HEXOKINASES 377 



Such inhibitions may be of importance in the metabolism of mixtures 

 of sugars. Fructose is usually phosphorylated more rapidly than glucose, 

 but in mixtures of the two the phosphorylation of fructose is markedly 

 suppressed and essentially only glucose is metabolized. Although little 

 is known of the nature of the binding of these hexoses to the enzyme, it 

 would appear that the configurations at C-3 and C-4 are particularly im- 

 portant; for example, allose differs from glucose only at C-3 and is not 

 readily bound, and galactose differs from glucose only at C-4 and is much 

 less bound. 



Inhibition by Hexose Phosphates 



Three hexose phosphates have been found to be fairly specific and inter- 

 esting inhibitors of hexokinases: these are a-D-glucose-6-P, a-L-sorbose-1-P, 

 and l,5-anhydro-D-glucitol-6-P. Inhibiting hexose phosphates should be 

 visualized in their pyranose or furanose forms, since it is likely that in- 

 teraction with the enzyme occurs with one side of these ring structures. 

 (See formulas on page 378). 



Glyceraldehyde has been known for many years to be an inhibitor of 

 glycolysis and Lardy et al. (1950) in a study to determine the site of action 

 found that L-glyceraldehyde prevents the phosphorylation of glucose or 

 fructose in brain extracts, but yet has no direct effect on the hexokinase. 

 This paradox was resolved by showing that aldolase catalyzes the conden- 

 sation of L-glyceraldehyde with glyceraldehyde-3-P to give a mixture of 

 D-fructose-1-P and L-sorbose-1-P. The latter compound was found to be a 

 potent inhibitor of hexokinase (for example, 0.08 mM inhibits 67% the 

 phosphorylation of glucose at 35 mM), whereas L-sorbose and L-sorbose-6-P 

 are inactive. The conventionally written structure for L-sorbose- 1-P 

 (as above) bears little obvious resemblance to D-glucose-6-P, but if the 

 former structure is inverted it is seen that the molecules are identical from 

 one side and differ only by the transposition of a hydroxyl group, as illus- 

 trated by Lardy et al. with molecular models. D-Glucose-6-P is the product 



CH3— O— PO'a' 

 O 



HO^ 



Q- L-Sorbopyranose- 1-P 



of the hexokinase phosphorylation of glucose and is an inhibitor of the 

 reaction (see below). It is surprising that the inhibition by L-sorbose-1-P 

 is not competitive with glucose; indeed, as the glucose concentration is 

 increased, the inhibition becomes somewhat greater. It is possible that 



