Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.1.1 (hexokinase)
5,274 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glucose and lipid metabolism in the brain, liver and in a transplanted tumour were found to be variously altered within 2 to 3 h of administering single doses of the radiosensitizer Ro-03-8799 to normal and tumour-bearing mice. Hepatic lactate and glycerol-3-phosphate (G3P) levels were decreased but those of the ketone body beta-hydroxybutyrate (beta-HOBu) were raised. However, in the tumour, these levels were all enhanced. The lactate levels in brain remained relatively constant but both beta-HOBu and G3P levels were altered in a manner similar to that in the liver. The levels of glucose were approximately doubled in blood, brain and tumour, but whereas tumour G6P levels increased, those in the brain were lowered to below the limits of detection. Hepatic glucose levels were significantly decreased after 1 h but G6P levels were not affected. These changes could neither be related to inhibitory effects on hepatic glucokinase or brain hexokinase activity nor to limiting amounts of ATP in both tissues. However, the activity of glucose-6-phosphatase (G6P'ase) was distinctly raised in the liver and the hepatic glycogen stores were also rapidly lowered. Overall, the results suggest that Ro-03-8799 exerts a stimulatory effect on glucose production in the liver. In both liver and brain the levels of free fatty acids and phospholipids were increased whereas those of esterified fatty acids were lowered. Most importantly, the changes in metabolite levels affect the cellular redox couples; those of the cytosol (lactate/pyruvate; G3P/dihydroxyacetone phosphate (DAP] are directed towards the oxidised state in the liver but to a more reduced state in the tumour. The mitochondrial couple (beta-HOBu/acetoacetate (AcAc)) in both tissues is shifted towards the reduced state. These metabolic changes may result in an increase in the degree of hypoxia in the tumour and may well play an important role in the development of neuropathies.
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PMID:Effects on intermediary metabolism in mouse tissues by Ro-03-8799. 282 72

Activities of key carbohydrate-metabolizing enzymes in biopsied human tissues of hepatocellular carcinoma and related conditions were determined by established methods. Among the enzymes analyzed, fetal-type liver enzymes (low-Km hexokinase, glucose 6-phosphate dehydrogenase, and pyruvate kinase-M2) showed increased activities, and adult-type liver enzymes [glucose 6-phosphatase, fructose 1,6-bisphosphatase, high-Km hexokinase (or glucokinase), and pyruvate kinase-L] showed decreased activities, resulting in undifferentiated enzyme patterns not only in fetal livers and hepatocellular carcinomas but also in livers of acute and chronic hepatitis and liver cirrhosis with or without tumors. Hepatocellular carcinomas showed a general tendency of having greater enzyme deviations than hepatitic and cirrhotic livers. The extent of the enzyme deviation in hepatocellular carcinomas varied considerably from one enzyme to another for each tumor tissue as compared with that in the benign liver diseases. Thus, the phenotypic heterogeneity was important for discriminating between the neoplastic and inflammatory changes in differentiation markers. The enzyme patterns of tumors and their corresponding host cirrhotic livers were unrelated, suggesting that the cirrhotic liver has a significance as preneoplastic state only in terms of having a high incidence of evolving hepatocellular carcinoma.
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PMID:Profiles of carbohydrate-metabolizing enzymes in human hepatocellular carcinomas and preneoplastic livers. 282 76

We show in the accompanying paper that the steady-state level of free Ca2+ maintained by the organelles of permeabilized RINm5F insulinoma cells varies inversely with the ATP/ADP ratio when this ratio is set by addition of creatine phosphokinase and fixed ratios of creatine to creatine phosphate. We, therefore, asked whether acute cyclic alterations in the cytosolic ATP/ADP ratio in the range known to modulate O2 consumption might be involved in regulating the physiological activity of Ca2+ -ATPases and the cytosolic free Ca2+ level. To explore this hypothesis we combined two experimental systems: 1) permeabilized RINm5F insulinoma cells that can maintain a low medium Ca2+ concentration and 2) a cell-free extract of rat skeletal muscle that spontaneously exhibits oscillatory behavior of glycolysis and linked oscillations in the ATP/ADP ratio, when provided with glucose. The free Ca2+ level maintained by the permeabilized cells oscillated in phase with the glycolytic oscillations and correlated closely with the ATP/ADP ratio but not with glucose 6-phosphate, fructose 6-phosphate, orthophosphate, or pH. When glucokinase replaced hexokinase as the glucose phosphorylating enzyme, Ca2+ oscillations were induced by increasing the glucose concentration from 2 to 8 mM. The results demonstrate a link between metabolite changes and free Ca2+ levels in a reconstituted physiological system. They support a model in which oscillations in glycolysis and the ATP/ADP ratio may cause oscillations in cytosolic free Ca2+, beta-cell electrical activity, and insulin release.
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PMID:Linked oscillations of free Ca2+ and the ATP/ADP ratio in permeabilized RINm5F insulinoma cells supplemented with a glycolyzing cell-free muscle extract. 283 Dec 25

Glucose metabolism was investigated in two established clonal insulinoma cell lines (RINm5F and HIT) and in a newly developed line of mouse insulinoma cells (IgSV195). The hexokinase capacity in the homogenates of RINm5F cells was 22.1 +/- 3.23 U/g protein, but glucokinase was barely detectable (0.06 +/- 0.013 U/g protein). In contrast, both HIT and IgSV195 cells contained glucokinase (1.5 +/- 0.17 and 1.0 +/- 0.16 U/g protein, respectively) in addition to hexokinase activity. Glucose usage by the intact cells qualitatively reflected the glucose phosphorylation found in the cell-free extracts. RINm5F cells exhibited a high glucose usage rate with one high-affinity component, whereas both HIT and IgSV195 cells showed two components with different glucose affinities. HIT and IgSV195 cells may be useful for a model of pancreatic beta-cell glycolysis.
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PMID:Control of glucose phosphorylation and glucose usage in clonal insulinoma cells. 283 51

It was investigated whether the well-known transplantable insulinoma of the hamster (the Kirkman tumor) contains glucokinase and if so, what its kinetic characteristics are, and whether its cellular levels might be regulated in a manner typical for islet tissue. The supernatant of tumor homogenates contained a low-affinity component (Km 9.7 mmol/L) of glucose phosphorylating activity, apparently glucokinase. Partially purified insulinoma glucokinase exhibited similar kinetic characteristics to liver glucokinase (Km for glucose 5.0 and 5.3 mmol/L, half-maximal saturation 6.9 and 6.3 mmol/L, Hill coefficient 1.63 and 1.62, Ki for mannoheptulose 0.9 and 0.6 mmol/L in hamster insulinoma glucokinase and hamster liver glucokinase, respectively). Insulinoma glucokinase activity was not affected by the age of the tumor. Tumor-bearing hamsters without further treatment stayed normoglycemic (172 +/- 9.5 mg/dL) for the duration of the experiment. Fasting caused hypoglycemia (49 +/- 5.0 mg/dL), and pretreatment with streptozotocin prior to tumor transplantation caused hyperglycemia (393 +/- 20.6 mg/dL) in the tumor-bearing hamsters. Blood glucose levels of the host hamsters did not affect the content of the insulinoma glucokinase (83 +/- 3.5 mU/g in hypoglycemic group, 88 +/- 9.0 mU/g in hyperglycemic group, and 86 +/- 3.5 mU/g in normoglycemic group). Thus, biosynthesis and degradation of insulinoma glucokinase does not seem to be regulated by glucose as found to be true for islet glucokinase. Since glucokinase is constitutively present, the stable transplantable Kirkman tumor could serve as a useful model for studying the pancreatic B-cell glycolysis system which is characterized by the presence of both hexokinase and glucokinase.
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PMID:Characteristics of glucokinase of the Kirkman insulinoma. 283 31

Rat liver glucokinase (ATP:D-hexose 6-phosphotransferase, EC 2.7.1.1) was purified to homogeneity, cleaved, and subjected to amino acid sequence analysis. Forty-five percent of the protein sequence was obtained, and this information was used to design oligonucleotide probes to screen a rat liver cDNA library. A 1601-base pair cDNA (GK1) contained an open reading frame that encoded the amino acid sequences found in the peptides used to generate the oligonucleotide probes. A second cDNA was subsequently identified (GK.Z2), which is 2346 base pairs long and corresponds to nearly the entire glucokinase mRNA. Blot transfer analysis of hepatic RNA showed that glucokinase mRNA exists as a single species of about 2400 nucleotides. Four hours of insulin treatment of diabetic rats resulted in a 30-fold induction of this mRNA. GK.Z2 has a long open reading frame which, with the known partial peptide sequence, allowed us to deduce the primary structure of glucokinase. The enzyme is composed of 465 amino acids and has a mass of 51,924 daltons. Glucokinase has 53 and 33% amino acid sequence identities with the carboxyl-terminal domains of rat brain hexokinase I and yeast hexokinase, respectively. If conservative amino acid replacements are also considered, glucokinase is similar to these two enzymes at 75 and 63% of positions, respectively. The putative glucose- and ATP-binding domains of glucokinase were identified, and these regions appear to be highly conserved in the hexokinase family of enzymes.
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PMID:The amino acid sequence of rat liver glucokinase deduced from cloned cDNA. 290 25

We recently described a preferential reduction of the secretory response to nutrient secretagogues (glucose; leucine plus glutamine) in islets maintained in culture after in vitro exposure to streptozotocin (SZ). The present study is an attempt to further clarify the biochemical mechanisms behind this defective insulin response. Mouse pancreatic islets were collagenase isolated and, after 4-5 days in culture, exposed during 30 min at 37 C to 1.8 mM SZ or vehicle alone (controls). The islets were subsequently cultured for 7 days in medium RPMI 1640 plus 10% calf serum, before the enzymatic and metabolic studies were performed. The activities of the glycolytic enzymes, hexokinase, glucokinase, and glyceraldehyde 3-phosphate dehydrogenase, were similar in the control and SZ-exposed islets. The relative amount of cytosolic and mitochondria-bound hexokinase was also unaffected by SZ. However, there was a 30-40% decrease in the activity of NAD+- and NADP+-dependent glutamate dehydrogenase and glutamate-aspartate transaminase in the SZ-treated islets. This coincided with a 40% decrease in L-[U-14C]glutamine oxidation in the SZ-treated islets. The D-glucose catabolism was further examined in the presence of D-[5-3H] and D-[6-14C] glucose. There was no difference between control and SZ islets in terms of glucose utilization at either 1.7 or 16.7 mM glucose. The oxidation of D-[6-14C]glucose was nevertheless decreased by more than 50% in SZ islets incubated at 16.7 mM (but not 1.7 mM) glucose. Altogether, these converging observations suggest a perturbation of distal regulatory processes, apparently at the mitochondrial level, in the D-glucose and L-glutamine catabolism of SZ-exposed islets. Whether this reflects a primary action of SZ on the islet mitochondria, or an inhibitory effect of SZ on the synthesis of mitochondrial enzymes, as a result of nuclear DNA damage, remains to be elucidated.
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PMID:Defective catabolism of D-glucose and L-glutamine in mouse pancreatic islets maintained in culture after streptozotocin exposure. 296 23

Pancreatic islets detect glucose level by phosphorylating it and converting the glycolytic rate to a signal to secrete insulin. Insulin secretion is greater from the alpha- than from the beta-anomer when the D-glucose level is below 22 mM. D-mannose behaves similarly but at nearly twofold higher concentrations. Two explanations have been proposed: 1) glucokinase, which has the same anomeric preference, is the principal hexose phosphorylating enzyme and limits glycolytic rate. 2) Phosphofructokinase limits glycolysis and hexokinase is the principal enzyme phosphorylating hexose; hexosediphosphate activators of phosphofructokinase are more readily synthesized from alpha-anomers of hexose phosphates. We have simulated both alternatives with a detailed anomerically specific model of the hexose-metabolizing glycolytic enzymes. The pathway preference for alpha-anomer of both hexoses was adequately reproduced with anomerically active limiting glucokinase. The other mechanism did not reproduce the observed pathway preference.
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PMID:Pancreatic islet discrimination of hexose anomers. I. Steady-state computer simulation. 297 Feb 27

Glucose usage by soluble fractions of cell extracts from two insulin-producing cell lines, RINm5F and HIT, was investigated. Analysis of enzyme activities indicated that glucose phosphorylation and phosphofructokinase are likely to be the rate-limiting steps of glycolysis in both RINm5F and HIT cell extracts. RINm5F extracts, which lack glucokinase, exhibited relatively flat concentration-dependency curves of glucose usage and showed substantial inhibition of hexokinase. HIT cell extracts, which contain glucokinase but lack hexokinase, exhibited sigmoidal concentration-dependency curves of glucose usage, reflecting almost fully expressed glucokinase activity. A reconstituted system prepared from RINm5F and HIT cell extracts exhibited a composite concentration-dependency curve of glucose usage and showed substantial inhibition of hexokinase and almost fully expressed glucokinase. However, conditions that activate phosphofructokinase, such as addition of ammonium sulfate or fructose 2,6-bisphosphate or alkalization, removed the inhibition of hexokinase without noticeably affecting the glucokinase component of usage. Results obtained with a reconstituted system containing RINm5F cell extract and purified glucokinase were consistent with these findings. The data presented here indicate that this reconstituted cell-free system serves as a valid model for the study of aspects of glycolytic control in the islet. This model illustrates the preeminent role of glucokinase in the control of glycolysis, consistent with its glucose-sensor function in the islet. In addition, these studies help to define the contribution of phosphofructokinase to the control of glycolysis and the mechanism whereby changes in phosphofructokinase activity could modulate, via changes in the glucose 6-phosphate concentration, the activity of hexokinase and hence the net glycolytic flux.
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PMID:Control of glucose metabolism in pancreatic beta-cells by glucokinase, hexokinase, and phosphofructokinase. Model study with cell lines derived from beta-cells. 297 77

Manganese causes a significant rise in hepatic glucokinase and hexokinase in 16-day-old suckling rats, and has an insulinomimetic effect in producing a precocious emergence of glucokinase (EC 2.7.1.2) and a rise in the low Km, hexokinases (EC 2.7.1.1) activities. These enzyme changes occur within 6 hr of manganese administration and there are accompanying increases in plasma insulin and hepatic cyclic GMP. That the effect of manganese is at a site other than, or in addition to, insulin secretion is suggested by the significant increases in glucokinase and hexokinase in 16-day-old streptozotocin-diabetic rats; in this group there is also an increase in hepatic cGMP similar in time scale to that of the normal-manganese-treated group. The effects of manganese and insulin were not additive. It is proposed that one site of action of manganese may be at the level of cyclic GMP systems. The results are also discussed in relation to the known action of manganese at the level of the protein phosphatases.
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PMID:The insulin-mimetic action of Mn2+: involvement of cyclic nucleotides and insulin in the regulation of hepatic hexokinase and glucokinase. 299 12


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