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)

The submitochondrial distribution of hexokinase was studied by repeated specific solubilizations and by tryptic digestion of isolated rabbit reticulocyte mitochondria. Whereas most of the enzyme is dissociably bound to the outer side of outer mitochondrial membrane, a small tightly bound portion is localized more internally. Electrophoretic separations did not reveal a specific isoenzyme pattern of the internal mitochondrial enzyme. Relationships between mitochondrial hexokinases and the intramitochondrial ATP pool, generated by oxidative phosphorylation, were studied by measuring 32P-fluxes following gamma-32P-ATP pulses on phosphorylating and non-phosphorylating mitochondria. Under both conditions, the specific activities in deoxyglucose-6-phosphate correspond closely to that of total gamma-ATP, thus not supporting a preferential use of intramitochondrial generated ATP by part of the mitochondrial hexokinases.
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PMID:Localization of hexokinase in mitochondria from rabbit reticulocytes and its relation to mitochondrial ATP-formation studied by measurement of 32P-fluxes. 703 69

Respiration and phosphorylation in functionally intact isolated reticulocyte mitochondria are controlled by the extramitochondrial ATP/ADP ratio. Mitochondrially bound hexokinase exhibits an apparent preference against mitochondrially formed ATP, as indicated by the lower apparent Km values under phosphorylating conditions. Thereby the control characteristics are shifted to higher ATP/ADP ratios compared to hexokinase free mitochondria. Respiration of intact reticulocytes was estimated to be smaller than had to be expected from the ATP/ADP ratios of total cells roughly corresponding to the cytosolic values. Inhibition of respiration leads to small drop of total adenine nucleotides and lowers the phosphorylation potential directly determined or calculated from metabolite indicators. Compartmentation of ADP by protein binding is discussed as a possible reason for the difference of determined and calculated phosphorylation potentials and the apparent discrepancy between the regulation of mitochondrial ATP-formation in isolated mitochondria and intact reticulocytes.
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PMID:Studies on the regulation of mitochondrial ATP formation in rabbit reticulocytes. 731 7

Glucose phosphorylating activities were measured in liver extracts from chicks at several developmental stages. Enzyme activity levels in supernates were low (about 0.16 units/g liver) from day 10th of egg incubation until the 17th day, at which time a transient increase to 0.5 units/g was observed. At hatching, the levels were again low (0.15 units/g) compared to adult levels (0.9 units/g). Particulate hexokinase activity was rather constant from day 10th to adulthood (about 0.3 units/g). Chromatography of liver supernates in DEAE-cellulose columns revealed the presence of four hexokinases in embryos up to day 15th of incubation. From that day onwards, the least retained from (hexokinase 4) was no longer found. The most retained form (hexokinase 1) disappeared at hatching, at which time a pattern consisting of hexokinases 2 and 3 was found to be very similar to the adult profile. The four isozymes were characterized as low Km glucose hexokinase of broad sugar specificities and molecular weights of about 100,000. Particulate hexokinase activity of embryonic chick liver was found to be composed of the same isozymes observed in cytosolic extracts. Incubation of particles with glucose 6-P or ATP failed to release hexokinase activity.
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PMID:Ontogeny of chick liver hexokinase isozymes. 734 73

Differences in modes of control of glycolysis in tumor cells, compared with normal cells, have suggested that phosphofructokinase may not catalyse the rate-controlling step. Instead, hexokinase activity may assume a more important regulatory role. Hexokinase activities are consistently lower than those of phosphofructokinase in tumor cells, and the former enzyme may be saturated with its substrate (M. Board et al., Biochem. J. 265: 503-509, 1990). The present work has focused on the glucose-phosphorylation step in tumor cell glycolysis. A range of eight human tumor cell-lines, one human tumor tissue, and four rat tumor cell lines were found to have an additional glucose-phosphorylating activity, with properties similar to hepatic glucokinase. Maximal activities range from 1.1-20 nmol/min/mg cell protein, and the activity is consistently absent from any untransformed cell line or tissue tested, except rat liver tissue (18 nmol/min/mg cell protein). Tumor cell glucokinase activity has been characterized by its high Km for glucose (8-11.8 mM); inhibition by the specific glucokinase inhibitor, mannoheptulose (I50, 12.5 mM); and lack of inhibition by 10 mM glucose-6-phosphate. Mannoheptulose also causes inhibition of glucose uptake by tumor cells (25-75% at 30 mM mannoheptulose) and inhibition of rates of growth of cultured tumor cell lines (I50, 21.4 mM). Rates of growth of human tumors in experimental animals are dramatically reduced (by 65-79%) by a dose of 1.7 mg/g mannoheptulose daily for 5 days. The potential of the naturally occurring sugar, mannoheptulose (which is purified from avocados and is assumed to be of low toxicity), as a cancer treatment is discussed.
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PMID:High Km glucose-phosphorylating (glucokinase) activities in a range of tumor cell lines and inhibition of rates of tumor growth by the specific enzyme inhibitor mannoheptulose. 761 62

Hexose-phosphorylating enzymes from the starch-utilizing yeast Schwanniomyces occidentalis were purified and two isoenzymes separated. The substrate pattern characterized one of these as a hexokinase phosphorylating glucose and fructose and the other as a glucokinase unable to phosphorylate fructose. The purified Schw. occidentalis hexokinase had a KM value of 0.98 mM for glucose and 9.3 mM for fructose. The hexokinase gene was cloned by cross hybridization with a probe from the Saccharomyces cerevisiae HXK2 gene. Deletion of Schw. occidentalis hexokinase by gene replacement yielded a mutant unable to grow on fructose as sole carbon source, but still growing on glucose. Deletion mutants of Schw. occidentalis hexokinase prevented glucose repression of invertase and maltase. Growth deficiencies and the defect of glucose repression of a S. cerevisiae hexokinase null mutant could be restored by heterologous expression of the Schw. occidentalis hexokinase. Moreover, the results clearly showed the existence of a separate glucokinase in Schw. occidentalis.
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PMID:Molecular and biochemical characterization of the hexokinase from the starch-utilizing yeast Schwanniomyces occidentalis. 761 56

In this study the glucose responsiveness of isolated, overnight-cultured islets of obese LA/N-corpulent (cp/cp) rats was compared with glucose phosphorylating activity to determine whether changes in the function of glucokinase could be identified. Islets from both male and female cp/cp rats showed a left-shifted concentration response to glucose, with EC50 values of 1.5 and 4.6 mM, respectively, compared with 9.2 mM for lean control islets. Islets from cp/cp rats were partially resistant to inhibition by mannoheptulose, a glucokinase inhibitor. Minimum inhibitory concentrations were 10 mM in cp/cp vs. 3 mM in lean rat islets. Glucose phosphorylating potential was markedly increased in islets of male cp/cp, but not female cp/cp, compared with lean rats. The maximal velocity (Vmax) of hexokinase was increased 5-fold, while the Km of glucokinase was significantly decreased, in male cp/cp compared with the lean control islets(3.6 vs. 35.2 mM). The Km for glucokinase was also decreased in female cp/cp rat islets (17.2 mM). The data from male cp/cp rat islets are consistent with the idea that increased glucose phosphorylation capacity can contribute to insulin hypersecretion and an extreme leftward shift in the concentration-response curve. However, other factors must also be considered because female cp/cp rats have moderately increased insulin secretory capacity without marked changes in total glucose phosphorylating capacity.
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PMID:Increased glucose phosphorylating activity correlates with insulin secretory capacity of male JCR:LA-corpulent rat islets. 767 Nov 92

Human hexokinase (HK) II, a glucose phosphorylating enzyme in muscle tissue, plays a central role in glucose metabolism. Since reduced insulin-stimulated glucose uptake and reduced glucose-6-phosphate content in muscle have been demonstrated in pre-non-insulin-dependent diabetes mellitus (pre-NIDDM) and NIDDM subjects, we have examined the coding region of the HKII gene in NIDDM patients to determine whether these patients show genetic polymorphisms that are associated with or contribute to the disease. Single-strand conformational polymorphism analysis and nucleotide sequencing were initially performed on the entire coding region of the HKII gene of 38 insulin-resistant NIDDM patients and 5 healthy control subjects. This analysis revealed four missense mutations at codons 142 (Gln to His), 148 (Leu to Phe), 497 (Arg to Gln), and 844 (Arg to Lys) and an additional six exon polymorphisms that did not predict any change in amino acid composition of the protein. One homozygous and nine heterozygous carriers of the codon 142 mutation were found among the NIDDM patients. The mutations at codons 148, 497, and 844 were each found in one diabetic subject and only on one allele. There were no carriers of compound heterozygous mutations. A subsequent study of 301 patients with NIDDM and 151 healthy control subjects revealed no additional mutations at codons 148, 497, or 844. The total frequency of the mutated allele at codon 142 was 18.9% among the control subjects and 17.0% among the NIDDM patients (chi 2 = 0.56, P = 0.45).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Identification of four amino acid substitutions in hexokinase II and studies of relationships to NIDDM, glucose effectiveness, and insulin sensitivity. 788 23

A single glucose-phosphorylating enzyme has been detected and purified from the citric acid accumulating fungus Aspergillus niger. The enzyme was formed constitutively, and high activities were formed on glucose and sucrose as carbon sources. Highest activities were formed during growth on high concentrations of glucose or sucrose. The enzyme, purified about 600-fold from cell-free extracts prepared from glucose-grown mycelia, gave a double band in denaturing (SDS)-polyacrylamide gel electrophoresis. Tryptic peptide patterns suggest that the lower molecular weight band was the product of either C- or N-terminal truncation. The specific activity of the enzyme was about 40 and 35 mumol/min and mg protein with glucose and fructose as substrates, respectively. The affinity for glucose was about 10(3)-fold higher than for fructose. The subunit molecular weight was 50,000 and the molecular weight of the native protein was 100,000 by gel permeation chromatography. Of the reaction products ADP, but not glucose 6-phosphate, inhibited hexokinase activity. Citrate inhibited (K1 0.15 mM) non-competitively with respect to both glucose and ATP, which was not due to Mg(2+)-chelation. 2-Deoxyglucose resistant mutant strains of A. niger were isolated which showed decreased growth rate and activity of hexokinase during growth on glucose, while their growth on fructose and hexokinase activities were comparable to the parent strain. They displayed a reduced rate of citric acid accumulation. It is concluded that the synthesis of very high hexokinase activities may counteract citrate inhibition, thereby guaranteeing a high glycolytic flux during citric acid accumulation.
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PMID:Characterization and regulatory properties of a single hexokinase from the citric acid accumulating fungus Aspergillus niger. 803 43

Glucose metabolism and glucose-stimulated insulin secretion are thought to be controlled at the level of glucose phosphorylation in pancreatic islet beta-cells. In the current study we have investigated the importance of glucose phosphorylation by using recombinant adenovirus as a gene delivery system for isolated rat islets. Treatment of islets with a virus containing the cDNA encoding the Escherichia coli beta-galactosidase gene (AdCMV-beta GAL) resulted in efficiencies of gene transfer of 70.3 +/- 2.5 and 61.2 +/- 2.2% in two independent experiments. Treatment of islets with a virus containing the cDNA encoding rat hexokinase I (AdCMV-HKI) resulted in a 10.7-fold increase in immunodetectable hexokinase protein and a similar increase in enzyme activity. A large percentage of the overexpressed hexokinase activity was associated with a cell fraction enriched in mitochondria. These changes in enzyme level were accompanied by a 2-fold increase in insulin release and [5-3H]glucose usage at basal glucose concentrations (3 mM). The rate of glucose usage at 20 mM glucose and the magnitude of the insulin secretory response to this stimulatory level of the sugar were unchanged relative to control islets. Overexpression of hexokinase I in isolated islets therefore creates a phenotype of elevated basal insulin release similar to that seen in islets from obese and insulin-resistant mammals. The discrepancy between the large increase in hexokinase activity and the small increase in glucose usage and insulin release may indicate, however, that other steps in glucose metabolism become rate-limiting after only modest increases in glucose-phosphorylating activity.
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PMID:Overexpression of hexokinase I in isolated islets of Langerhans via recombinant adenovirus. Enhancement of glucose metabolism and insulin secretion at basal but not stimulatory glucose levels. 806 45

Uptake and metabolism of mannose were studied in astroglia-rich primary cultures derived from neonatal rat brains. A saturable component of mannose uptake was found with half-maximal uptake at 6.7 +/- 1.0 mM mannose. In addition, a non-saturable component dominated the uptake at high concentrations of mannose. Glucose, cytochalasin B, or phloretin in the incubation buffer inhibited the carrier-mediated uptake of mannose. Within the astroglial cells mannose is phosphorylated to mannose-6-phosphate. In cell homogenates, the KM value of mannose-phosphorylating activity was determined to be 24 +/- 7 microM. The Vmax value of this activity is only 40% that of glucose-phosphorylating activity. Mannose-6-phosphate was converted to fructose-6-phosphate by mannose-6-phosphate isomerase. The specific activity of this enzyme in homogenates of astroglial cultures was higher than that of hexokinase. Two products of mannose utilization in astroglial cells are glycogen and lactate. The amounts of each of these products increased with increasing concentrations of mannose. In contrast to the generation of lactate, that of glycogen from mannose was enhanced in the presence of insulin. In conclusion, we suggest that mannose is taken up into the cells of astroglia-rich primary cultures by the glial glucose transporter and is metabolized to fructose-6-phosphate within the astroglial cells.
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PMID:Utilization of mannose by astroglial cells. 813 58


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