40 Philip Siekevitz 



have found a correlation between increased gluconeogenesis 

 and increased glucose-6-phosphatase activity when the 

 supply of available glucose in the diet is reduced. In the 

 fasted animals, glucose-6-phosphatase activity is also increased 

 (cf. Weber and Cantero, 1957). It is my contention that the 

 reduced glucose in the diet could lead to a temporary reduc- 

 tion of glucose in the blood, then in the ER lumina, and in 

 some way to an increased phosphatase activity, leading, 

 because of shifts in equilibria, to an increase in the breakdown 

 of liver glycogen, and to a steady-state level of glucose in the 

 blood. It is well known that the equilibrium of the concen- 

 trations of small molecules between liver and the blood is very 

 rapid. Again, it has been suggested (Cahill et al., 1958) that 

 the rate of reoxidation of TPNH may control glucose-6- 

 phosphate dehydrogenase activity, and this could be regulated, 

 according to the scheme, by the rate of oxidation of this com- 

 pound by the microsomal enzyme, the TPNH-cytochrome c 

 reductase. 



The rates of enzymic activity, in this case hexokinase, 

 phosphoglucomutase, and phosphorylase, might be enhanced 

 by being attached to the ER membranes. This could be 

 accomplished in two ways; in the first, hexokinase could be 

 "activated" according to the several biochemical considera- 

 tions cited above ; in the second, an inactive enzyme could be 

 activated by a process taking place at the membrane surface. 

 A theoretical example of the latter is phosphorylase, for an 

 " inactive " phosphorylase b has to be converted to an " active" 

 phosphorylase a (Cori, 1955; Cowgill and Cori, 1955) before 

 catalysis can take place. It is known now that an enzyme, 

 phosphorylase b kinase, does this converting by phosphory- 

 lating the enzyme in the presence of ATP (Krebs and Fischer, 

 1956; Rail, Sutherland and Wosilait, 1956). Is it not possible 

 that this kinase is part of the ER membrane, and the process 

 of activating phosphorylase in the cell consists of moving it 

 from the cytoplasmic matrix to the ER membrane site? 



It is not difficult to conceive how enzymes which are 

 normally in a "soluble" state in the cytoplasmic matrix 



