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PubMed1992

Exploring the hexokinase glucose binding site through correlation analysis and molecular modeling of glucosamine inhibitors.

A series of N-substituted glucosamines has been designed, synthesized, and tested as inhibitors of yeast hexokinase. All derivatives exhibited competitive inhibition kinetics with respect to glucose. Quantitative structure-activity relationships were derived from the resulting inhibition data. The most significant equation demonstrated the existence of highly specific steric effects for the seven meta-substituted benzoylglucosamines included in the relationship. Molecular modeling of potential complexes between the inhibitors and the hexokinase substrate binding site strongly suggests that the steric effects arise from potential contacts with two amino acid residues lying in the region occupied by the amide substituents.

Binding Sites↗
PubMed1997

Yeast hexokinase inhibitors designed from the 3-D enzyme structure rebuilding.

This work describes a search for hexokinase inhibitors based on the interactions analysis at the active site of the X-ray resolved o-tolulyl-glucosamine-hexokinase (OTG-HK) complex structure. As the actual enzyme sequence was unknown when the X-ray structure was made (only 30% homology), the structure of the complex was rebuilt by modelling on the X-ray structure frame which allowed residues in close vicinity to the inhibitor to be defined, particularly Glu249 and Gln278. Compounds with inhibitor-bearing groups able to interact with these residues were synthesized and assayed. Some of them revealed strong affinities, in the Km range for glucose. Kinetic analysis of their behaviour towards glucose and ATP together with spectroscopic studies using NMR, allowed the determination of the corresponding inhibition patterns and provided complementary information on HK.

Amino Acid Sequence↗
PubMed1977

The effect of non-protein energy source and age on hexokinase concentration in chick muscle.

Muscle hexokinase was ascertained in the gastrocnemius muscles of 160 male chicks. Observations were made in four age groups and two diets. No differences in enzyme activity were observed which could be attributed to the feeding of either the high-carbohydrate or high-fat diet. Hexokinase activity declined significantly between 6 and 12 days of age in the chicks fed the respective diets.

Age Factors↗
PubMed1999

Glut-1 and hexokinase expression: relationship with 2-fluoro-2-deoxy-D-glucose uptake in A431 and T47D cells in culture.

Uptake of 2-[18F]-2-deoxy-D-glucose (FDG) has been used as a marker of increased glucose metabolism to visualize, stage, and monitor progression of human cancers with positron emission tomography. Many human tumors have been shown to overexpress the Glut-1 glucose transport protein. The aim of this study is to define whether a quantitative relationship exists between the amount of Glut-1 expressed by cells and their ability to accumulate FDG. We characterized the expression of the known facilitative and sodium-dependent glucose transporter isoforms in six different cancer cell lines used in our laboratory (A431, MDA-MB-231, T47D, CaCo II, MCF7, and HepG2). A431 and T47D cells express, respectively, the highest and lowest amount of Glut-1 mRNA by Northern blot of all of the cells analyzed, and no other glucose transporter isoforms were detectable by this method in both cell lines. Both total and plasma membrane-associated Glut-1 protein levels were higher in A431 than in T47D cells, consistent with the higher Glut-1 mRNA levels. However, T47D cells accumulate FDG more rapidly than do A431 cells. 3-O-Methylglucose transport is higher in A431 cells. Although hexokinase I and II mRNA levels are higher in A431 cells than in T47D cells, the ability of mitochondrial preparations to phosphorylate FDG is higher in T47D cells. Our data indicate that in these cultured cells, FDG uptake correlates better with FDG phosphorylating activity of mitochondrial preparations rather than the level of expression of the Glut-1 or hexokinase I and II genes.

Biological Transport↗
PubMed1975

A variant of hexokinase isoenzymes detected in ascites tumor cells.

In the hexokinase isoenzyme pattern on the cellulose acetate membrane electropherogram of the supernatant fraction of Ehrlich ascites tumor cells, a band was detected moving slower than of common Type I isoenzyme. This band was assumed to be due to the presence of a variant of the hexokinase isoenzymes in the cells, since such a band was not detected in the normal tissues, and a change in the intensity of the band in response to a sulfhydryl agent, etc., differed from that of the common Type I and II isoenzymes. The band was also found in AH-7974 and MH-134 ascites tumor cells, in spite of the difference in the species of the tumor-bearing animals and originating tissue.

Animals↗
PubMed2002

Relationship between retention index in dual-phase (18)F-FDG PET, and hexokinase-II and glucose transporter-1 expression in pancreatic cancer.

UNLABELLED: Recently, some studies have shown that delayed scanning with (18)F-FDG PET may help to differentiate malignant from benign pancreatic lesions. However, no study has evaluated the relationship between temporal changes in (18)F-FDG uptake and expression of hexokinase or glucose transporter. METHODS: Twenty-one consecutive patients with pancreatic cancer were studied preoperatively by dual-phase (18)F-FDG PET, performed 1 and 2 h after injection of (18)F-FDG. The standardized uptake value (SUV) of the pancreatic cancer was determined, and the retention index (RI) (%) was calculated by subtracting the SUV at 1 h (SUV1) from the SUV at 2 h (SUV2) and dividing by SUV1. The percentages of cells strongly expressing hexokinase type-II (HK-II) and glucose transporter-1 (GLUT-1) were scored on a 5-point scale (1 = 0%-20%, 2 = 20%-40%, 3 = 40%-60%, 4 = 60%-80%, 5 = 80%-100%) by visual analysis of immunohistochemical staining of paraffin sections from the tumor specimens using anti-HK-II and anti-GLUT-1 antibody (HK-index and G-index, respectively). RESULTS: SUV2 (mean +/- SD, 5.7 +/- 2.6) was higher than SUV1 (5.1 +/- 2.1), with an RI of 8.5 +/- 11.0. Four cases of cancer, in which SUV2 showed a decline from SUV1, showed a low HK-index (1.8 +/- 1.1), whereas 4 cases with an RI of > or =20 and 13 cases with an intermediate RI (0-20) showed significantly higher HK-indices (4.3 +/- 0.7 and 3.1 +/- 1.5, respectively; P < 0.05). RI showed a positive correlation with HK-index, with an R(2) of 0.27 (P < 0.05), but no significant correlation with the G-index. SUV1 showed no relationship with the HK-index but showed a weak positive correlation with the G-index, with an R(2) of 0.05 (P = 0.055). CONCLUSION: These preliminary findings suggest that the RI obtained from dual-phase (18)F-FDG PET can predict HK-II expression and that the SUV (at 1 h) has a positive correlation with GLUT-1 expression but not with HK-II expression.

Adenocarcinoma↗
PubMedDate not supplied

[Physico-chemical and kinetic properties of hexokinase isoenzymes from human normal and tumor tissues].

Individual hexokinase isoenzymes (isoHK) are isolated from normal and malignant human stomach mucosa. IsoHK from tumour tissue are found to have KM for glucose 10 times as low as isoHK from normal tissue. Molecular weights of individual isoHK from normal and tumour tissues are similar (at the range of 112,000-125,000). The treatment of protein preparation with 8M urea in the presence of 1% sodium docecyl sulphate resulted in the appearance of a single band with molecular weight of 58,000-60,000 for all the isoHK under polyacrylamide gel electrophoresis. Intensive bands with molecular weight of 60,000 and 96,000 and a number of minor bands were observed under polyacrylamide gel disc elect-ophoresis in the absence of urea. 2-Mercaptoethanol did not affect the results of disc electrophoresis. It is concluded that the molecule of human hexokinase consists of two subunits with molecular weight of 60,000.

Electrophoresis, Polyacrylamide Gel↗
PubMed1976

[Activity of hexokinase isoenzymes in the nuclei of cell cultures infected with oncogenic type-12 adenovirus].

The isoenzymic spectrum of a glycolytic enzyme-hexokinase (HK. 2,7.1.1) in the globuline fraction of cell nuclei of rat embryo fibroblasts (REF), infected with human adenovirus of type 12, was studied at 3, 5, 8, 18, 24 days of cultivation. Control studies revealed 3 hexokinase isoenzymes, the third one showing the highest activity and electromobility. In cultures under experiment the first enzyme was found to be lost at 5, 8, 18 days of infection and its activity to be enhanced on the 24th day. The activity of enzymes II and III increased yet on the 3d day of the culture infection. These alterations were especially pronounced to the start of morphological transformation (18th day) and at the 24th day, when the culture was entirely transformed.

Adenoviridae↗
PubMed1992

Glucose 6-phosphate and hexokinase can be used as an ATP-regenerating system by the Ca(2+)-ATPase of sarcoplasmic reticulum.

In the presence of hexokinase, vesicles derived from the sarcoplasmic reticulum of skeletal muscle are able to accumulate Ca2+ in a medium containing ADP and glucose 6-phosphate. No significant Ca2+ uptake is observed if one of these components is omitted from the assay medium. Due to its high affinity for ATP, the Ca(2+)-ATPase can use the very low concentrations of ATP formed from glucose 6-phosphate and ADP to form a Ca2+ gradient. This finding indicates that glucose 6-phosphate and hexokinase can be used as an ATP-regenerating system. The Ca2+ uptake supported by glucose 6-phosphate and ADP is inhibited by glucose and D-xylose. Half-maximal inhibition is observed in the presence of 0.4 mM glucose and 100 mM D-xylose. The transport ratio (Ca2+ transported:substrate utilized) is the same for glucose 6-phosphate and ATP. The Ca2+ gradient formed when glucose 6-phosphate and ADP are the substrates can be used to synthesize ATP from ADP and Pi. The concentration of ATP formed after reversal of the Ca2+ pump is much higher than that expected from direct equilibration of the reaction between glucose 6-phosphate and ADP.

Adenosine Triphosphate↗
PubMedDate not supplied

[Kinetic characteristics of creatine kinase and hexokinase from rat skeletal muscles during dietary deficit of vitamin K and administration of pelentane].

Kinetic parameters of rat creatine kinase isozymes at different vitamin K supply and treatment with antivitamin K--pelentan have been determined. MM-isozyme (skeletal muscle) has selective sensitivity to the vitamin K deficit, while BB and MB-isozymes (brain, kidney and heart) have not. The value KM for ATP of MM-isozymes increases, while maximal activity decreases. Pelentan treatment does not lead to the change of MM-creatine kinase affinity to ATP. Soluble hexokinase of skeletal muscle in rats with vitamin K deficiency and treated with pelentan has higher affinity to glucose as compared to normal rat enzyme. It has been supposed that skeletal muscle hexokinase exists in a particular molecular form under vitamin K deficiency.

Animals↗
PubMed2006

[Regulation effect of d-alpha-tocopherol on the expression of hexokinase induced by high glucose in cultured human peritoneal mesothelium cells].

OBJECTIVE: To investigate the effect of d-alpha-tocopherol on the expression of hexokinase (HK) induced by high glucose in cultured human peritoneal mesothelium cell (HPMC). METHODS: Specimens of human omentum were obtained from consenting patient undergoing elective abdominal surgery. HPMC were isolated and subcultured by enzymatic disaggregation. Morphology and immunocytochemical method were used for identification. HPMC were divided into normal glucose group (0.1% glucose, equal to 5.5 mmol/L), high glucose group (0.5%, 1.0%, 1.5%, 2.5%, 4.25% glucose) and d-alpha-tocopherol group. After 24 h, standard G6PDH-coupled assay, temperature sensitive essay were used to detect the activity of total HK and its isozyme. Immunocytochemical staining was used for observation the intracellular location of HKII. Western blotting was used to analyze the protein expression of HKII and RT-PCR was used to detect the mRNA expression of HKII. The net glucose utilization was assayed by glucose disappearance from medium by hexokinase method. RESULTS: Primary cultured HPMC reacted positively for cytokeratin and vimentin and had numerous surface microvilli under electron microscope. High glucose induced HK activity in a dose-dependent manner and increased HKII isoform selectively. At concentration of 1.5%, 2.5% and 4.25% glucose for 24 h, the relative activity of total HK were 115.4%, 129.1% and 155.2%, respectively comparing with normal control (P < 0.05), and selectively increased HKII isoform expression. D-alpha-tocopherol blocked the activity of total HK and HKII induced by glucose. The relative activity of total HK inhibited by d-alpha-tocopherol was 82.1% (P = 0.001). After incubated with d-alpha-tocopherol, the net glucose utilization were decreased from (25.3 +/- 3.9) mmol/L to (17.3 +/- 2.1) mmol/L (P = 0.018). HKII stained light brown in cytoplasm of HPMC in normal group, accompanying with the increased concentration of glucose, the staining of HKII became strong and accumulated to nuclear. D-alpha-tocopherol made it thinning. The protein and mRNA expression of HKII were accorded with its activity. CONCLUSION: D-alpha-tocopherol inhibited the expression of HKII in activity, protein and mRNA induced by high glucose and decreased the net glucose utilization, which might become a method to improve ultrafiltration in peritoneal dialysis.

Cell Line↗
PubMed1991

Determination of nucleoside triphosphates by use of combined reactions of hexokinase and glucose-6-phosphate dehydrogenase.

ATP is known to be easily determined fluorometrically after it is utilized to produce the corresponding amount of NADPH by combined reactions of hexokinase and glucose-6-phosphate dehydrogenase. We studied further whether nucleoside triphosphates other than ATP can be also determined in a similar manner if they were incubated for a longer period with an increased amount of hexokinase. It was shown that CTP, GTP, ITP, and UTP can be utilized to produce the corresponding amount of NADPH after an incubation of at least 60 min and that 0 to 50 nmols of these nucleotides were able to be determined fluorometrically.

Adenosine Triphosphate↗
PubMed1976

[Action of an ATP analog, adenosine 5'-hyophosphophosphate in the reactions catalysed by hexokinase and fructose-6-phosphate kinase].

Adenosine 5'-hypoposphate phosphorylates glucose and fructose 6-phosphate in the presence of hexokinase and fructose 6-phosphate kinase respectively. It behaves as a competitive inhibitor versus ATP in the hexokinase reaction. Its affinity for the two enzymes is similar to that of ATP, the maximal velocities being however much lower.

Adenosine Triphosphate↗
PubMedDate not supplied

[Hexokinase in Alzheimer's disease].

Decreased hexokinase activity has been reported in brain, fibroblast, leukocytes and microvessels of patients with Alzheimer's disease. In this paper the results of an investigation on hexokinase activity in an Italian large pedigree are reported. The activity was comparable with that of the normal controls. These results suggest that Alzheimer's disease may be an heterogenic disorder.

Aged↗
PubMed1985

Monoclonal antibodies against rat brain hexokinase. Utilization in epitope mapping studies and establishment of structure-function relationships.

The effects of seven monoclonal antibodies on various functions of rat brain hexokinase (ATP:D-hexose-6-phosphotransferase, EC 2.7.1.1) have been assessed. Specifically, effects on catalytic properties (Km values for substrates, glucose and ATP X Mg2+; Ki for inhibition by glucose 6-phosphate), binding to the outer mitochondrial membrane, and glucose 6-phosphate-induced solubilization of mitochondrially bound hexokinase were examined. Epitope mapping studies with the native enzyme provided information about the relative spatial distribution of the epitopes on the surface of the native molecule. Binding of nucleotides (ATP or ATP X Mg2+) was shown to perturb the epitopes recognized by two of these antibodies. Neither nucleotides nor other ligands (glucose, glucose 6-phosphate, Pi) had detectable effect on epitopes recognized by the other five antibodies. Peptide mapping techniques in conjunction with immunoblotting permitted assignment of the epitopes recognized by several of the antibodies to specific segments within the overall primary structure. These results, together with previous work relating to the organization of structural domains within the molecule, permitted development of a three-dimensional model which provides a useful representation of major structural and immunological features of the enzyme, and depicts the association of those features with specific functions.

Adenosine Triphosphate↗
PubMed1989

Changes in hexokinase and glucose-6-phosphate dehydrogenase in red cells during hypo and hyperthyroidism.

Activities of hexokinase and glucose-6-phosphate dehydrogenase have been measured in red blood cells from thyroidectomized, triiodothyronine treated and hyperthyroid rats. After thyroidectomy, significant decrease in the activities of hexokinase and glucose-6-phosphate dehydrogenase was observed as compared to controls. The effects were reversed with triiodothyronine administration to the thyroidectomized rats. Hyperthyroidism increased both enzymes. The observations further confirm the hypermetabolic effects of thyroid hormones on the cellular metabolism.

Animals↗
PubMed1989

Improved stability of 2,3-bisphosphoglycerate during storage of hexokinase-overloaded erythrocytes.

Human red blood cells were overloaded with homogeneous human hexokinase using a procedure of encapsulation based on hypotonic hemolysis and isotonic resealing and reannealing to achieve a final activity that was 15 times higher than that in control cells. Storage for 5 weeks at 4 degrees C of hexokinase-overloaded erythrocytes shows that these cells undergo small K+ leakage and mean cell volume increase compared with control cells. Furthermore, after these 5 weeks of storage the 2,3-bisphosphoglycerate content was normal while the ATP concentration was slightly reduced. These results and other properties suggest that encapsulation of key glycolytic enzymes in erythrocytes can provide a new way to maintain in vitro functionally active red blood cells for at least 5 weeks.

2,3-Diphosphoglycerate↗
PubMed1987

Trypanosoma (Nannomonas) congolense: properties of hexokinase and phosphofructokinase from cultured procyclic trypomastigotes and bloodstream forms.

The distribution and kinetics of two key glycolytic enzymes hexokinase (HK) and phosphofructokinase (PFK) were studied in animal-infective bloodstream forms (haematozoic trypomastigotes) and uninfective procyclic forms (insect trypomastigotes) of Trypanosoma congolense. The results show that in both forms of T. congolense HK and PFK are particulate and are probably localized in a membrane-delimited organelle, the glycosome. Hexokinases of bloodstream and procyclic forms of T. congolense are kinetically similar with respect to their affinity for glucose and ATP, the apparent Km for glucose being within the range, of 91 microM to 100 microM and that for ATP, 65 microM to 91 microM. Phosphofructokinase of both forms responds to its substrate in a complex manner: a plot of initial velocity versus substrate concentration displays intermediary plateau regions.

Adenosine Triphosphate↗