Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.13.3 (histidine kinase)
 2,405 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An electrophoretic system which gives a clear separation of human hexokinases HK1, HK2 and HK3 is described. The distribution of the hexokinase isozymes in various human tissues, both adult and fetal, is reported. Some properties of the isozymes were investigated. HK2 was found to be more thermolabile than HK1, and there was also a small but significant difference in molecular size. Unlike HK3, HK1 and HK2 are not inhibited by high glucose concentrations. Screening of red cell lysates from 800 unrelated European individuals revealed no genetic variants of HK1 and HK2. However, in view of their difference in properties, it seems probable that the HK1 and HK2 isozymes are determined by separate gene loci.
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PMID:An electrophoretic study of the distribution and properties of human hexokinases. 123 74

Hexokinase (EC 2.7.1.1) catalyzes the first step in glucose metabolism, using ATP for the phosphorylation of glucose to glucose 6-phosphate. A portion of the HK1 gene was cloned by mixed oligonucleotide primer amplification of cDNA using primers of high complexity. The amino acid sequence for a partial fragment of bovine cardiac muscle HK was determined and used to create primer mixtures of 256- and 1024-fold complexity. Two products were generated from bovine cardiac muscle cDNA which show 82% nucleotide and 93% amino acid identity with a region of rat brain HK1 and cDNA. This work demonstrates that extension and amplification of cDNA probes may be successful even when amino acid sequence data indicate substantial codon degeneracy.
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PMID:Synthesis and characterization of a bovine hexokinase 1 cDNA probe by mixed oligonucleotide primed amplification of cDNA using high complexity primer mixtures. 271 57

The uhpABCT locus of Escherichia coli is responsible for expression of the sugar-phosphate transport system and its induction by external glucose 6-phosphate. Expression of uhpT-lacZ fusions depended on the function of uhpA, uhpB, and uhpC but not of uhpT. A plasmid carrying only uhpT conferred transport activity in a host strain deleted for the uhp region. Thus, uhpT encodes the polypeptide required for transport function, and the other three uhp genes regulate uhpT transcription. The presence of uhpA at elevated copy number resulted in a substantial increase in uhpT expression. This elevated expression was only about 50% of the level seen in induced haploid cells, and no further increase occurred after addition of inducer. Activation by multicopy uhpA was not affected by the status of uhpC but was decreased in the absence of uhpB, suggesting a role for UhpB in directly activating UhpA. Transcription of uhpA, monitored by expression of a uhpA-lacZ fusion, was not affected by either inducer or the presence of the wild-type uhpA allele. The presence of multiple copies of the uhpT promoter region reduced uhpT expression in strains with uhpA in single copy number but not in those with multiple copies, consistent with competition for the activator. Amino acid sequence comparisons showed that UhpA was homologous to a family of bacterial regulatory proteins, some of which act as transcriptional activators (OmpR, PhoB, NtrC, and DctD). The C-terminal portion of UhpB displayed matches to the corresponding portions of another family of proteins (EnvZ, PhoMR, NtrB, and DctB) that participate in regulation of gene expression in response to environmental factors.
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PMID:Role of uhp genes in expression of the Escherichia coli sugar-phosphate transport system. 304 48

Hexokinase plays an important role in glucose-utilizing tissues like normal brain and cancers. In these tissues, hexokinase (HK) is mainly bound to mitochondria (mHK). Our objectives were to evaluate total HK (tHK) activity and mHK fraction in gliomas and to determine whether mHK binding could be targeted for therapy. Tumors were obtained from 26 patients and 13 were xenografted. HK, lactate and ATP were measured in cytosol and mitochondria extracts. The tHK expressed in mU/mg protein were 147 +/- 19 and 78 +/- 12, in fresh gliomas and xenografts, respectively, and of 489 in the normal brain. The mHK fraction was 76% in normal brain, 74 +/- 4% in fresh tumors and 53 +/- 6% in xenografts. Lactate/mHK ratios were higher in gliomas than in normal brain. The ATP was 10, 52 +/- 31 and 19 +/- 8 nmol/mg protein in normal brain, xenografts and fresh gliomas respectively. Loss of one copy of chromosome 10 which carries the HK1 gene, was evidenced in 11 of the 13 xenografted gliomas. The anti-tumor effect of lonidamine (LND), which affects glycolysis in interfering with mHK activity, was tested in nude mice bearing 4 gliomas. LND (125 mg/kg, given i.p., twice daily for 5 days) led to a growth inhibition of TG-7-RO of 72%, with 2-fold growth retardation, and had no effect for TG-8-OZ. Intermediate LND-sensitivities for TG-11-DU and TG-10-PY were noted. The LND-sensitivity was correlated with the mHK activity (R2 = 0.73) and mHK fraction (R2 = 0.88). HK binding to mitochondria is a key of glycolysis in malignant gliomas, and targetting this binding with appropriate agents could be an effective therapeutic approach.
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PMID:Mitochondria-bound hexokinase as target for therapy of malignant gliomas. 762 99

Mammalian hexokinase types one and three (HK1 and HK3) are 100 kDa isozymes that phosphorylate glucose to glucose-6-phosphate. HK1 is present in most tissues but is especially prominent in brain and kidney. HK3 is less well studied, but may be most prominent in the spleen and lymphocytes. In this study, we determined the ontogeny of the expression of these isoforms in the rat. Using immunohistochemistry, we identified HK1 and HK3 immunoreactivity in the brain, heart, kidney, liver, skeletal muscle and spleen from gestational day 14 (E14) to 45 days after birth (P45). With the exception of the liver and spleen, we observed a similar age- and cell-dependent staining pattern for both isoforms in all organs studied. The brain and spleen were analyzed in more detail to identify specific regions of immunoreactivity during maturation. A transient expression of HK1 and HK3 was noted in the cell bodies of mature neurons, including layers V and VI of the cerebral cortex and the cerebellar Purkinje cells followed by localization to the white matter of the cerebrum and cerebellum. In the spleen, HK3 immunoreactivity was detected postnatally and appeared to track with the infiltration of B cells. Our demonstration of changing patterns of immunoreactivity for HK1 and HK3 in fetal and postnatal organs suggests that these HK isoforms are involved the process of development. We speculate that HK1 and HK3 share a complex interaction during development of these organs and regulate glucose metabolism at multiple levels during development.
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PMID:Developmental expression of hexokinase 1 and 3 in rats. 945 58

A histidine kinase protein (Cph1) with sequence homology and spectral characteristics very similar to those of the plant phytochrome has been recently identified in the cyanobacterium Synechocystis sp. strain PCC 6803. Cph1 together with Rcp1 (a protein homologue to the response regulator CheY) forms a light-regulated two-component system whose function is presently unknown. Levels of cph1 rcp1 mRNA increase in the dark and decrease upon reillumination. A dark-mediated increase in cph1 rcp1 mRNA levels was inhibited by the presence of glucose, but not by inhibition of the photosynthetic electron flow. The half-life of cph1 rcp1 transcript in the light was about fourfold shorter than in the dark, indicating that control of cph1 rcp1 transcript stability is one of the mechanisms by which light regulates expression of the cyanobacterial phytochrome. After 15 min of darkness, 3-min pulses of red, blue, green, and far-red light were equally efficient in decreasing the cph1 rcp1 mRNA levels. Red light downregulation was not reversed by far-red light, suggesting that cph1 rcp1 mRNA levels are not controlled by a phytochrome-like photoreceptor. Furthermore, a Synechocystis strain containing an H538R Cph1 point mutation, unable to phosphorylate Rcp1, shows normal light-dark regulation of the cph1 rcp1 transcript levels. Our data suggest a role of cyanobacterial phytochrome in the control of processes required for adaptation in light-dark and dark-light transitions.
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PMID:Light-dependent regulation of cyanobacterial phytochrome expression. 1061 60

The porin composition of the Escherichia coli cell envelope was analyzed during growth at different external pHs (pHo) as a function of the acetyl phosphate (AcP) level (DeltaackA pta or ackA mutant, pyruvate or glucose as the carbon source) in the presence or absence of EnvZ. Our results indicate that the AcP level is influenced by the pHo, leading to modulation of the amount of OmpR-P and subsequent pHo-dependent expression of ompF and ompC. We also propose the existence of a specific signal, independent of EnvZ and AcP, leading to OmpR phosphorylation in response to pyruvate.
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PMID:Involvement of carbon source and acetyl phosphate in the external-pH-dependent expression of porin genes in Escherichia coli. 1061 80

The phosphorylation of glucose, a crucial step in cellular metabolism, is catalysed by hexokinases (HK), of which there are four (HKI-IV) in mammalian tissues. The brain HK, (HK1), like HKII and HKIII, has a molecular weight of approximately 100 kDa. HKII is insulin-sensitive and found in adipose and muscle cells. HKIV, also known as glucokinase, has a molecular weight of 50 kDa and is specific to liver and pancreas. Most brain HK is bound to mitochondria via porins, enabling coordination between glucose consumption and oxidation. Tumour cells are known to be highly glycolytic, and correspondingly increased expression of glycolytic enzymes, including HK, have been detected in resected tumours from patients with lung, gastrointestinal and breast cancer. In the latter group, further increases in HK activity were associated with metastatic disease. Some studies have demonstrated increased HK activity in renal tumours, and also have reported changes in the isoenzymic expression of HK. Experimental studies of the initiation and progression of liver tumours have demonstrated a shift in expression from that of HKIV to HKI and HKII, with increased HK binding to mitochondria and a > 100-fold increase in HK activity. However, studies using xenografts derived from gliomas found decreased HK activity corresponding with loss of chromosome 10, the carrier of the HKI gene. Compared with normal tissues, a number of mechanisms are associated with changes in HK activity seen in tumours of the liver and other sites, and these include HK gene dosage, increased transcription, modulation of HK promoter activity by a broader range of effectors, and increased mitochondrial binding of HK. Increased HK activity, together with increased glucose transport by tumour cells, has been exploited in cancer imaging using the positron-labelled glucose analogue (18F)fluoro-2-deoxy-D-glucose (FDG), which is transported into cells and then phosphorylated, but undergoes little further metabolism. Accumulated FDG then can be detected using positron emission tomography (PET).
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PMID:Mammalian hexokinases and their abnormal expression in cancer. 1091 95

The histidine kinase (HK) component of many two-component regulatory systems exhibits regulated ability to phosphorylate itself and to participate in transfer of phosphate to and from its cognate response regulator. The signaling system that controls expression of the UhpT sugar phosphate transporter in Escherichia coli in response to external glucose 6-phosphate includes the HK protein UhpB and the polytopic membrane protein UhpC, a UhpT homolog which is required for responsiveness to an inducer and activation of UhpB. The existence of a UhpBC signaling complex is suggested by the requirement for UhpC for the activity of certain constitutively active variants of UhpB, the dominance and epistasis relationships of uhp alleles, and the finding that expression of UhpB in excess of UhpC has a strong dominant-negative effect. Expression of a hybrid protein containing the cytoplasmic C-terminal half of UhpB fused to glutathione S-transferase (GST) also interfered with Uhp signaling. This interference phenotype could not result solely from the phosphatase activity of UhpB, because interference affected both overexpressed UhpA and UhpA variants which are active in the absence of phosphorylation. Variant forms of UhpB which were active in the absence of UhpC carried amino acid substitutions near motifs conserved in HK proteins. The GST fusion protein inhibited the ability of UhpA to bind and activate transcription at the uhpT promoter. Unlike the wild-type situation, a GST fusion variant carrying one of the UhpB-activating substitutions, R324C, displayed autokinase activity and phosphate transfer to UhpA but retained the ability to sequester UhpA when it was altered in the conserved residues important for phosphate transfer. Thus, the default state of UhpB is kinase off, and activation of its phosphate transfer activity requires either the action of UhpC or the occurrence of certain mutations in UhpB. The interference phenotype shown by UhpB in excess of UhpC appears to include the binding and sequestration of UhpA.
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PMID:The histidine kinase domain of UhpB inhibits UhpA action at the Escherichia coli uhpT promoter. 1105 70

Spermatozoa are highly polarized cells with specific metabolic pathways compartmentalized in different regions. Previously, we hypothesized that glycolysis is organized in the fibrous sheath of the flagellum to provide ATP to dynein ATPases that generate motility and to protein kinases that regulate motility. Although a recent report suggested that glucose is not essential for murine sperm capacitation, we demonstrated that glucose (but not lactate or pyruvate) was necessary and sufficient to support the protein tyrosine phosphorylation events associated with capacitation. The effect of glucose on this signaling pathway was downstream of cAMP, and appeared to arise indirectly as a consequence of metabolism as opposed to a direct signaling effect. Moreover, the phosphorylation events were not affected by uncouplers of oxidative respiration, inhibitors of electron transfer, or by a lack of substrates for oxidative respiration in the medium. Further experiments aimed at identifying potential regulators of sperm glycolysis focused on a germ cell-specific isoform of hexokinase, HK1-SC, which localizes to the fibrous sheath. HK1-SC activity and biochemical localization did not change during sperm capacitation, suggesting that glycolysis in sperm is regulated either at the level of substrate availability or by downstream enzymes. These data support the hypothesis that ATP specifically produced by a compartmentalized glycolytic pathway in the principal piece of the flagellum, as opposed to ATP generated by mitochondria in the mid-piece, is strictly required for protein tyrosine phosphorylation events that take place during sperm capacitation. The relationship between these pathways suggests that spermatozoa offer a model system for the study of integration of compartmentalized metabolic and signaling pathways.
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PMID:Functional relationships between capacitation-dependent cell signaling and compartmentalized metabolic pathways in murine spermatozoa. 1111 97


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