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

Recent evidence has suggested a role for the polyol pathway in pathogenesis of cell damage in diabetes Glucose may be phosphorylated to glucose-6-phosphate via hexokinase and enter glycolysis or reduced to sorbitol via aldose reductase to enter the polyol pathway. The poorly diffusible sorbitol is converted via sorbitol dehydrogenase to fructose. Hexokinase, aldose reductase and sorbitol dehydrogenase activities were measured in glomeruli (G) and small arteries (SA) taken from normal and diabetic human kidneys, Hexokinase in diabetic G was 1688, which was significantly decreased from normal, 3147 mmoles/kg-1/h-1. Alodse reductase was significantly elevated in diabetic G,56-6, compared to normal G,10-8 mmoles/kg-1/h-1. In contrast, sorbitol dehydrogenase was significantly depressed in diabetic G, 3-7 VERSUs 10-9 mmoles/kg-1/h-1. The enzymatic changes observed in diabetic G would facilitate accumulation of sorbitol and therefore could contribute to the progression of glomerulosclerosis. The activity of hexokinase was also significantly reduced in SA, whereas aldose reductase and sorbitol dehydrogenase were unchanged.
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PMID:Quantitative histochemistry of the sorbitol pathway in glomeruli and small arteries of human diabetic kidney. 48 51

Reviewed are (1) the biochemical basis and pathophysiology of diabetic complications and (2) the structure-activity relationships, pharmacology, pharmacokinetics, clinical trials, and adverse effects of aldose reductase inhibitors (ARIs). ARIs are a new class of drugs potentially useful in preventing diabetic complications, the most widely studied of which have been cataracts and neuropathy. ARIs inhibit aldose reductase, the first, rate-limiting enzyme in the polyol metabolic pathway. In nonphysiological hyperglycemia the activity of hexokinase becomes saturated while that of aldose reductase is enhanced, resulting in intracellular accumulation of sorbitol. Because sorbitol does not readily penetrate the cell membrane it can persist within cells, which may lead to diabetic complications. ARIs are a class of structurally dissimilar compounds that include carboxylic acid derivatives, flavonoids, and spirohydantoins. The major pharmacologic action of an ARI involves competitive binding to aldose reductase and consequent blocking of sorbitol production. ARIs delay cataract formation in animals, but the role of aldose reductase in cataract formation in human diabetics has not been established. The adverse effects of ARIs include hypersensitivity reactions. Although the polyol pathway may not be solely responsible for diabetic complications, studies suggest that therapy with ARIs could be beneficial. Further research is needed to determine the long-term impact and adverse effects of ARIs in the treatment of diabetic complications.
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PMID:Potential use of aldose reductase inhibitors to prevent diabetic complications. 211 49

The effect of cataractogenesis on the behavior of some enzymes involved in glucose metabolism was examined histochemically both in human lenses and in rat lenses from rats with alloxan-induced diabetes. Several modifications in the currently available techniques were made in order to localize glucose-6-phosphate dehydrogenase, aldose reductase, sorbitol dehydrogenase, hexokinase and ketohexokinase in ocular lens. Human cataractous lenses showed a precipitous drop in glucose-6-phosphate dehydrogenase activity, whereas the lenticular tissues of alloxan-treated rats showed a gradual decrease of this enzyme with the prolongation of diabetes. Aldose reductase activity increased in hypermature and senile diabetic cataracts, whereas sorbitol dehydrogenase activity decreased in these lenses. Similarly, in alloxan-diabetic rat lenses the activity of aldose reductase increased while that of sorbitol dehydrogenase decreased with the prolongation of diabetes. Attempts were made to localize hexokinase and ketohexokinase in ocular lens.
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PMID:Studies on cataractogenesis in humans and in rats with alloxan-induced diabetes. II. Histochemical evaluation of lenticular enzymes. 298 23

Rat lenses treated with greater than 0.06 mM hydrogen peroxide (HP) appeared to sustain epithelial damage, particularly a loss of enzymes including hexokinase, which controls the supply of glucose-6-phosphate. This may account for the lower level of hexose monophosphate shunt activation observed in these lenses. Other alterations include a decrease of lactate production and disturbance to ionic balance. These changes occurred despite HP removal by glutathione reductase/peroxidase system, catalase and other mechanisms. This suggests an inherent weakness for the lens to resist stresses from high levels of HP. Further, competition for NADPH between aldose reductase and glutathione reductase apparently affects the lens's ability to detoxify HP. This implies a role for oxidation in diabetic cataractogenesis.
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PMID:The lens's response to exogenous hydrogen peroxide. 322 97

Methods for 2-deoxyglucose (2-DG) and 2-deoxyglucose 6-phosphate (DG6P) are described which are based on the fact that DG6P is oxidized by glucose-6-phosphate dehydrogenase (G6PDH), but at a rate 1000-fold slower than for glucose 6-phosphate, whereas hexokinase phosphorylates 2DG and glucose at comparable rates. Therefore, by adding the two enzymes in a suitable order, and in appropriate concentrations, 2DG, glucose, DG6P, and glucose 6-P can all be separately measured. To avoid a side reaction from the use of a high level of G6PDH, when measuring DG6P, glucose is first removed with glucose oxidase plus aldose reductase.
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PMID:Enzymatic assays for 2-deoxyglucose and 2-deoxyglucose 6-phosphate. 355 57

1. In human erythrocytes, alpha-D-[U-14C]glucose is more efficiently oxidized than beta-D-[U-14C]glucose at a low concentration of the hexose (0.1 mM), but not so at higher glucose concentrations. 2. This unexpected situation may be attributable in part to the lower Km of hexokinase for alpha- than beta-D-glucose, this difference in affinity compensating for the higher maximal velocity found with the beta- rather than alpha-anomer. 3. A contributive role for aldose reductase in the anomeric control of D-glucose 6-phosphate circulation in the pentose phosphate pathway should not be ruled out, since aldose reductase inhibitors decrease the production of 14CO2 by erythrocytes exposed to D-[U-14C]glucose. 4. Nevertheless, the essential role of hexokinase in such an anomeric control is supported by the finding that, in the presence of menadione, which augments considerably D-[U-14C]glucose oxidation but fails to affect D-[5-3H]glucose utilization, the anomeric alpha/beta ratio in 14CO2 production from D-[U-14C]glucose follows, at increasing concentrations of the hexose, the same pattern as that found for its phosphorylation.
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PMID:Anomeric specificity of D-glucose phosphorylation and oxidation in human erythrocytes. 362 7

1. The activities of three enzymes which act on glucose, namely hexokinase, aldose reductase and glucose dehydrogenase, were measured in extracts of eye lens from cow, calf, rabbit, rat and guinea pig, and in human cataractous lenses. 2. The K(m) (glucose) of these three enzymes in extracts of cow lens was found to be 0.12mm, 28mm and 690mm respectively. 3. The physiological importance of hexokinase, aldose reductase and glucose dehydrogenase in the lens of normal and diabetic animals is discussed.
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PMID:A study of three enzymes acting on glucose in the lens of different species. 604 6

By introducing fructose into the glycolysis, it is possible to stimulate ATP formation. As is the case in animal experiments, in human lenses, too, the first step in the phosphorylation to fructose-1-phosphate via the enzyme ketohexokinase. The present investigation deals with the question whether enzymes present in the lens are responsible for the further steps in fructose degradation. Particularly the aldolase isoenzyme C splits fructose-1-phosphate into glyceraldehyde and dihydroxyacetone phosphate in the same way as in glucose catabolism. Dihydroxyacetone phosphate can further be directly degraded and thus utilized to ATP formation. From glyceraldehyde, glycerol (aldose reductase) or glycerate (aldehyde dehydrogenase) can be formed. The presence of triosekinase, which phosphorylates glyceraldehyde directly to glyceraldehyde-3-phosphate, could only be determined in the lens tissue of young animals. The presence of glycerokinase (glycerol leads to glycerophosphate) could not be verified. Thus, in the lens tissue 1 ATP molecule net per fructose molecule can be formed. In older age, the glucose breakdown is limited by hexokinase and phosphofructokinase, so that the glucose, after transformation via the sorbitol pathway to fructose, can also be utilized for the energy metabolism.
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PMID:Investigations of the enzymes involved in the fructose breakdown in the cattle lens. 628 47

A pathway from glucose via sorbitol bypasses the control points of hexokinase and phosphofructokinase in glucose metabolism. It also may produce glycerol, linking the bypass to lipid synthesis. Utilization of this bypass is favored by a plentiful supply of glucose--hence, conditions under which glycolysis also is active. The bypass further involves oxidation of NADPH, so the pentose phosphate pathway and the bypass are mutually facilitative. Possible consequences in different organs under normal and pathological, especially diabetic, conditions are detailed. Enzymes with related structures (for example, sorbitol dehydrogenase and alcohol dehydrogenase, and possibly, aldehyde reductase and aldose reductase, respectively) are linked functionally by this scheme. Some enzymes of the bypass also feature in glycolysis (aldolase and alcohol dehydrogenase), and these enzymes, with the reductases involved, are proteins known to occur in different classes or multiple isozyme forms. Two of the enzymes (aldolase and alcohol dehydrogenase) both involve classes with and without a catalytic metal (zinc). The existence of parallel pathways and the occurrence of similar enzymic steps in one pathway may help to explain the abundance and multiplicity of enzymes such as reductases, aldolases, and alcohol dehydrogenases.
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PMID:Enzyme relationships in a sorbitol pathway that bypasses glycolysis and pentose phosphates in glucose metabolism. 640 81

A BASIC computer program has been developed which has been used to show that bovine lens aldose reductase with NADPH as substrate follows a 1:1 function, while rabbit lens hexokinase has a rate equation of minimum degree 2:2, and bovine lens polyol dehydrogenase has a rate equation of minimum degree 1:2 with xylitol as substrate. The parameter estimates obtained are very close to those from the BMDP3R curvefitting program on an ICL 2980 mainframe computer, with identical conclusions as to the minimum degree of the rate equation. The computer program can be run on any microcomputer with high resolution graphics in less than 48 K of random access memory.
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PMID:Microcomputer analysis of hyperbolic and non-hyperbolic steady-state kinetics. 643 8


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