234 1. MALONATE 



molecules, and various carboxylate anions can accept the coenzyme A so 

 that acetoacetate is formed: 



2 Acetyl-CoA :^ acetoacetyl-CoA + CoA 

 Acetoacetyl-CoA -|- malonate :;^ malonyl-CoA + acetoacetate 



succinate and butyrate being normally the most active. In this way mal- 

 onate can give rise to acetoacetate as well as by its block of the cycle. 

 Labeled malonate forms labeled acetoacetate in rat liver (Nakada et al., 

 1957). This type of reaction has also been shown to occur in yeast, and dog 

 heart and skeletal muscle (Menon and Stern, 1960). The enzyme, succinyl- 

 /3-ketoacyl-CoA transferase, was purified from pig heart and catalyzes the 

 transfer to both malonate and glutarate. The following reaction: 



Succinyl-CoA + malonate :^ malonyl-CoA + succinate 



also occurs. It is interesting to speculate that some of the succinyl-CoA 

 formed in the oxidation of a-ketoglutarate transfers its coenzyme A to 

 malonate when it is present; if the malonyl-CoA is not readily metabolized, 

 this could deplete the a-ketoglutarate oxidase of coenzyme A and slow down 

 the reaction. Condensation of malonyl-CoA with coenzyme A derivatives 

 may be important in fatty acid synthesis. In pigeon liver and carrot roots 

 there is an enzyme catalyzing the condensation of malonyl-CoA with either 

 acetyl-CoA or butyryl-CoA; although the product is unknown, it was isolat- 

 ed chromatographically (Steberl et al., 1960). This product can form pal- 

 mitate with other enzyme fractions. When malonyl-2-C^^-CoA is incubated 

 with extracts from various rat tissues, various Cig-Cig acids are formed, 

 depending on the acyl-CoA acceptor used (Horning et al., 1960). One acyl- 

 CoA unit is incorporated into long-chain fatty acids and the rest of the 

 C-chain in supplied from malonyl-CoA. Labeled fatty acids are also formed 

 from malonate- 1-C^* in particle suspensions of the locust fat body (Tietz, 

 1961). A highly purified preparation from pigeon liver, which converts 

 malonyl-CoA and acetyl-CoA to palmitate in the presence of NADPH, has 

 been reported (Bressler and Wakil, 1961). In the absence of NADPH, mal- 

 onyl-CoA and acetyl-CoA condense to form an unknown product (which 

 is not acetoacetate, butyrate, or /^-hydroxybutyrate). The conversion of 

 malonyl-CoA to fatty acids is perhaps mediated through such condensa- 

 tions to Cg acids, forming butyryl-CoA, which would again condense with 

 malonyl-CoA, and so lengthen the chain. 



A few words should be said about the pathways of methylmalonate me- 

 tabolism since it has been recently found to be an important intermediate 

 in fatty acid |metabolism, and malonate can interfere markedly with at 

 least one of these reactions. Methylmalonate was shown to be an interme- 

 diate in the metabolism of propionate in various tissues (Flavin et al., 1955; 

 Katz and Chaikoff, 1955; Feller and Feist, 1957). In the course of this work 



