Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.1.1 (hexokinase)
 5,274 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Since the first report of GPI deficiency in 1967 many patients from all over the world have been described. The patients suffer from a typical nonspherocytic hemolytic anemia with hemolytic crises during acute infections. The disease is inherited as an autosomal recessive, half of the patients are homozygotic, the others are double heterozygotes. The biochemical properties of the deficient enzymes vary widely. Thus, many well characterized enzymes have been designated as different variants. The modification of physicochemical properties surpasses kinetic aberrations. All defective variants are more or less unstable. The activity diminishes progressively, leading to a rise in G6P concentration and in red cells after aging in vitro to a dramatic impairment of glycolysis and concomittant hemolysis. The cause of the metabolic block is the diminished GPI activity itself and not an inhibition of hexokinase by the high G6P.
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PMID:Inherited glucosephosphate isomerase deficiency. A review of known variants and some aspects of the pathomechanism of the deficiency. 39 2

Hexokinase, a key glycolytic enzyme, is involved in the initial phosphorylation reaction of imported glucose and specific blocking of this activity may therefore arrest the development of malaria parasites. We describe here the cloning of a single copy hexokinase gene of Plasmodium falciparum (PfHK) from cDNA or genomic DNA libraries. The deduced amino acid sequence of PfHK has 26% identity with human hexokinase I and its predicted molecular mass assigns it as an invertebrate type isoenzyme of hexokinase. A single 1.5-kb exon is translated from a 3-kb mRNA in asexual stages of the parasite. In contrast to aldolase and GPI, the gene for this glycolytic enzyme is located on chromosome 8. Poly- and monoclonal antibodies against recombinant PfHK support our cloning results at the protein level as they detect a protein of the predicted size and isoelectric point by Western blotting in parasite protein samples. Moreover, polyclonal rabbit IgG against recombinant PfHK partially inhibits the hexokinase activity of a P. falciparum lysate which provides direct proof that the gene cloned encodes hexokinase of the parasite.
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PMID:Molecular analysis of Plasmodium falciparum hexokinase. 147 5

The distribution of glucosephosphate isomerase (GPI, D-glucose-6-phosphate ketol isomerase) in mouse nervous tissue has been determined at the light microscopic level by immunofluorescence and histochemical procedures. The fluorescence procedure, which utilizes anti-GPI antibodies, detected lower levels of GPI than the histochemical procedure, which relies upon the catalytic activity of the enzyme. The distribution of GPI in nervous tissue is very similar to that of hexokinase. High levels of GPI were found in the Purkinje cells, the molecular layer, and the glomeruli of the granular layer in the cerebellar cortex; the pontine nuclei and the inferior olivary nuclei of the pons and medulla; the neurons of the thalamus and hypothalamus; the pyramidal cells, the dentate nuclei, and Ammons' horn of the cerebral cortex; the ventral horn cells of the spinal cord; and ventricular cells, choroid plexus cells, and the leptomeninges. The neuropil throughout the central nervous system (CNS) stained uniformly with moderately high levels of GPI. No GPI was observed in the myelin sheaths of the CNS.
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PMID:Immunofluorescence and histochemical localization of glucosephosphate isomerase in neural tissues. 698 35

Isoenzyme typing was used to study a number of oocyst isolates of Cryptosporidium parvum from different geographical locations and of human or animal origin. All isolates showed identical enzyme motility when glucose phosphate isomerase (GPI; 23 isolates tested) or lactate dehydrogenases (LDH; 20 isolates tested) was assayed. However, two isoenzyme forms were observed with phosphoglucomutase (PGM; 9 animal isolates showed one form, while 8/9 human isolates showed a second form) and hexokinase (HK; 4 human isolates showed one form and 6 animal isolates showed a second form). Thus, PGM and HK each exhibit 2 isoenzymes corresponding to 2 parasite populations associated with separate hosts. The data from this study, plus supportive evidence obtained by different methods and by independent researchers, lend support to the hypothesis that separate cycles of transmission of C. parvum may exist within human and animal hosts.
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PMID:Differentiation between human and animal strains of Cryptosporidium parvum using isoenzyme typing. 788 31

Notwithstanding the numerous drugs available for liver cancer, emerging evidence suggests that chemotherapeutic resistance is a significant issue. HGF and its receptor MET play critical roles in liver carcinogenesis and metastasis, mainly dependent on the activity of receptor tyrosine kinase. However, for unknown reasons, all HGF-MET kinase activity-targeted drugs have failed or have been suspended in clinical trials thus far. Macroautophagy/autophagy is a protective 'self-eating' process for resisting metabolic stress by recycling obsolete components, whereas the impact of autophagy-mediated reprogrammed metabolism on therapeutic resistance is largely unclear, especially in liver cancer. In the present study, we first observed that HGF stimulus facilitated the Warburg effect and glutaminolysis to promote biogenesis in multiple liver cancer cells. We then identified the pyruvate dehydrogenase complex (PDHC) and GLS/GLS1 as crucial substrates of HGF-activated MET kinase; MET-mediated phosphorylation inhibits PDHC activity but activates GLS to promote cancer cell metabolism and biogenesis. We further found that the key residues of kinase activity in MET (Y1234/1235) also constitute a conserved LC3-interacting region motif (Y1234-Y1235-x-V1237). Therefore, on inhibiting HGF-mediated MET kinase activation, Y1234/1235-dephosphorylated MET induced autophagy to maintain biogenesis for cancer cell survival. Moreover, we verified that Y1234/1235-dephosphorylated MET correlated with autophagy in clinical liver cancer. Finally, a combination of MET inhibitor and autophagy suppressor significantly improved the therapeutic efficiency of liver cancer in vitro and in mice. Together, our findings reveal an HGF-MET axis-coordinated functional interaction between tyrosine kinase signaling and autophagy, and establish a MET-autophagy double-targeted strategy to overcome chemotherapeutic resistance in liver cancer. Abbreviations: ALDO: aldolase, fructose-bisphosphate; CQ: chloroquine; DLAT/PDCE2: dihydrolipoamide S-acetyltransferase; EMT: epithelial-mesenchymal transition; ENO: enolase; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GLS/GLS1: glutaminase; GLUL/GS: glutamine-ammonia ligase; GPI/PGI: glucose-6-phosphate isomerase; HCC: hepatocellular carcinoma; HGF: hepatocyte growth factor; HK: hexokinase; LDH: lactate dehydrogenase; LIHC: liver hepatocellular carcinoma; LIR: LC3-interacting region; PDH: pyruvate dehydrogenase; PDHA1: pyruvate dehydrogenase E1 alpha 1 subunit; PDHX: pyruvate dehydrogenase complex component X; PFK: phosphofructokinase; PK: pyruvate kinase; RTK: receptor tyrosine kinase; TCGA: The Cancer Genome Atlas.
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PMID:The HGF-MET axis coordinates liver cancer metabolism and autophagy for chemotherapeutic resistance. 3078 11

Cellular metabolism reprogramming is a hallmark in cancers including breast cancer. Switching off the glycolytic energy in cancer has been indicated as one of the anti-cancer strategies. Aberrant haptoglobin (HP) expression has been shown to cause metabolic dysfunction and implicated in different malignancies. However, its roles in breast cancer and glycolysis remain elusive. Here, we reported HP was upregulated in breast cancer tissues and the circulation. HP conferred oncogenic roles by regulating cell cycle progression and apoptosis in breast cancer cells. Further analysis identified the correlation between HP and glycolytic enzymes such as glucose-6-phosphate isomerase (GPI) and hexokinase (HK). Glycolytic activities were altered upon HP knockdown which were confirmed by glucose uptake and LDH activity assays. GPI was found to be downstream effector of HP while knockdown of GPI led to decreased glycolytic activity and restored oxygen consumption. GPI silencing decreased cell migration/invasion ability and sensitized breast cancer cells to chemo-drug. Moreover, animal study suggested inhibition of both HP and GPI significantly impeded tumor growth in mice. Collectively, we report for the first time the oncogenic roles of HP, at least partially, through regulating glycolysis and its downstream effector, GPI, contributes in maintaining EMT and chemoresistance in breast cancer.
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PMID:Human haptoglobin contributes to breast cancer oncogenesis through glycolytic activity modulation. 3304 22