EFFECTS OF MALONATE ON GLUCOSE METABOLISM 123 



lism because in the total oxidation of glucose to CO, and water, five-sixths 

 of the oxygen is taken up in cycle reactions. This effect would be due to a 

 block of the cycle and would be roughly equivalent to the inhibition of 

 of pyruvate oxidation via the cycle. (2) Malonate may cause an increased 

 uptake and utilization of glucose as a result of inhibition of oxidative reac- 

 tions in the cycle, the mechanism being essentially that of the Pasteur reac- 

 tion. (3) Malonate may have direct actions on the cellular uptake of glucose 

 or on the glycolytic pathways. Evidence for each of these mechanisms will 

 be presented, and then a more detailed analysis of the possible shifts in 

 metabolic patterns brought about by malonate will be given. 



Effects on Oxygen Uptake Associated with Glucose Oxidation 



There are many reports on the effects of malonate on respiration with 

 glucose as the substrate, but in few have the data provided a correction for 

 an effect on the endogenous respiration. Indeed, an endogenous correction 

 to determine the oxygen uptake associated only with glucose oxidation 

 is particularly unreliable, even when the data are available. This is because 

 of the well-known effect of glucose in suppressing endogenous respiration and 

 mitochondrial oxidations (Crabtree effect). Thus the nonglucose respiration 

 may be significantly changed when glucose is added and, perhaps, completely 

 suppressed in some cases. 



Let us assume that the oxygen uptake measured derives only from glucose 

 and that malonate acts only on the cycle. What inhibitions could one theo- 

 retically expect? The inhibition will depend, other than on the degree of 

 cycle block, on the final products of glucose oxidation before and after the 

 addition of malonate. The following equations give the molar oxygen up- 

 takes for the oxidation of glucose to varying degrees of completeness: 



To CO2 and water 



CeHi^Oe + 6 O2 ^ 6 CO, + 6 H,0 



To pyruvate 



CgHi^Oe + O2 -> 2 CH3COCOOH + 2 H2O 



To acetate 



CeHiaOe + 2 0, -> 2 CH3COOH -f- 2 CO, + 2 H^O 



To succinate 



CfiHi^Oe + 5/2 O2 -> HOOCCH2CH2COOH + 2 CO2 + 3 H2O 



CsHiaOg + 2 HOOCCH2COCOOH + 4 0, -> 2 HOOCCH2CH2COOH + 6 CO2 + 4 H^O 



To lactate 



CsHi^Oe + 2 H -). 2 CH3CHOHCOOH 



The second equation for the formation of succinate might express the situa- 

 tion in which there is a source of oxalacetate other than from pyruvate 



