128 1. MALONATE 



and under certain conditions malonate could inhibit through the chelation 

 of these ions. A possibly sensitive enzyme is lactate dehydrogenase, which 

 functions in anaerobic glycolysis, although insufficient quantitative work 

 has been done, and it is likely that the enzyme from different sources would 

 be inhibited to different degrees by malonate. It is unfortunate that so 

 little work on the effects of malonate on anaerobic glycolysis has been done, 

 since studies under aerobic conditions are always complicated by the sec- 

 ondary reactions discussed above. In a number of cases, an inhibition of 

 aerobic glycolysis has been observed, i.e., a decreased formation of lactate 

 in air or 95% oxygen, and these inhibitions are usually small. In bull sperm 

 (Lardy and Phillips, 1943 b), 10 mM malonate inhibits 6.7%; in beef 

 thyroid homogenates (Weiss, 1951), 33 mM malonate inhibits 8%; and in 

 rat liver supernate (Aisenbergef oi., 1957), 25 mM malonate inhibits 15.7%. 

 Although rises in lactate can be explained on an indirect basis, a decrease 

 in the rate of lactate formation must usually be attributed to some inhibi- 

 tion along the glycolytic pathway, since it is not very likely that malonate 

 would shift the fate of pyruvate from lactate to the cycle. Greater inhibi- 

 tions have been observed: in mouse brain, 40 mM malonate inhibits lactate 

 formation 57% and in mouse liver mitochondria 100%, this being taken as 

 evidence of some direct effect on glycolysis (du Buy and Hesselbach, 1956). 

 This concentration is, of course, rather high and could have depleted the 

 Mg++ from either the 3-phosphoglyceraldehyde dehydrogenase or enolase 

 systems, or could have inhibited lactate dehydrogenase. Since the substrate 

 in these cases was 3-phosphoglyceraldehyde, an action earlier in the pathway 

 is impossible. There are also miscellaneous reports which might be inter- 

 preted as indicating an inhibition of glycolytic pathways, for example the 

 results of Greville (1936) on rat brain, in which 20 mM malonate inhibits 

 glucose oxidation around 50% and pyruvate oxidation only around 15%. 

 Only one instance of a direct test on anaerobic glycolysis has come to my 

 attention, that of Covin (1961), who found that 5 mM malonate inhibits 

 lactate formation in rat ventricle slices, but the rate of lactate formation in 

 this tissue is so slow, that Covin expressed some doubts as to the reliability 

 of the measurements. One must conclude from the incomplete data, that 

 there is some evidence for a minor inhibition of glycolysis by malonate, 

 especially at the higher concentrations. 



The problem of the direct inhibition of glycolysis by malonate has been 

 studied particularly well by Eva and George Fawaz at the American Univer- 

 sity of Beirut. They had observed that 30 mM malonate almost completely 

 blocks the cycle, leads to the accumulation of succinate, and yet does not 

 depress the dog heart significantly (Fawaz et ol., 1958). However, 60 mM 

 malonate causes rapid reduction in cardiac frequency and contractile 

 failure, although no more succinate accumulates than with 30 mM. This de- 

 pression of cardiac function must be related to an action other than on the 



