Discussion 225 



As the computer solution is initiated, the rate-eontroUing intermediate 

 of respiration X-I (X) is rapidly expended with the corresponding 

 utilization of oxygen (O). The initially low ADP concentration (D) 

 falls towards zero and oxygen utilization slackens appreciably. As a 

 result of the expenditure of XI the ATP store in the mitochondria 

 (2TP) (B) has increased slightly. The cells are then in state 4 which is 

 characterized by a low respiratory rate set by the low rate of utilization 

 of endogenous ATP (equations 16 and 17). The system is now in the 

 proper condition for the demonstration of the metabolic transient 

 caused by glucose addition and this is marked by the arrow and by the 

 appearance of the glucose concentration at the top of the trace (G). 

 The first effect is an abrupt decrease of the ATP store available for 

 glucose phosphorylation (ITP) (A) and this substance continues to 

 diminish. Simultaneously, the concentrations of intermediates in 

 glucose phosphorylation rise, with a jump in the case of the hexokinase 

 intermediate ENG (E) and smoothly in the case of the phosphohexo- 

 kinase intermediate ETG (T). With a short delay, DPN (N) is reduced 

 by the formation of glyceraldehyde phosphate (GAP). 



At the mitochondria, the rise of ADP concentration (D) leads to an 

 abrupt increase of the XI intermediate (X) and hence to a rapid 

 stimulation of the utilization of oxygen (O). 



Since the store of ATP [ITP(A)] available to glucose phosphorylation 

 is nearly completely expended, the rate of glucose utilization falls to a 

 very low value. The ADP made available by the rapid rush of glucose 

 utilization begins to fall and causes a reduction of the conr'i;iitration of 

 the X-I compound (X). Thus, at a computation time between 295 and 

 340 the oxygen (O) and glucose (G) metabolism comes very nearly to a 

 halt, and the ATP store II (2TP) (B) reaches a high concentration. 



At computation time, addition of DBP (see Fig. IB) allows ATP 

 from mitochondrial store II (2TP) to be transferred to the cytoplasmic 

 store I (ITP). At this moment there is a rapid rise of ATP in store I (A) 

 together with a rapid drop in intermediates T and E of glucose phos- 

 phorylation and a reduction of pyridine nucleotide (N). Glucose utiliza- 

 tion is stimulated and the ADP formed stimulates the respiration. In 

 the ensuing computation intervals (344—491) the metabolism of the 

 cell goes through a transition which might well be termed a Pasteur 

 effect. The computation was stopped at this time, and the aerobic- 

 anaerobic transition is not shown. Then the cessation of ATP synthesis 

 in the mitochondria would be compensated by the glycolytic production 

 of ATP. 



In this very preliminary digital computer analysis of interaction of 

 glycolysis and respiration, we have employed a very simplified system 

 for all the chemical reactions. In addition, we have been forced to 

 make arbitrary choices of concentrations and velocity constants. 

 Nevertheless, the system demonstrates important metabolic regulations 

 which we have been able to study experimentally in ascites tumour 

 suspensions. First, it shows the acceleration of respiration caused by 

 glucose addition together with a subsequent inhibition of both glucose 

 and oxygen metabolism. Lastly, it shows a type of Pasteur response in 



CELL METAB.— 8 



