EFFECTS OF MALONATE ON LIPID METABOLISM 135 



little affected by malonate up to 10 mM, whereas the electrically stimulated 

 respiration is readily depressed (down to the resting level at 10 mM mal- 

 onate) and the stimulated lactate formation markedly increased. This means 

 that the glucose metabolism appearing upon stimulation is quite sensitive 

 to malonate and perhaps involves a greater participation of the cycle. 

 These results were confirmed by Kimura and Niwa (1953) in guinea pig 

 brain stimulated by K+, and a stimulation of lactate formation by 10 mM 

 malonate was observed by Tsukada and Takagaki (1955). An abolition of 

 the inhibition of respiration upon addition of fumarate occurs (Takagaki et 

 at., 1958). Rat brain slices behave similarly, the resting respiration in the 

 presence of glucose being unaffected by malonate up to 0.8 mM, while the 

 stimulated respiration is readily suppressed (Wallgren, 1960). A malonate 

 concentration as low as 0.2 mM inhibits the stimulated respiration 15%. 

 Pyruvate utilization and the associated oxygen uptake are also inhibited 

 more strongly in stimulated slices than in resting slices (Takagaki et al., 

 1958). The C^^Og from labeled pyruvate is formed about twice as rapidly in 

 high K+ medium compared to the controls (Kini and Quastel, 1959), and 

 this is inhibited more strongly by malonate in the K+-stimulated slices, 

 while the stimulated respiration is depressed to the endogenous level. 



These results taken together clearly indicate a dependency of malonate 

 inhibition on the metabolic activity of brain tissue, whether altered by 

 electrical stimulation or K+. A Pasteur effect is observed and it is possible 

 that the inhibition by malonate would have been greater if it had not 

 induced a greater utilization of glucose. The data do not necessarily imply 

 a specific activation of the cycle; a greater uptake or utilization of glucose 

 would impose a greater load on the cycle, and this might be inhibited more 

 readily. Whatever the explanation for these effects, such results have 

 important bearing on the actions of malonate on intact and functioning 

 nervous tissue. 



EFFECTS OF MALONATE ON LIPID METABOLISM 



The major pathway for fatty acid oxidation is a helical degradation into 

 acetyl-CoA, which normally enters the cycle by condensation with oxal- 

 acetate. Each turn of the helix, releasing one acetyl-CoA, takes up 2 atoms 

 of oxygen, and the complete oxidation of acetyl-CoA through the cycle 

 takes up 4 more atoms of oxygen. Thus, approximately two-thirds of the 

 oxygen uptake due to fatty acid oxidation occurs in the cycle,* and one 

 would expect malonate to depress this fraction in proportion to the cycle 



* The term "cycle." as before, will indicate the tricarboxylate cycle only, and the 

 pathway of degradation of fatty acids to acetyl-CoA and other terminal products 

 will be designated the "helix" for convenience. 



