Computer Simulation Study of Hexokinase II from Ehrlich Ascites Cells

Garfinkel, Lillian

doi:10.1111/j.1432-1033.1975.tb03943.x

Cited by 1 publication

(1 citation statement)

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“…The enzyme is localized in the outer mitochondrial compartment and can be solubilized under specified conditions by Glc-6-P and ATP (21). Although the mitochondrial enzyme in brain and some other tissues has been reported to be inhibited by Glc-6-P, there is much controversy surrounding the time and ion dependence of this inhibition and its physiological significance (16,27). There does seem to be general agreement, however, that particulate forms of hexokinase are less sensitive to inhibition by Glc-6-P thanaresoluble forms of the enzyme (16,(28)(29)(30).…”

Section: Discussionmentioning

confidence: 89%

High aerobic glycolysis of rat hepatoma cells in culture: Role of mitochondrial hexokinase

Bustamante

Pedersen

1977

Proc. Natl. Acad. Sci. U.S.A.

336

216

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A tumorigenic anchorage-dependent cell line (H-91) was established in culture from an azo-dye-induced rat ascites hepatoma. When grown in a glucose-containing medium the cells exhibit high rates of lactic acid production characteristic of rapidly growing tumor cells. However, when glucose is replaced with galactose the cells grow equally well but exhibit only moderately elevated rates of lactic acid production. The molecular basis for this observation cannot be attributed to differences in permeability because initial rates of glucose and galactose entry into hepatoma cells are identical. Rather, the activity of hexokinase (ATP:Dhexose 6-phosphotransferase, EC 2.7.1.1) is found to be high in hepatoma cells, about 20-fold higher than that of control and regenerating rat liver. Moreover, tumor hexokinase activity is not inhibited by low concentrations (<0.6 mM) of the reaction product glucose 6-phosphate. Additionally, 50% of the hexokinase activity of hepatoma cells is found associated with the mitochondrial fraction. This fraction is 3fold enriched in hexokinase activity relative to the homogenate and 4-fold enriched relative to the nuclear and postmitochondrial fractions. Tumor mitochondrial hexokinase appears to be coupled directly to oxidative phosphorylation, because addition of glucose to respiring hepatoma mitochondria (after a burst of ATP synthesis) resu ts in stimulation of respiration. In contrast, glucose has no effect on the respiration of mitochondria from control and regenerating liver. These results suggest that the high glycolytic capacity of HI9 hepatoma cells is due, at least in part, to an elevated form of hexokinase concentrated in the mitochondrial fraction of the cell.The most characteristic biochemical phenotype of cancer cells is their propensity for high aerobic rates of glycolysis (1-4). Rapidly growing tumor cells, in particular those growing in ascitic form, are known to exhibit markedly elevated rates of lactic acid production when compared with normal cells (1-4). Cells from slowly growing tumors also have elevated rates of aerobic glycolysis (4), although the elevation is not nearly as dramatic.The reason for the high aerobic lactic acid production of rapidly growing cancer cells has puzzled biochemists for more than 50 years, and as of this date a satisfactory explanation acceptable to most workers in the field of cancer research has not been forthcoming. Possible explanations for the very "high glycolysis" of rapidly growing cancer cells usually involve mitochondria, which are assumed to be either defective in some capacity or less effective than glycolytic enzymes in competing for common intermediates (2, 5).To more definitely establish the relationship(s) between mitochondria and glycolysis in rapidly growing cancer cells, the studies described in this paper have focused on differences in the catabolism of glucose and galactose by a hepatoma cell line growing in culture. Because such cancer cells grow equally well on both carbohydrate sources but produce large amounts o...

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Section: Discussionmentioning

confidence: 89%