How is hexokinase inhibited

Phosphoglycerate mutase requires D -glycerate-2,3-diphosphate for activation by donating one of its phosphoryl groups to form a covalently linked phosphoryl enzyme. A recent study using proteome analysis showed that this enzyme seems to be differentially overexpressed in human lung squamous carcinoma Li et al. Enolase catalyses the conversion of 2-phosphoglycerate to phosphoenolpyruvate. The enzyme is highly conserved, and tissue-specific isoforms are found with minor kinetic differences Marangos et al.

Three major isoforms of enolase have been identified in mammals. The expression of enolase is regulated both developmentally and tissue specifically, but the enzyme kinetic properties of all isoenzymes are similar. Pyruvate is an essential metabolic intermediate that channels into several metabolic pathways. Pyruvate kinase is a tetramer that is allosterically activated by phosphoenolpyruvate and negatively regulated by ATP.

Interestingly, tumor cells in particular express the PK isoenzyme type M2 M2-PK , which seem to regulate the proportions of glucose carbons for synthetic processes or for glycolytic energy production Mazurek et al. The dimeric form of M2-PK is present predominantly in tumor cells known as tumor M2-PK , and such dimerization appears to be caused by direct interaction of M2-PK with certain oncoproteins.

This regulatory mechanism is thought to allow tumor cells to survive in environments with varying oxygen and nutrients Mazurek et al. Lactate dehydrogenase is a tetramer of A and B subunits, encoded by two separate genes.

Lactate dehydrogenase-5 was also identified as a DNA-helix-destabilizing protein and speculated to be involved in transcription Williams et al. The phenomenon of aerobic glycolysis increase in cancer cells was first described by Otto Warburg over 70 years ago.

Although the cause—effect relationship between the increase in aerobic glycolysis and the development of cancer is controversial Zu and Guppy, , increased glycolysis has been consistently observed in many cancer cells of various tissue origins for a review, see Semenza et al.

Indeed, the positron emission tomography PET widely used in clinical diagnosis of cancer is based on the fact that cancer cells are highly glycolytic and actively uptake glucose.

The Warburg effect can be viewed as a prominent biochemical symptom of cancer cells that reflects a fundamental change in their energy metabolic activity. Several mechanisms have been suggested to affect energy metabolism and thus contribute to the Warburg effect.

These mechanisms include 1 mitochondrial defects, 2 adaptation to hypoxic environment in cancer tissues, 3 oncogenic signals, and 4 abnormal expression of certain metabolic enzymes. Table 1 provides a summary and explanations of these possible mechanisms.

Mitochondrial respiration injury has long been suspected to be a factor responsible for increased glycolysis in cancer cells Warburg, , although the underlying molecular mechanisms remain unclear. For instance, frequent mtDNA mutations have been observed in prostate cancer Chen and Kadlubar, , breast cancer Zhu et al.

Several factors seem to contribute to the high mutation rates in mtDNA. These factors include the close physical location of mtDNA to the ROS generation sites in the mitochondria, lack of histone protection, and weak DNA repair capacity in the mitochondria. Because the mitochondria genome encodes 13 important protein components of the respiratory chain, mutations in mtDNA are likely to affect its encoded proteins and compromise the function of the respiratory chain.

Since most of the mtDNA is structural gene sequence without introns, the possibility is high that a mutation in mtDNA would cause malfunction of the respiratory chain. Because oxidative phosphorylation in the mitochondria and glycolysis in the cytosol are two major metabolic pathways, by which ATP may be generated from glucose, malfunction of the mitochondrial respiratory chain would force the cells to use glycolytic pathway to generate ATP.

Because the production of ATP is much more efficient through oxidative phosphorylation 36 ATP per glucose than by glycolysis two ATP per glucose , a small loss of respiratory function would require a substantial increase of glycolytic activity to maintain the energy balance. Hypoxia is a strong modulator of energy metabolism.

Without mtDNA mutations, a functional defect in mitochondrial respiration may also force the cancer cells to use glycolytic pathway for ATP when oxygen is limited. This most likely occurs when cancer cells are in a hypoxic tissue environment. It is well documented that hypoxia is frequently present in human malignancies, especially in solid tumor tissues when the tumor mass reaches certain size and oxygen penetration becomes limited.

Under such conditions, oxidative phosphorylation may not proceed normally because of insufficient oxygen, even if the mitochondria in cancer cells do not have structural defects. Increased glycolysis will result in elevated production of lactate, which leads to acidification of tumor tissue and provides a microenvironment that promotes and selects cells with malignant behaviors.

Thus, increase in glycolysis may be viewed as cellular adaptation to hypoxia Gatenby and Gillies, The cellular response to hypoxia is controlled in part by HIF-1, which activates the expression of target genes involved in angiogenesis, glucose uptake, glycolysis, growth factor signaling, apoptosis, invasion, and metastasis Brahimi-Horn and Pouyssegur, Therapeutic resistance associated with hypoxia is a significant problem in clinical treatment of cancer, and inhibition of glycolysis may provide a novel approach to overcoming such resistance.

In fact, recent studies showed that under hypoxic conditions, cells exhibited increased sensitivity to glycolytic inhibitors 2-deoxyglucose 2-DG , oxamate, or 3-bromopyruvate 3-BrPA Liu et al. Studies using gene transfection approaches have revealed an intriguing possible mechanism by which malignant transformation by oncogenic signals may regulate energy metabolic pathways and renders the cancer cells highly glycolytic and become addictive to glycolysis for ATP production.

Early studies in rodent cells showed that transfection with ras or src oncogenes led to a marked increase in the glucose uptake, accompanied by an increase in the expression of glucose transporter at both the mRNA and protein levels Flier et al. In embryotic cells, H-ras was shown to stimulate glycolysis and inhibits oxygen consumption Biaglow et al. Several studies demonstrated that the signaling through the insulin receptor activates PI3K and Akt and result in stimulation of glucose uptake and glycolysis Ruderman et al.

After diffusion into cells through facilitative transport, which can be activated by Akt Kohn et al, ; Rathmell et al. Thus, the activity of hexokinase play a key role in regulating the glucose uptake, and the activated forms of Akt have been shown to stimulate hexokinase activity Gottlob et al. Interestingly, Akt has also been shown to phosphorylate and activate phosphofructokinase and release the inhibition of phosphofructokinase by ATP Van Schaftingen and Hers, ; Deprez et al.

Another oncogene Bcr-Abl has also been implicated to play a role in glycolysis, and inhibition of Bcr-Abl by Gleevec seems to reverse the Warburg effect by switching glucose metabolism from glycolysis to mitochondrial oxidative phosphorylation Gottschalk et al. Stable isotope-based dynamic metabolic profiling studies suggest that in myeloid cells isolated from patients, non-oxidative ribose synthesis from glucose and decreased mitochondrial glucose oxidation appear to be a metabolic signature of drug resistance and disease progression Serkova and Boros, Together, these observations suggest that oncogenic signals may play important roles in regulation of energy metabolism, and contribute to the Warburg effect.

Alterations of enzyme expression in cancer cells have also been postulated to cause metabolic changes leading to the Warburg effect. Increase of hexokinase II expression in cancer and its possible role in promoting glycolysis are described above. Notably, it was recently observed that TKTL1, a transketolase-like enzyme, is highly expressed in a variety of human cancer tissues Coy et al.

The enzyme TKTL1 exhibits ketolase enzyme activity capable of cleaving xylulosephosphate 5-carbon sugar to glyceraldehydephosphate 3-carbon , which can then be channeled to the energy-yielding phase of the glycolytic pathway to generate ATP and lactate.

The authors suggest that since transketolase regulate the glucose metabolic flow into the pentose phosphate pathway, high expression of TKTL1 would lead to an increased activity of this pathway to produce pentosephosphates and NADPH needed for tumor growth, and to generate lactate through the metabolic intermediate glyceraldehydephosphate. This may provide a biochemical explanation for the Warburg effect Coy et al. Interestingly, inhibition of transketolase by oxythiamine seems to have anticancer activity Rais et al.

Germline mutations in FH and SDH are associated with certain hereditary tumors such as leiomyomatosis, renal cell carcinoma, pheochromocytoma, and paraganglioma Astuti et al. The exact underlying mechanisms are still poorly understood.

Several mechanisms, including pseudo-hypoxia, mitochondrial dysfunction and impaired apoptosis, oxidative stress, and anabolic drive have been postulated to be involved in this predisposition to neoplasia through TCA cycle defects Pollard et al.

Thus, it is possible that the increased ROS generation in cancer cells associated with their intrinsic oxidative stress may lead to suppression of the ROS-sensitive enzymes involved in TCA cycle, forcing the cells to increase glycolysis to maintain ATP supply. Oxidative stress seems to be another biochemical characteristic of cancer cells attributed to multiple mechanisms including mitochondrial respiratory malfunction and oncogenic stress see review, Pelicano et al.

Although the biochemical and molecular mechanisms leading to increased aerobic glycolysis in cancer cells are rather complex and can be attributed to multiple factors such as mitochondrial dysfunction, hypoxia, and oncogenic signals, the metabolic consequences seem similar: the malignant cells become additive to glycolysis and dependent on this pathway to generate ATP.

Because ATP generation via glycolysis is far less efficient two ATP per glucose than through oxidative phosphorylation 36 ATP per glucose , cancer cells consume far more glucose than normal cells to maintain sufficient ATP supply for their active metabolism and proliferation.

As such, maintaining a high level of glycolytic activity is essential for cancer cells to survive and growth. This metabolic feature has led to the hypothesis that inhibition of glycolysis may severely abolish ATP generation in cancer cells and thus may preferentially kill the malignant cells Munoz-Pinedo et al.

As illustrated in Figure 2 , under physiological conditions, normal cells with intact mitochondrial function can effectively use glucose and other metabolic intermediates to generate ATP through the TCA cycle and oxidative phosphorylation in the mitochondria green arrows. However, the ability of cancer cells to use the mitochondrial respiratory machinery to generate ATP is compromised for the reason described above.

This forces the cancer cells to increase their glycolytic activity to maintain sufficient ATP generation. It is postulated that such a metabolic adaptation eventually renders cancer cells highly addictive to and dependent on the glycolytic pathway red arrows , and become vulnerable to glycolytic inhibition Gatenby and Gillies, ; Xu et al.

When glycolysis is inhibited, the intact mitochondria in normal cells enable them to use alternative energy sources such as fatty acids and amino acids to produce metabolic intermediates channeled to the TCA cycle for ATP production through respiration.

As such, cells with normal mitochondria are expected to be less sensitive to agents that inhibit glycolysis. Metabolic basis for targeting the glycolytic pathway as an anticancer strategy. Cancer cells are more depend on glycolysis coupled with the pentose phosphate pathway indicated by the red arrows for ATP generation, whereas normal cells with competent mitochondrial function may use various metabolic intermediates as energy sources to effectively generate ATP through the mitochondrial oxidative phosphorylation indicated by green arrows.

Inhibition of glycolysis is expected to have a severe impact on ATP generation and preferentially affect the cancer cells. The potential target enzymes and respective inhibitors are indicated in blue. Recent studies have provided supporting evidence that inhibition of glycolysis may exert preferential effect on cells with compromised mitochondrial function due either to genetic defects or a lack of oxygen. For instance, inhibition of hexokinase by 3-BrPA causes a depletion of ATP in cancer cells, and this effect is especially severe in cells with mitochondrial DNA deletion and respiration defects, leading to massive cell death Ko et al.

Interestingly, inhibition of hexokinase also leads to a rapid dephosphorylation of Bclassociated death promoter homolog BAD , a molecule known to be importantly involved in both glycolysis and apoptosis Danial et al.

The same study also showed that inhibition of glycolysis effectively kills colon cancer cells HCT and lymphoma cells Raji in hypoxic environment, in which cells exhibit high glycolytic activity and a decreased sensitivity to other anticancer agents including taxol, doxorubicine, arsenic trioxide, vincristine, and ara-C.

Another glycolytic inhibitor 2-DG also exhibits preferential killing of cancer cells with mitochondrial defects or under hypoxia Liu et al, , In addition, the transketolase-like enzyme TKTL1 has been shown to be overexpressed in cancer cells and may increase the activity of the pentose phosphate pathway, leading to generation of glyceraldehydephosphate and subsequent production of ATP and lactate Coy et al.

Thus, inhibition of the transketolase enzyme activity may provide another mechanism to preferentially impact the energy metabolism in cancer cells.

The anticancer activity of oxythiamine an inhibitor of transketolase observed in animal model provides supporting evidence Rais et al. If the increased glucose flow into the pentose phosphate pathway is a significant mechanism contributing to the Warburg effect, inhibitors of this pathway may be useful as potential anticancer agents.

The observations that cancer cells exhibit increased glycolysis and are more dependent on this pathway for ATP generation have led to the evaluation of glycolytic inhibitors as potential anticancer agents. Table 2 lists several compounds that inhibit glycolytic pathway or suppress the pentose phosphate pathway.

Their mechanisms of action and therapeutic potential are discussed below. This compound is a glucose analog and has long been known to act as a competitive inhibitor of glucose metabolism Brown, Inhibition of this rate-limiting step by 2-DG causes a depletion of cellular ATP, leading to blockage of cell cycle progression and cell death in vitro Maher et al.

However, the effectiveness of 2-DG is significantly affected by the presence of its natural counterpart glucose and seems to only partially reduce the availability of glucose for glycolysis. Interestingly, incubation of cells with 2-DG leads to a decrease in the amount of hexokinase associated with mitochondria, suggesting that this compound may also affect the mitochondrial glucose metabolism Lynch et al.

In vitro studies show that 2-DG exhibits cytotoxic effect in cancer cells, especially those with mitochondrial respiratory defects or cells in hypoxic environment Liu et al. In vivo , 2-DG significantly enhances the anticancer activity of adriamycin and paclitaxel in mice bearing human osteosarcoma or non-small-cell lung cancer xenografts Maschek et al, However, the same study showed that administration of 2-DG alone did not exhibit significant anticancer activity in vivo.

A recent study showed that 2-DG induces the expression of P-glycoprotein encoded by the MDR1 gene, raising a possibility that this might help cancer cells to develop chemoresistance Ledoux et al. This compound is a derivative of indazolecarboxylic acid, and has been known for a long time to inhibit aerobic glycolysis in cancer cells Floridi et al. In cell culture, lonidamine decreases oxygen consumption in both normal and neoplastic cells. Interestingly, it seems to enhance aerobic glycolysis in normal cells, but suppresses glycolysis in cancer cells, likely through inhibition of the mitochondrially bound hexokinase Floridi et al.

Importantly, in vivo administration of lonidamine to a patient with B-cell chronic leukemia resulted in a decrease of lactate production comparable to that observed in vitro Natali et al. Subsequent studies in Ehrlich ascites tumor cells showed that lonidamine inhibits both respiration and glycolysis in a dose-dependent manner leading to a decrease in cellular ATP Floridi et al.

The same study also showed that this compound causes an increase in the intracellular content of doxorubicin in both doxorubicin-resistant and sensitive cells owing to reduced ATP availability. In human breast cancer MCF-7 cells, lonidamine enhances the cytotoxicity of several alkylating agents, including cisplatin, 4-hydroperoxycyclophosphamide, melphalan, and BCNU Rosbe et al. The proven ability of lonidamine to inhibit energy metabolism in cancer cells and to enhance the activity of other anticancer agents has led to clinical trials phase II—III of this compound in combination with other anticancer agents for the treatment of breast cancer, glioblastoma multiforme, ovarian cancer, and lung cancer De Lena et al.

This compound is an inhibitor of hexokinase and has been shown to abolish ATP production and cause severe depletion of cellular ATP Ko et al.

Like 2-DG, 3-BrPA also exhibits potent cytotoxic activity against cancer cells with mitochondrial respiratory defects and cells in hypoxic environment Xu et al. Interestingly, depletion of ATP by 3-BrPA also effectively induces apoptosis in multi-drug-resistant cells, suggesting that deprivation of cellular energy supply may be a novel way to overcome multi-drug resistance Xu et al.

It should be noted that 3-BrPA is an alkylating agent, which may also interact with other molecules in the cells. Thus, its cytotoxic activity may not be exclusively attributed to inhibition of hexokinase. Animal studies showed that 3-BrPA has significant in vivo therapeutic activity against liver cancer when the compound was given by local infusion, and seems to inhibit metastasis when given intravenously Geschwind et al. The significant anticancer activity of 3-BrPA warrants further evaluation for potential use in cancer treatment.

The Bcr-Abl oncogene is a fusion DNA sequence created by chromosome translocation and codes for a constitutively active tyrosine kinase fusion protein. Imatinib treatment decreased the activity of both hexokinase and glucosephosphate dehydrogenase G6PD in leukemia cells, leading to suppression of aerobic glycolysis Boren et al. A decrease in G6PD activity would lead to lower glucose flow into the pentose phosphate pathway, and thus deprives transformed cells of metabolic intermediates for ATP generation and substrates for macromolecule synthesis.

Although imatinib is an antileukemia drug, its ability to suppress aerobic glycolysis may make it useful for the treatment of certain solid tumors.

This compound is a thiamine antagonist and inhibits transketolase and pyruvate dehydrogenase, which require thiamine pyrophosphate TPP as a cofactor for their enzyme activity. As transketolase is a crucial enzyme of the pentose phosphate pathway, inhibition of this enzyme would cause a suppression of the pentose phosphate pathway and thus deprives cells of the metabolic intermediate glyceraldehydephosphate for ATP generation and of the substrates NADPH, ribose-phosphate for macromolecule synthesis.

This metabolic inhibition seems to be responsible, at least in part, for the significant anticancer activity observed in vitro and in vivo Rais et al.

Because one of the transketolase isozyme TKTL1 has recently been found to be highly expressed in cancer cells and is considered as an important factor contributing to the Warburg effect Coy et al.

The pentose phosphate pathway can also be inhibited by 6-aminonicotinamide. This compound is believed to inhibit glucosephosphate dehydrogenase G6PD , which catalyses the conversion of GP 6-phosphogluconolactone, the first step of the pentose phosphate pathway.

Because of the essential roles of this pathway in generating reducing power NADPH and important metabolic intermediates pentosephosphate for synthesis of macromolecules, it is not surprising that 6-AN exhibits anticancer activity in vitro , causes oxidative stress, and sensitizes cells to anticancer agents and radiation Budihardjo et al. Several other compounds are potentially useful to modulate glucose metabolism.

Genistein is a natural compound found in soybean, and has been shown to decreases glucose uptake and glucose carbon incorporation into nucleic acid ribose in pancreatic adenocarcinoma cells Boros et al. It also has inhibitory effect on tyrosine kinase and protein kinase El-Zarruk and van den Berg, ; Waltron and Rozengurt, , causes cell cycle arrest, and suppresses angiogenesis Lian et al. Genistein seems potentially useful as a chemosensitization and radiosensitization agent Garg et al.

Inhibition of glycolysis by 5-TG occurs rapidly, and is competitive with respect to glucose. Mannoheptulose is another non-metabolizable glucose analog with anticancer effect.

This compound was shown to inhibit glucokinase, decrease glucose uptake, and suppress tumor cell growth Board et al. This compound has been shown to have antifertility effect due to its ability to affect energy metabolism in sperm Jelks and Miller, , although recent evidence suggest that sperm can remain motile with normal ATP concentrations despite inhibition of GAPDH by this compound Ford, The pentavalent arsenic compounds can abolish ATP generation by causing arsenolysis during the GAPDH-catalysing reaction in the glycolytic pathway Figure 1 , step 6 , preventing the generation of 1,3-bisphosphoglycerate, although the GAPDH activity is not directly inhibited.

Glufosfamide is a conjugate of D -glucose with the active metabolite of isophosphoramide mustard. This novel compound utilizes the elevated glucose uptake of tumor cells expressing the SAAT1 glucose transporter for entering the cells Veyhl et al. Glufosfamide does not require metabolic activation in the liver and the active moiety is released upon entry into tumour cells. This compound has been tested for its therapeutic activity against head and neck cancer, pancreatic adenocarcinoma, and non-small-cell lung cancer Briasoulis et al.

Glufosfamide represent a novel oxazaphosphorine analog that uses the glucose transporter system for cellular entry to damage nuclear DNA Seker et al.

Although cancer cells exhibit increased glycolysis and depend more on this pathway for ATP generation, inhibition of glycolysis alone may not be sufficient to effectively kill the malignant cells. Since all cancer cells contain mitochondria, some degree of ATP generation through oxidative phosphorylation is still possible when glycolysis is inhibited. This may compromise the efficiency of glycolytic inhibitors to deplete cellular ATP.

One way to achieve a high level of ATP depletion and improve therapeutic activity is to combine multiple ATP-depleting agents with different mechanisms of action Martin et al. Indeed, early studies showed that the combination of N - phosphonacetyl - L -aspartate PALA , 6-methylmercaptopurine riboside MMPR , and 6-aminonicotinamide 6-AN is an effective ATP-depleting regimen that increases the anticancer activity of radiation, adriamycin, or taxol Koutcher et al.

Combination of glycolytic inhibitor 2-deoxyglucose with adriamycin or paclitaxel also resulted in a significant increase of in vivo therapeutic activity in animal tumor models bearing osteosarcoma or non-small-cell lung cancer xenografts Maschek et al. On the origin of cancer cells. Glycolysis, tumor metabolism, cancer growth and dissemination. A new pH-based etiopathogenic perspective and therapeutic approach to an old cancer question.

Evaluation of 2-deoxy- d -glucose as a chemotherapeutic agent: mechanism of cell death. Br J Cancer. Breast cancer stem cells rely on fermentative glycolysis and are sensitive to 2-deoxyglucose treatment.

Cell Death Dis. Wilson JE. Isozymes of mammalian hexokinase: structure, subcellular localization and metabolic function. J Exp Biol. Robey RB, Hay N. Mitochondrial hexokinases, novel mediators of the antiapoptotic effects of growth factors and Akt. Hexokinase 2 is a key mediator of aerobic glycolysis and promotes tumor growth in human glioblastoma multiforme.

J Exp Med. Expression of hexokinase II and Glut-1 in untreated human breast cancer. Nuclear Med Biol. Cancer Sci. Elevated Hexokinase II expression confers acquired resistance to 4-Hydroxytamoxifen in breast cancer cells. Mol Cell Proteomics. PIM2-mediated phosphorylation of hexokinase 2 is critical for tumor growth and paclitaxel resistance in breast cancer. Hexokinase 2 confers resistance to cisplatin in ovarian cancer cells by enhancing cisplatin-induced autophagy.

Int J Biochem Cell Biol. Hexokinase 2 is required for tumor initiation and maintenance and its systemic deletion is therapeutic in mouse models of cancer. Cancer Cell. Sugar specificity of human. 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.

Cancer Res. Dietary Intake regulates the circulating inflammatory monocyte pool. Nordal A, Benson A. Isolation of mannoheptulose and identification of its phosphate in Avocado Leaves1. J Am Chem Soc. Dakubo GD. Replication-selective virotherapy for cancer: biological principles, risk management and future directions.

Nat Med. Newcastle disease virus as an Antineoplastic Agent. Isolation and sero-diagnosis of newcastle disease virus infection in human and chicken poultry flocks in three cities of middle Euphrates. Kufa J Veterinary Med Sci. Google Scholar.

Newcastle disease virus, rituximab, and doxorubicin combination as anti-hematological malignancy therapy. Oncolytic Virotherapy. Oncolytic newcastle disease virus iraqi virulent strain induce apoptosis in vitro through intrinsic pathway and association of both intrinsic and extrinsic pathways in vivo.

Mol Therapy. Article Google Scholar. Caspase dependent and independent anti- hematological malignancy activity of AMHA1 attenuated newcastle disease virus. Int J Mol Cell Med. Proteomic analysis of chicken peripheral blood mononuclear cells after infection by Newcastle disease virus.

J Veterinary Sci. Targeted metabolic reprogramming to improve the efficacy of oncolytic virus therapy. Mol Ther. Antagonism of glycolysis and reductive carboxylation of glutamine potentiates activity of oncolytic adenoviruses in cancer cells. Inhibition of pyruvate dehydrogenase kinase enhances the antitumor efficacy of oncolytic reovirus.

Front Mol Biosci. Antiviral effects of olea europaea leaves extract and interferon-beta on gene expression of newcastle disease virus. Adv Anim Vet Sci. In vitro synergistic enhancement of newcastle disease virus to 5-fluorouracil cytotoxicity against tumor cells. Chou T-C.

Drug combination studies and their synergy quantification using the Chou-Talalay method. Gold nanoparticles inhibiting proliferation of human breast cancer cell line. Res J Biotechnol. Energy Procedia. Techniques to monitor glycolysis.

Methods Enzymol. Mitochondrial monolysocardiolipin acyltransferase is elevated in the surviving population of H9c2 cardiac myoblast cells exposed to 2-deoxyglucose-induced apoptosis.

Biochem Cell Biol. Inhibition of the Warburg effect with a natural compound reveals a novel measurement for determining the metastatic potential of breast cancers. Coore H, Randle P. Inhibition of glucose phosphorylation by mannoheptulose. Biochem J. A precision therapeutic strategy for hexokinase 1-null, hexokinase 2-positive cancers.

Targeting Hexokinase 2 May Block cancer glucose metabolism. Cancer Discov. Receptor tyrosine kinase ErbB2 translocates into mitochondria and regulates cellular metabolism.

Nat Commun. Decreased glycolytic metabolism contributes to but is not the inducer of apoptosis following ILstarvation. Cell Death Differ. Bioenergetics of human cancer cells and normal cells during proliferation and differentiation. Cancer Ther OncolInt J. Download references. This space is too large to bind glucose so it is said to be in the inactive form. The alternative is when the alpha 13 helix is modulated to form a smaller space thus activating the protein [4].

Glucokinase includes the where glucose forms hydrogen bonds at the bottom of the deep crevice between the large domain and the small domain. E, E shown in green of the large domain, T, K shown in red of the small domain, and N, D shown in yellow of a connecting region form hydrogen bonds with glucose.

The shows a different conformation. The again shows structural differences. The differences in these two conformations allows glucokinase to function properly in different levels of glucose concentration. Proposed Mechanism for Glucokinase: As described above, glucokinase has a distinct conformation change from the active and inactive form.

Experiments have also shown an intermediate open form based on analysis of the movement between the active and inactive form. The switch in conformations between the active form and the intermediate is a kinetically faster step than the change between the intermediate and the inactive form.

The inactive form of gluckokinase is the thermodynamically favored unless there is glucose present. Glucokinase does not change conformation until the glucose molecule binds. The conformation change may be triggered by the interaction between Asp and the glucose molecule.

Once glucokinase is in the active form, the enzymatic reaction is carried out with the presence of ATP. The experiments suggest that glucokinase is found in hepatocyte nuclei and are found inactive at low plasma glucose levels, but found active when higher glucose levels are present. GKRP would then would likely be an allosteric inhibitor of glucokinase that specifically binds to the inactive form of glucokinase.

The crystal structures of the glucokinase-GKRP complex are being determined to clearly identify the interactions between glucokinase and glucokinase regulatory protein. Role in Organ Systems: In the liver glucokinase increases the synthesis of glycogen and is the first step in glycolysis, the main producer of ATP in the body.

Glucokinase is responsible for phospohorylating the majority of glucose in the liver and pancreas. Glucokinase only binds to and phosphorylates glucose when levels are higher than normal blood glucose level, allowing it to maintain constant glucose levels [4].

By phosphorylating glucose, glucokinase creates glucose 6-phosphate. Glucose 6-phosphate can then be used by the liver through the glycolytic pathway. Along with this process in the liver, glucokinase also facilitates glycogen synthesis.

Through this the majority of the body's glucose is stored. Glucose 6-phosphate is also one of the starting materials of the TCA cycle which is responsible for the majority of ATP production in the body. In the pancreas, a rise in glucose levels increases the activity of glucokinase causing an increase in glucose 6-phosphate.

This causes the triggering of the beta cells to secret insulin [5]. Glucokinase is the first step in this reaction. Insulin then allows other cells in the body to take up glucose, actively lowering the glucose level.