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)

Hexokinases catalyze the phosphorylation of glucose and initiate cellular glucose metabolism. Hexokinase II (HKII) is the principal hexokinase isoform in skeletal muscle, heart, and adipose tissue. Isoproterenol and exogenous cyclic AMP (cAMP) increase HKII gene transcription in L6 myotubes. Various segments of the HKII promoter that direct the expression of the chloramphenicol acetyltransferase reporter gene were transfected into L6 myotubes to identify basal and cAMP response elements. The 5'-flanking region that extends 90 base pairs upstream of the transcription start site includes a CCAAT box and a cAMP response element (CRE); both contribute to basal promoter activity and each provides an independent, maximal response to cAMP. An inverted CCAAT motif, or Y box, located just upstream of the CCAAT box, contributes to basal promoter activity but is not involved in the cAMP response. Homo- and heterodimers composed of the CRE-binding protein and activating transcription factor-1 bind specifically to the CRE. The Y box and the CCAAT box specifically bind the factor NF-Y (also known as CBF).
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PMID:Identification and characterization of basal and cyclic AMP response elements in the promoter of the rat hexokinase II gene. 866 88

Hexokinase II protein is augmented in denervated skeletal muscle; therefore, we determined if hexokinase II gene transcription rates and mRNA levels are increased with denervation. The right hindlimb skeletal muscles of male rats were denervated while the left hindlimbs were sham operated. Seventy-two h following surgery, rats were sacrificed and the gastrocnemius and soleus muscles were harvested for nuclear and RNA isolation. Nuclear run-on and ribonuclease protection analyses indicated that denervation increased hexokinase II transcription rates and mRNA levels 42% and 88%, respectively (p < 0.05). Total hexokinase activity rose 23% in denervated gastrocnemius muscle. In conclusion, the increase in hexokinase II gene transcription and mRNA may account for the increase in hexokinase II protein and the subsequent rise in total hexokinase activity in denervated rat skeletal muscle.
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PMID:Transcriptional regulation of hexokinase II in denervated rat skeletal muscle. 929 50

A single bout of exercise increases the rate of insulin-stimulated glucose uptake and metabolism in skeletal muscle. Exercise also increases insulin-stimulated glucose 6-phosphate in skeletal muscle, suggesting that exercise increases hexokinase activity. Within 3 h, exercise increases hexokinase II (HK II) mRNA and activity in skeletal muscle from rats. It is not known, however, if a single bout of moderate-intensity exercise increases HK II expression in humans. The present study was undertaken to answer this question. Six subjects had percutaneous biopsies of the vastus lateralis muscle before and 3 h after a single 3-h session of moderate-intensity aerobic (60% of maximal oxygen consumption) exercise. Glycogen synthase, HK I, and HK II activities as well as HK I and HK II mRNA content were determined from the muscle biopsy specimens. The fractional velocity of glycogen synthase was increased by 446 +/- 84% after exercise (P < 0.005). Hexokinase II activity in the soluble fraction of the homogenates increased from 1.2 +/- 0.4 to 4.5 +/- 1.6 pmol.min-1.microgram-1 (P < 0.05) but was unchanged in the particulate fraction (4.3 +/- 1.3 vs. 5.3 +/- 1.5). HK I activity in neither the soluble nor particulate fraction changed after exercise. Relative to a 28S rRNA control signal, HK II mRNA increased from 0.091 +/- 0.02 to 0.195 +/- 0.037 (P < 0.05), whereas HK I mRNA was unchanged (0.414 +/- 0.061 vs. 0.498 +/- 0.134, P < 0.20). The increase in HK II activity after moderate exercise in healthy subjects could be one factor responsible for the enhanced rate of insulin-stimulated glucose uptake seen after exercise.
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PMID:Regulation of hexokinase II activity and expression in human muscle by moderate exercise. 948 62

To investigate the effect of exercise on GLUT-4, hexokinase, and glycogenin gene expression in human skeletal muscle, 10 untrained subjects (6 women and 4 men, 21.4 +/- 1.2 yr, 66.3 +/- 5.0 kg, peak oxygen consumption = 2.30 +/- 0.19 l/min) exercised for 60 min on a cycle ergometer at a power output requiring 73 +/- 4% peak oxygen consumption. Muscle samples were obtained by needle biopsy before, immediately after, and 3 h after exercise. Gene expression was quantified, relative to 29S ribosomal protein cDNA, by RT-PCR. GLUT-4 gene expression was increased immediately after exercise (1.7 +/- 0.4 vs. 0.9 +/- 0.3 arbitrary units; P < 0.05) and remained significantly higher than baseline 3 h after the end of exercise (2. 2 +/- 0.4 vs. 0.9 +/- 0.3 arbitrary units; P < 0.05). Hexokinase II gene expression was significantly higher than the resting value 3 h after the end of exercise (2.9 +/- 0.4 vs. 1.3 +/- 0.3 arbitrary units; P < 0.05). Exercise increased glycogenin mRNA more than twofold (2.8 +/- 0.6 vs. 1.2 +/- 0.2 arbitrary units; P < 0.05) 3 h after the end of exercise. For the first time, we report that a single bout of exercise is sufficient to cause upregulation of GLUT-4 and glycogenin gene expression in human skeletal muscle. Whether these increases, together with the associated increase in hexokinase II gene expression, lead to increased expression of these key proteins in skeletal muscle and contribute to the enhanced skeletal muscle glucose uptake, glycogen synthesis, and insulin action observed following exercise remains to be determined.
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PMID:Effects of exercise on GLUT-4 and glycogenin gene expression in human skeletal muscle. 1118 56

Glucose phosphorylation, catalyzed by hexokinase, is the first committed step in glucose uptake in skeletal muscle. Hexokinase II (HKII) is the isoform that is present in muscle and is regulated by insulin and muscle contraction. Glucose phosphorylation and HKII expression are both reduced in obese and type 2 diabetic subjects. A single bout of exercise increases HKII mRNA and activity in muscle from healthy subjects. The present study was performed to determine if a moderate exercise increases HKII mRNA expression and activity in patients with type 2 diabetes. Muscle biopsies were performed before and 3 hours after a single bout of cycle ergometer exercise in obese and type 2 diabetic patients. HKII mRNA and activity and glycogen synthase activity were determined in the muscle biopsies. Exercise increased HKII mRNA in obese and diabetic subjects by 1.67 +/- 0.34 and 1.87 +/- 0.26-fold, respectively (P <.05 for both). Exercise did not significantly increase HKI mRNA. When HKII mRNA increases were compared with the 2.26 +/- 0.36-fold increase in HKII mRNA previously reported for healthy lean subjects, no statistically significant differences were found. In contrast to the increase in HKII activity observed after exercise by lean healthy controls, exercise did not increase HKII activity in obese nondiabetic or diabetic subjects. Exercise increased glycogen synthase activity (GS(0.1) and GS(FV)) significantly in both obese nondiabetic and type 2 diabetic patients. The present results indicate that there is a posttranscriptional defect in the response of HKII expression to exercise in obese and type 2 diabetic subjects. This defect may contribute to reduced HKII activity and glucose uptake in these patients.
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PMID:Exercise increases hexokinase II mRNA, but not activity in obesity and type 2 diabetes. 1131 25

Two isoforms of hexokinase (type I and type II) are expressed in skeletal muscle; however, the intracellular distribution of these hexokinase isoforms in human skeletal muscle is unclear. The current study was undertaken to assess this issue because binding of hexokinase to subcellular structures is considered to be an important mechanism in the regulation of glucose phosphorylation. Vastus lateralis muscle was obtained from healthy lean individuals. Muscle homogenate was separated at 45,000g into particulate and cytosolic fractions. The activity and subcellular distribution of hexokinase isozymes in human skeletal muscle was determined using ion-exchange chromatography and a highly sensitive high-performance liquid chromatography-based hexokinase assay. This criterion method was used to validate a modified thermal inactivation method for distinguishing type I and type II isoforms. Mean hexokinase activity was 3.88 +/- 0.65 U/g wet wt or 0.64 +/- 0.11 U/mU creatine kinase (CrK) in the particulate fraction and 0.45 +/- 0.22 U/g wet wt or 0.07 +/- 0.03 U/mU CrK in the cytosolic fraction. Hexokinase I and II accounted for 70-75 and 25-30% of total hexokinase activity, respectively. Nearly all (95%) of hexokinase I activity (0.52 +/- 0.09 U/mU CrK) was found in the particulate fraction, consistent with the known high affinity of hexokinase I for mitochondria. Hexokinase II activity was also largely bound to the particulate fraction (72%), but 28% was found within the cytosolic fraction. Thus, within the particulate fraction, the relative contributions of hexokinase I and hexokinase II were 81 and 19%, whereas within the cytosolic fraction, the relative contributions for hexokinase I and hexokinase II were 37 and 63%.
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PMID:Hexokinase isozyme distribution in human skeletal muscle. 1137 24

Type II hexokinase is overexpressed in most neoplastic cells, and it mainly localizes on the outer mitochondrial membrane. Hexokinase II dissociation from mitochondria triggers apoptosis. The prevailing model postulates that hexokinase II release from its mitochondrial interactor, the voltage-dependent anion channel, prompts outer mitochondrial membrane permeabilization and the ensuing release of apoptogenic proteins, and that these events are inhibited by growth factor signalling. Here we show that a hexokinase II N-terminal peptide selectively detaches hexokinase II from mitochondria and activates apoptosis. These events are abrogated by inhibiting two established permeability transition pore modulators, the adenine nucleotide translocator or cyclophilin D, or in cyclophilin D knock-out cells. Conversely, insulin stimulation or genetic ablation of the voltage-dependent anion channel do not affect cell death induction by the hexokinase II peptide. Therefore, hexokinase II detachment from mitochondria transduces a permeability transition pore opening signal that results in cell death and does not require the voltage-dependent anion channel. These findings have profound implications for our understanding of the pathways of outer mitochondrial membrane permeabilization and their inactivation in tumors.
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PMID:Hexokinase II detachment from mitochondria triggers apoptosis through the permeability transition pore independent of voltage-dependent anion channels. 1835 Jan 75

It has long been observed that cancer cells rely more on glycolysis to generate ATP and actively use certain glycolytic metabolic intermediates for biosynthesis. Hexokinase II (HKII) is a key glycolytic enzyme that plays a role in the regulation of the mitochondria-initiated apoptotic cell death. As a potent inhibitor of hexokinase, 3-bromopyruvate (3-BrPA) is known to inhibit cancer cell energy metabolism and trigger cell death, supposedly through depletion of cellular ATP. The current study showed that 3-BrPA caused a covalent modification of HKII protein and directly triggered its dissociation from mitochondria, leading to a specific release of apoptosis-inducing factor (AIF) from the mitochondria to cytosol and eventual cell death. Co-immunoprecipitation revealed a physical interaction between HKII and AIF. Using a competitive peptide of HKII, we showed that the dissociation of hexokinase II from mitochondria alone could cause apoptotic cell death, especially in the mitochondria-deficient rho(0) cells that highly express HKII. Interestingly, the dissociation of HKII itself did not directly affect the mitochondrial membrane potential, ROS generation, and oxidative phosphorylation. Our study suggests that the physical association between HKII and AIF is important for the normal localization of AIF in the mitochondria, and disruption of this protein complex by 3-BrPA leads to their release from the mitochondria and eventual cell death.
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PMID:Role of mitochondria-associated hexokinase II in cancer cell death induced by 3-bromopyruvate. 1928 79

Hexokinase II is a key enzyme in the glycolytic pathway and CD133+ human hepatoma cells possess cancer stem cell-like properties. The expression and enzyme activity of hexokinase II in CD133+ and CD133- hepatoma cells were examined. CD133 on the surface of the hepatoma BEL-7402 cells was analyzed by flow cytometry and the cells were magnetically sorted into CD133+ and CD133- groups. CD133+ cells comprised 1.04% of the total BEL-7402 cell population. Reverse transcription-polymerase chain reaction (PCR) and quantitative real-time PCR were used to assay the expression of hexokinase II mRNA in these two groups. The level of mRNA in CD133- cells was 4.35 times greater than the level in CD133+ cells. 3,6-biphosphoglucose dehydrogenase-coupled colorimetric method and temperature-sensitive trials were applied to determine the enzyme activity of hexokinase II, which was 1.02 U/g protein in CD133+ cells and 2.47 U/g protein in CD133- cells. Hexokinase II was the major active hexokinase isoform in CD133+ cells, comprising 92.7% of the overall cellular hexokinase activity. The results indicate that hexokinase II is vitally meaningful for CD133+ hepatoma BEL-7402 cells. Hexokinase II represents a new therapeutic target for treating CD133+ hepatoma cells.
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PMID:Hexokinase II in CD133+ and CD133- hepatoma BEL-7402 Cells. 2190 86

Fatty acid synthase (FASN) is a key enzyme that plays a critical role in numerous metabolic functions by catalyzing the synthesis for long-chain fatty acids. FASN is highly expressed in various human cancers. This preferential expression makes FASN an attractive target for anticancer therapy. Hexokinase II (HKII) is overexpressed in most cancer cells, and it generally localizes to the outer mitochondrial membrane. Recent studies have demonstrated the protective role of mitochondrial HKII in preservation of mitochondrial integrity. The association of hexokinase with mitochondria has emerged as a powerful mechanism in protecting numerous cell types against cell death. We performed this study to examine the mechanism underlying apoptosis induced by cerulenin and with specific focus on its effect on HKII in ZR-75-1 human breast cancer cells. Additionally, we sought to elucidate whether inhibition of the PI3K/Akt pathway can potentiate the anticancer effect of cerulenin. Here, we showed that cerulenin disrupts the physical association between HKII and AIF, leading to eventual cell death. In addition, LY294002, a PI3K/Akt inhibitor, sensitized ZR-75-1 breast cancer cells to cerulenin-induced apoptosis. Collectively, cerulenin induces apoptosis via disrupting the interaction between AIF and HKII and inhibition of PI3K sensitizes cells to cerulenin-induced apoptosis in ZR-75-1 cells.
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PMID:Cerulenin-induced apoptosis is mediated by disrupting the interaction between AIF and hexokinase II. 2242 50


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