34 Philip Siekevitz 



apparently enhanced activity for the hexokinase bound to 

 mitochondria are various : it could be due to an increase in the 

 local concentration of the substrate, to a decrease in local 

 concentration of the products, to differences in ion concen- 

 trations or pH between the surface of the mitochondria and 

 the medium (cf. Danielli, 1944), or to an increased possibility 

 of binding substrate to an orientated enzyme molecule. This 

 latter reason could explain the findings (Wenner, Dunn and 

 Weinhouse, 1953) that glucose oxidation by kidney, liver, and 

 heart homogenates does not require the addition of ATP, for 

 the concentration of ATP at the membrane site of action, 

 while low, could still be sufficient to saturate the hexokinase 

 at this site. 



The possibility of enhancement of enzyme activity upon the 

 orientation of the enzyme molecule onto a particular surface, 

 has, of course, been raised by other authors, but the foregoing 

 experiment is among the first to indicate that such a pheno- 

 menon can take place. The particular relevance of these 

 observations to the cytological organization of enzymes lies 

 in the further possibilities that enzymes which can be local- 

 ized in the soluble matrix of the cell may not necessarily 

 effect their activity there, but become "activated", you 

 might say, only when they become bound to some intra- 

 cellular membrane. This postulated movement of enzyme 

 molecules onto and off membranes might well be the activity 

 which is involved in the regulation of the course of substrate 

 metabolism. Since hexokinase is one of the key enzymes 

 involved in carbohydrate metabolism, we (Siekevitz and 

 Potter, 1955) thought to see if a hormone, in this case insulin, 

 had any effect on the binding of hexokinase to the mito- 

 chondria. Much to our disappointment, it had no effect, but 

 it still is a good idea, to be investigated whenever a suitable 

 test system becomes available. 



Cori (1955) said that ultimately biochemistry must deal 

 with integrated enzymic activity at the cellular level of 

 organization rather than with individual enzyme reactions. 

 He made this remark at the end of a paper dealing with some 



