Disease relevance of Hk1

• The mature tumor hexokinase protein has been overexpressed in active form in Escherichia coli and purified 9-fold [1].
• In extending these studies, we have isolated a cDNA clone of hexokinase from a lambda gt11 library of the highly glycolytic, c37 mouse hepatoma cell line [1].
• We conclude that the hexokinase gene may not be a good target for therapies designed to counteract insulin resistance or hyperglycemia [2].
• We conclude that primary hypothyroidism causes a decline in brain Glut 1 associated with no change in Glut 3 levels and a compensatory increase in hexokinase enzyme activity [3].
• Downeast anemia (dea), a new mouse model of severe nonspherocytic hemolytic anemia caused by hexokinase (HK(1)) deficiency [4].

High impact information on Hk1

• BACKGROUND: Cellular metabolism in glioblastoma multiforme, the most common primary brain tumor in humans, is characterized by a high rate of aerobic glycolysis that is dependent on mitochondria-bound hexokinase [5].
• We sought to inhibit glioblastoma metabolism by simultaneously inhibiting hexokinase with lonidamine and binding benzodiazepine receptors with diazepam [5].
• We report here that the competitive hexokinase inhibitor 2-deoxyglucose releases the bound fraction of aldolase in 3T3 cells within 10 min, and that this process is reversible upon washout of the inhibitor [6].
• Elevation of hexokinase activity also significantly reduced blood glucose levels of diabetic mice [7].
• To test these hypotheses, we have produced transgenic mice that have a 2-fold increase in hexokinase activity specific to the pancreatic beta cell [7].

Chemical compound and disease context of Hk1

• To assess the correlation between hyperglycemia and glucose catabolic gene levels in diabetic and healthy mice, we determined mRNA levels of pivotal proteins such as glucose transporters, hexokinase II, glycogen synthase, glutamine:fructose-6-phosphate amidotransferase and uncoupling proteins [8].
• Lithium detaches hexokinase from mitochondria and inhibits proliferation of B16 melanoma cells [9].
• Clotrimazole and bifonazole detach hexokinase from mitochondria of melanoma cells [10].
• When expressed per 100 g body weight, hepatic glucokinase + hexokinase as well as phosphofructokinase and pyruvate kinase activities in obese mice were higher both in the fed and fasted states when compared to lean controls in the comparable nutritional condition [11].
• Cytotoxic effect of dactylarin on Ehrlich ascites carcinoma cells is caused by the inhibition of some SH-dependent glycolytic enzymes, especially of hexokinase (EC 2.7.1.1), glyceraldehyde-3-phosphate dehydrogenase (EC 1.2.1.12) and 6-phosphofructokinase (EC 2.7.1.11) [12].

Biological context of Hk1

• Hk1-sa mRNA is first expressed during meiosis and continues to be present in postmeiotic germ cells, while the more abundant Hk1-sb mRNA is detected only in postmeiotic germ cells [13].
• To test the role of glucose uptake and phosphorylation in growth factor-independent survival, cells were transfected with Glut1 and hexokinase 1 (Glut1/HK1) cells [14].
• This clone, comprising 4,198 base pairs, contains a single open reading frame of 2,754 nucleotides which encode a 918-amino acid hexokinase with a mass of 102,272 daltons [1].
• Multiple isoforms of type 1 hexokinase (HK1) are transcribed during spermatogenesis in the mouse, including at least three that are presumably germ cell specific: HK1-sa, HK1-sb, and HK1-sc [15].
• Because the study of protein targeting in germ cells is hampered by the lack of established cell lines in culture, constructs containing different domains of the germ cell-specific hexokinase transcripts were linked to a green fluorescent protein and transfected into hexokinase-deficient M+R42 cells [16].

Anatomical context of Hk1

• However, they lack the porin-binding domain (PBD) present in this region of Hk1, used for binding to a pore-forming protein in the outer mitochondrial membrane [13].
• The unusual distribution of HK1-sc in sperm suggests novel functions, such as extramitochondrial energy production, and also demonstrates that a hexokinase without a classical porin-binding domain can localize to mitochondria [15].
• Overexpression of hexokinase alone in skeletal muscle had no effect on glucose transport or metabolism in isolated muscles, nor did it alter blood glucose levels or the rate of whole-body glucose disposal [2].
• A novel NH(2)-terminal, nonhydrophobic motif targets a male germ cell-specific hexokinase to the endoplasmic reticulum and plasma membrane [16].
• Targeting of a germ cell-specific type 1 hexokinase lacking a porin-binding domain to the mitochondria as well as to the head and fibrous sheath of murine spermatozoa [15].

Associations of Hk1 with chemical compounds

• Two-dimensional SDS-PAGE suggested that all of the sperm HK1-sc was tyrosine phosphorylated, and that the somatic HK1 isoform was not present [15].
• Exposure of Clone 9 liver cell line, 3T3-L1 fibroblasts, and C(2)C(12) myoblasts to CoCl(2) resulted in an increase glucose uptake and in the activity of glucose phosphorylation ("hexokinase") and lactate dehydrogenase [17].
• Hexokinase activity in 1-cell embryos was the lowest by far of the five enzymes measured, and the 0.035 +/- 0.010 pmol of nicotinamide adenine dinucleotide phosphate hydrogenase formed/embryo/min was also lower than in any of the somatic organs examined [18].
• Together, the postnatal increase in GLUT-1 and -3 concentrations and hexokinase I enzymatic activity led to a parallel increase in murine brain 2-deoxyglucose uptake [19].
• Hexokinase II is increased, leading to an approximately twofold increase in glucose-6-phosphate levels [20].

Physical interactions of Hk1

• These fractions were characterized by the presence of both monamine oxidase and cytochrome c oxidase activities and bound hexokinase [21].

Other interactions of Hk1

• Loss of mitochondrial hexokinase activity was correlated to the induction of apoptosis in WEHI7.2 and CAT38 cells [22].
• Indeed, in hGK-KO hepatocytes overexpressing SREBP-1c, the effect of glucose on glycolytic and lipogenic genes is lost because of the impaired ability of these hepatocytes to efficiently metabolize glucose, despite a marked increase in low K(m) hexokinase activity [23].
• Surprisingly, even though HKII(+/-) mice had significantly reduced (by 50%) hexokinase II mRNA and activity levels in skeletal muscle, heart, and adipose tissue, they did not exhibit impaired insulin action or glucose tolerance even when challenged with a high-fat diet [24].
• The same values of flux control coefficients for hexokinase and for phosphofructokinase (0.8 and 0.2 respectively) were found in absence and in presence of copper [25].
• Mesangial cell hexokinase (HK) activity is increased by a diverse array of factors that share both an association with pathological conditions and a common requirement for classic MAPK pathway activation [26].

Analytical, diagnostic and therapeutic context of Hk1

• Southern blot analyses revealed approximately 5.5 kb of additional sequence in the 5' portion of the dea Hk1 gene, which was identified by direct sequencing as an early transposon (ETn) insertion in intron 4 [4].
• For the analysis of messenger ribonucleic acid (mRNA) expression, reverse-transcription polymerase chain reaction and Northern blot were used and the enzyme activity of hexokinase in cancer tissues was measured by continuous spectrophotometric rate determination [27].
• The blastocyst polymerase chain reaction (PCR) product, when cloned and sequenced was found to be 98% homologous with mouse tumour hexokinase I. Taken together, these data suggest that the hexokinase gene is not under transcriptional control during early mouse embryo development but plays a significant role in the regulation of glucose consumption [28].
• Assignment of the genes coding for pyrophosphatase and hexokinase-1 to mouse chromosome 10: implications for comparative gene mapping in man and mouse [29].
• We have now used site-directed mutagenesis for the first time in studies of hexokinase to evaluate the role of amino acid residues predicted to interact with either glucose or ATP [30].

References