via the hexose monophosphate shunt. Assuming that [14C]glutamate formed by carbon-dioxide fixation of pyruvate was also dependent on the metabolism of glucose through the hexose monophosphate shunt, the estimated value was approximately 9.5% of the total glucose converted into glutamate. The results of the present investigation, taken in conjunction with other findings, suggest that the utilization of glucose via the hexose monophosphate shunt is functionally important in the rat brain.

6-Aminonicotinamide↗
PubMed1989

Separation and characterization of four hexose kinases from developing maize kernels.

Four forms of hexose kinase activity from developing maize (Zea mays L.) kernels have been separated by ammonium sulfate precipitation, gel filtration chromatography, blue-agarose chromatography, and ion exchange chromatography. Two of these hexose kinases utilized d-glucose most effectively and are classified as glucokinases (EC 2.7.1.2). The other two hexose kinases utilized only d-fructose and are classified as fructokinases (EC 2.7.1.4). All hexose kinases analyzed had broad pH optima between 7.5 and 9.5 with optimal activity at pH 8.5. The two glucokinases differed in substrate affinities. One form had low K(m) values [K(m)(glucose) = 117 micromolar, K(m)(ATP) = 66 micromolar] whereas the other form had much higher K(m) values [K(m)(glucose) = 750 micromolar, K(m)(ATP) = 182 micromolar]. Both fructokinases had similar substrate saturation responses. The K(m)(fructose) was about 130 micromolar and the K(m)(ATP) was about 700 micromolar. Both exhibited uncompetitive substrate inhibition by fructose [K(i)(fructose) = 1.40 to 2.00 millimolar]. ADP inhibited all four hexose kinase activities, whereas sugar phosphates had little effect on their activities. The data suggest that substrate concentrations are an important factor controlling hexose kinase activity in situ.

Journal Article↗