EFFECTS OF MALONATE ON LIPID METABOLISM 147 



tabulation). The stimulating action of a-ketoglutarate was attributed to 

 the generation of NADH by which hydrogen atoms are provided for fatty 

 acid synthesis. Dils and Popjak (1962) claimed that malonyl-CoA is not 



Incorporation of acetate into 

 fatty acids (m/< moles/ 100 mg) 



Control 18.2 



Malonate 118 



Oxalacetate 72 . 7 



Malonate + oxalacetate 241 



a-Ketoglutarate 51.7 



Malonate + a-ketoglutarate 517 



formed from malonate in these extracts and that the stimulation of fatty 

 acid synthesis must be an indirect effect, possibly the suppression of the 

 deacylation of malonyl-CoA formed from acetyl-CoA, or the inliibition of 

 the decarboxylation of malonyl-CoA. Kallen and Lowenstein (1962) pointed 

 out that if this were the mechanism by which malonate acts, it should also 

 stimulate the synthesis of fatty acids from malonyl-CoA, which it does not; 

 indeed, malonate at 10 niM inhibits the conversion of malonyl-CoA into 

 fatty acids 33%. There is actually a stimulation of the formation of fatty 

 acids from acetyl-CoA. Furthermore, Spencer and Lowenstein (1962) found 

 that malonate is incorporated into fatty acids in an extramitochondrial 

 extract from rat mammary gland; acetate stimulates malonate incorpora- 

 tion just as malonate stimulates acetate incorporation. All of the stimula- 

 tion by malonate, however, cannot be explained by its conversion to mal- 

 onyl-CoA since several times more acetate than malonate is incorporated. 

 The varying effects of malonate on different preparations from a single 

 tissue are well illustrated in the studies of Abraham et al. (1961) with rat 

 mammary gland, where malonate stimulates fatty acid synthesis markedly 

 in cell-free systems (maximal stimulation around 130% at 17 mM malon- 

 ate), inhibits the synthesis 63% in slices, and has very little affect when 

 glucose is present. Glucose was assumed to provide NAD(P)H by forming 

 cycle substrates and also to augment the ATP level, which in the absence 

 of glucose might have been reduced by malonate. In the homogenates ATP 

 was added so that this aspect of the action of malonate could not be exhibit- 

 ed. The response to malonate is markedly dependent on the experimental 

 conditions, as shown by Hosoya and Kawada (1961) with human placental 

 slices, additions of estradiol, ATP, NAD, or bicarbonate altering the fatty 

 acid synthesis and its modification by malonate. It may be noted that fatty 

 acid synthesis in particulate preparations from the locust fat body occurs 

 rapidly only in the presence of malonate (Tietz, 1961). 



