EFFECTS ON AMINO ACID AND PROTEIN METABOLISM 151 



to the activity of the cycle and the other pathways for the utilization of 

 acetyl-CoA, warrants further investigations of the actions of malonate and 

 other cycle inhibitors both in vitro and in vivo. One approach to the met- 

 abolic defect in hypercholesteremia could be made in this way. 



The incorporation of inorganic P^^ into phospholipids is almost invari- 

 ably inhibited strongly by malonate. This has been shown in peanut mito- 

 chondria (Mazelis and Stumpf, 1955), mycobacteria (Tanaka, 1960), guinea 

 pig brain dispersions (R. M. C. Dawson, 1953), rat liver mitochondria 

 (Marinetti et al., 1957), and other tissues. In cat brain slices, the effects of 

 malonate are very slight and it is possible that malonate does not penetrate 

 well (Strickland, 1954). Yet 3 mM malonate inhibits such incorporation 

 87% in K+-stimulated rat brain slices, although this may be due to a more 

 active cycle participation in the active tissue, inasmuch as respiration is 

 93% inhibited (Yoshida and Quastel, 1962). The phosphorylation of phos- 

 pholipid precursors probably involves the formation of high-energy phos- 

 phate compounds and malonate could depress this as the result of a block of 

 the cycle. A direct effect on the phosphorylation is unlikely. On the other 

 hand, the incorporation of activity into phospholipids from palmitate-1-C^^ 

 in rat liver homogenates (Jedeikin and "Weinhouse, 1954) or from acetate- 

 1-C^* in rat liver slices (Kline and DeLuca, 1956) is affected scarcely at aU by 

 malonate. The phospholipids comprise a very heterogenous group and the 

 response to malonate probably depends on which type of phospholipid is 

 under investigation. 



EFFECTS OF MALONATE ON AMINO ACID 

 AND PROTEIN METABOLISM 



The pathways of amino acid metabolism often lead to or from the cycle 

 so that malonate would be expected to influence amino acid utilization and 

 formation by its inhibition of succinate oxidase. The intracellular accumu- 

 lation of amino acids and their incorporation into proteins are processes 

 requiring energy and consequently malonate could depress these important 

 reactions involved in cellular growth by a depletion of high-energy phosphate 

 derived from the cycle. Finally, malonate might act directly on the enzjones 

 catalyzing amino acid transformations. Information on these matters is 

 fragmentary but enough work has been done to demonstrate some interest- 

 ing effects of malonate on this phase of metabolism. 



Effects on Amino Acid Metabolism 



None of the enzymes involved directly in amino acid metabolism seems 

 to be very sensitive to malonate (Table 1-12) but a number of important 

 reactions have never been studied. Enz>Tnes catalyzing the reactions of 



