Hexokinase Subject

B. Two key enzymes, hexokinase and glucokinase, catalyze the reaction of glucose with ATP to form glucose 6- ph osphate, which becomes trapped in the cell and subject to metabolism. 

King RF, Macfie J, Hill G (1981) Activities of hexokinase, phosphofructokinase, fructose bisphosphatase and 2-oxoglutarate dehydrogenase in muscle of normal subjects and very ill surgical patients. Clin Sci 60 451-456... 

Enzymes hexokinase in all tissues and also, in the liver, glucoki-nase. Both of these enzymes are subject to regulatory mechanisms. 

In general, flux through the glycolytic pathway is regulated by the activity of hexokinase, 6-phosphofructo-l-kinase, and pyruvate kinase. These enzymes have in common that the metabolic steps they catalyze are non-equilibrium reactions. All other enzymes in the glycolytic pathway appear to catalyze a near-equilibrium reaction and are, therefore, not subject to regulation of the conversion of glucose to pyruvate or lactate. 

Glycolysis is tightly regulated in coordination with other energy-yielding pathways to assure a steady supply of ATP. Hexokinase, PFK-1, and pyruvate kinase are all subject to allosteric regulation that controls the flow of carbon through the pathway and maintains constant levels of metabolic intermediates. 

When real data from the experiment on glycolysis in a rat liver extract (Fig. 15-33) were subjected to this kind of analysis, investigators found flux control coefficients (for enzymes at the concentrations found in the extract) of 0.79 for hexokinase, 0.21 for PFK-1, and 0.0 for phosphohexose isomerase. It is not just fortuitous that these values add up to 1.0 we can show that for any complete pathway, the sum of the flux control coefficients must equal unity. 

Figure 13.3 The regulation of the glycolysis pathway. Glucose-6-phosphate is a noncompetitive inhibitor of hexokinase. Phosphofructokinase and pyruvate kinase are also allosteric enzymes subject to control.

The exact role of the isoenzymic form of hexokinase and the variability in tissue specificity need to be better understood. Several models for hexokinase s mode of action have been proposed, but too little is known of the molecular structure of the enzyme to permit a detailed description of the molecular contacts between enzyme and substrate. The reader is referred to specialized review articles on the subject [36]. The role of hexokinase in the regulation of glycolysis is discussed in a separate chapter. Suffice to point out here that the enzyme is inhibited by glucose-6-phos-phate and that the inhibition is relieved by Pi. 

A possible direct effect of insulin on the hexoklnase reaction has been the subject of much speculation. Conflicting reports on the matter have done little to provide conclusive evidence in support of such a role for insulin. The nature and function of the various mammalian hexokinases have been reviewed.39 Rat liver hexoklnase exists in 4 electrophoretlcalJy distinguishable forms and one of these, hexoklnase II, can be further fractionated into 2 different forms.39 one form of hexoklnase II Is diminished In diabetic animals and levels of this enzyme are restored to normal by insulin.39... 

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