EFFECTS OF MALONATE ON GLUCOSE METABOLISM 125 



endogenous respiration of Ehrlich ascites cells is inhibited around 35% by 

 30 vaM malonate, but when glucose is present there is very little effect of 

 malonate (Seelich and Letnansky, 1960). Put in another way, in the pres- 

 ence of malonate the addition of glucose increases the 0, uptake somewhat 

 instead of depressing it as it does in uninhibited cells. Another possible 

 reason for a failure of malonate to depress glucose respiration is the oc- 

 currence of oxidative pathways unassociated with the cycle. Caldariomyces 

 fumago has no hexokinase and the usual Embden-Meyerhof glycolytic 

 pathw^ay is absent; the oxidation of glucose occurs more directly through 

 glucose and gluconate oxidases (Ramachandran and Gottlieb, 1963). The 

 respiration in this organism is not affected by malonate at 10 mM. 



Effects on Glucose Utilization 



A depression of cycle oxidations by malonate would be expected to cause 

 an increased utilization of glucose, as do hypoxic conditions, in cells capable 

 of exhibiting a Pasteur reaction. This is a manifestation of one interrela- 

 tionship between the cycle and the glycolytic pathway, and is partially 

 mediated through changes in the concentrations of inorganic phosphate 

 and phosphate acceptors, such as ADP. For such a response to occur, the 

 utilization of glucose must have been initially limited by the coupled 

 phosphorylation at the 3-phosphoglyceraldehyde oxidation step. Another 

 mechanism for the influence of cycle activity on glucose utilization involves 

 the membrane transport of glucose and its phosphorylation. The inward 

 transport of glucose under certain conditions may limit glucose utilization, 

 and it has been shown that anoxia accelerates this transport in rat heart 

 (Morgan et al., 1961 a, b). It is quite possible that malonate by its depres- 

 sion of cycle activity, can alter these transport processes. A third mechanism 

 might involve the rate of oxidation of NADH. The addition of pyruvate to 

 ascites cells stimulates the formation of C^^02 from labeled glucose (Wenner 

 and Paigen, 1961) Initially the rate of pyruvate oxidation is limited by the 

 rate of NADH oxidation and the exogenous pyruvate acts as an electron 

 acceptor, 1 mole of lactate appearing for each mole of pyruvate oxidized 

 through the cycle. The accumulation of pyruvate as a result of the cycle 

 block by malonate could initiate this dismutation so that more glucose 

 would be utilized than otherwise. Indeed, lactate formation is often increased 

 during malonate inhibition. In all these ways, and perhaps others, a cycle 

 block might affect glucose uptake and utilization. 



A stimulation of glycolysis by malonate was first observed by Kutscher 

 in Heidelberg (Kutscher and Sarreither, 1940; Kutscher and Hasenfuss, 

 1940). Malonate was injected into guinea pigs, the muscle removed later, 

 and the formation of lactate determined in a brei. In some cases, glucose, 

 succinate, or fumarate was also injected. Malonate accelerates lactate for- 

 mation and this is overcome by both succinate (see accompanying tabula- 



