ANTAGONISM WITH FUMARATE 115 



tate and its partial decarboxylation to pyruvate, the cycle presumably 

 becomes activated. The high inhibition of fumarate oxidation by malonate 

 cannot, of course, be attributed solely to an inhibition of succinate oxidase, 



Additions Og uptake % Inhibition 



16.7 

 71.9 



and an effect on oxalacetate decarboxylase or some other enzyme at the 

 relatively high malonate concentration (33 mM) must be assumed. It is 

 desired to point out that the effects with fumarate are unrelated to the 

 inhibition of the endogenous respiration observed with malonate and 

 throw no light on the mechanism of the inhibition. 



Let us now turn to some experiments in which the addition of fumarate 

 provides results indicative of the mechanism of malonate inhibition. The 

 most significant studies usually have involved the determination of the 

 utilization or formation of a particular substance. In the original work 

 of Quastel and Wheatley (1935) mentioned above, the disappearance of 

 acetoacetate in rat liver slices was determined, and fumarate was found to 

 increase its utilization in the presence of malonate, whereas in the absence 

 of malonate it had essentially no effect. Krebs and Eggleston (1940) likewise 

 showed that fumarate would increase the utilization of pyruvate in pigeon 

 muscle in the presence of malonate, at high malonate concentrations the 

 amount of pyruvate utilized being equivalent to the fumarate added. The 

 results obtained by Stare et at. (1941) with pigeon muscle show definitely 

 that the block of pyruvate utilization produced by malonate is effectively 

 overcome by fumarate (see accompanying tabulation). Results such as 



Additions PjTuvate utilized 



Endogenous 16 . 3 



Malonate 7 . 2 



Fumarate 21.4 



Malonate + fumarate 23.3 



these demonstrate that fumarate can counteract the effect of malonate on 

 a specific process and, from the nature of the experiments, it is likely that 

 the cycle block is being overcome in a sense, that is, that oxalacetate is 

 being made available for condensation with acetyl-CoA. They also provide 



