306 2. MALE ATE 



the stimulation of aerobic glycolysis is almost abolished. If pyruvate were 

 merely acting as a hydrogen acceptor from 3-phosphoglyceraldehyde, 

 more lactate should be formed instead of less. Furthermore, Lardy and 

 Phillips (1943 b) found that maleate does not reduce spermatozoa ATP, 

 although motility is lost; ATP-forming reactions occur but the utilization 

 of ATP is depressed. One may note here that the possible effects of maleate 

 of ATPases have not been studied. 



A clue to the mechanism of maleate action may be found in the unex- 

 pected effects of ghitamate (Fig. 2-2). Although respiration in the presence 

 of glutamate is readily depressed to low levels, there is a rapid and marked 

 acceleration of aerobic glycolysis, which, however, is temporary. The rate 

 of aerobic glycolysis actually reaches the anaerobic level in the presence 

 of glutamate. It may be noted that a-ketoglutarate does not alter the re- 

 sponse of aerobic glycolysis to maleate. This problem undoubtedly involves 

 the regulation of pyruvate metabolism by NH4+ levels and transaminations. 

 NH4+ is known to augment aerobic glycolysis in brain. Weil-Malherbe sug- 

 gested that maleate may inhibit the utilization of NH4+ and hence lead to its 

 accumulation, but analyses of the brain for NII4+ did not confirm this. It 

 was shown later that maleate does not affect NH4+ formation in brain slices 

 suspended in glucose medium (Weil-Malherbe and Green, 1955 a). NH4+ 

 and glutamate may increase aerobic glycolysis by diverting cycle inter- 

 mediates to reduce the supply of oxalacetate, less pyruvate entering the 

 cycle to be oxidized. Glutamate might do this' primarily through transami- 

 nation with oxalacetate. However, we have seen that the aspartate :a-keto- 

 glutarate transaminase is reasonably sensitive to maleate (Table 2-2). 

 This may account for the early but temporary peak in aerobic glycolysis 

 when maleate and glutamate are present, maleate penetrating into the 

 slices and inhibiting rather slowly. The question whether the stimulation 

 of aerobic glycolysis by maleate alone is related in any way to NH4+ me- 

 tabolism or transamination remains to be answered. Since glutamate alone 

 augments aerobic glycolysis and pyruvate alone depresses aerobic gly- 

 colysis in brain, the effects of these substances on the maleate response may 

 be basically unrelated to the mechanism of maleate action. Data on the 

 brain levels of keto acids and amino acids during treatment with maleate 

 would help to solve this problem. We shall have occasion later to discuss 

 the effects of maleate on amino acid metabolism and transamination in 

 the whole animal (page 318). 



EFFECTS ON VARIOUS METABOLIC PATHWAYS 



Maleate has been shown to affect several important metabolic processes 

 in microorganisms and tissues. In this section we shall discuss some of 

 these in anticipation of the time when these observations may possibly be 



