The supply of precursors for the synthesis of fatty acids.

Citrate, isocitrate, and malonate stimulate acetate incorporation into fatty acids in cell-free preparations of mammary gland, liver, and heart (1-14). Fatty acid synthesis in the mammal requires reduced nicotinamide adenine dinucleotide phosphate as reducing agent, but citrate and isocitrate do not exert their effect simply through the generation of reduced nicotinamide adenine dinucleotide phosphate by the isocitrate dehydrogenase reaction (13). Instead, these tricarboxylic acids stimulate the formation of malonyl-CoA (11, 13, 15). It has been postulated that free malonate acts by inhibiting the deacylation or decarboxylation of malonyl-CoA, and not by being incorporated into fatty acids during their synthesis by mammary gland preparations (14, 16). The present paper shows that citrate is rapidly incorporated into fatty acids. The reaction that initiates this incorporation is catalyzed by the citrate cleavage enzyme. In the mammary gland, the activity of this enzyme is greater than that of the acetate-activating enzyme. Malonate is also incorporated into fatty acids, but at a rate that is slower than the fully stimulated rate of incorporation of acetate. The stimulating effect of malonate can be accounted for in large part by the activation of malonate to malonyl-C0A.l