146 1. MALONATE 



ate so that an inhibition of C^^02 formation from proprionate-l-C^* would 

 imply an action of malonate somewhere along this pathway. It is possible 

 that malonate, or malonyl-CoA formed from it, could compete with the 

 malonyl-CoA from propionate and in this way reduces the formation of 

 0^*02- It is known that the addition of methylmalonate simultaneously 

 with propionate depresses the propionate utilization strongly (Feller and 

 Feist, 1957). Lactating rat mammary gland preparations convert propion- 

 ate to fatty acids in part, the principal pathway being direct condensation 

 with malonyl-CoA to form the odd-chain fatty acids. Malonate at 10 vnM 

 inhibits this incorporation 50-65%, whatever the position of C^^ in pro- 

 pionate, and simultaneously C^^Og is depressed around 30% from proprion- 

 ate-l-C^* and propionate-2-C^^, and nearly 50% from priopionate-3-C^^ 

 (Cady et al., 1963). This was interpreted not as a direct action on the pro- 

 pionate pathway but as a reduction of ATP or NAD(P)H, these being nec- 

 essary for fatty acid synthesis, as a consequence of inhibition of the cycle. 

 In Rhodospirillum rubrum, both the oxidation (Clayton et al., 1957) 

 and the photosynthetic dissimilation (Clayton, 1957) of propionate are 

 inhibited by malonate to approximately the same extent as are the similar 

 reactions of succinate, and this was given as evidence to support the meta- 

 bolism of propionate to succinate in these organisms. 



Effects on Synthesis of Fatty Acids 



There are at least three systems for the synthesis of fatty acids; one is the 

 reversal of the /^-oxidation in the helix and the other two involve the for- 

 mation of malonyl-CoA from acetyl-CoA, one mitochondrial and the other 

 nonmitochondrial (Green and Wakil, 1960). There are obvious relationships 

 between fatty acid synthesis and oxidative metabolism of various sub- 

 strates. The controls that establish the rates of fatty acid synthesis, or the 

 balance between oxidation and synthesis, have not been elucidated and it is 

 difficult to determine in a particular case what the effect of a cycle block 

 would probably be. The level of acetyl-CoA and the availability of the var- 

 ious pathways for its metabolism must be an important factor, but the 

 concentrations of coenzyme A, ATP, NADH and NADPH could also play 

 a significant role. 



Malonate has been found to produce a variety of effects. Most of the 

 studies have involved the incubation of tissue preparations with acetate- 

 1-C^* and the subsequent determination of labeled fatty acids formed from 

 the acetate. In some cases a marked stimulation of fatty acid synthesis 

 in the presence of malonate has been observed. Malonate at 50 milf inhib- 

 its the O2 uptake of nonparticulate extracts of rat mammary gland and 

 yet increases the formation of fatty acids, sometimes as much as 10-fold 

 (Popjak and Tietz, 1955), The addition of oxalacetate or a-ketoglutarate 

 with the malonate increases the synthesis aven more (see accompanying 



