140 1. MALONATE 



especially the activating system for the formation of acetoacetyl-CoA, and 

 possesses an active deacylase to split acetoacetyl-CoA. Therefore, acetoace- 

 tate accumulation is most readily observed in liver and most investi- 

 gations have been on this tissue. The urinary acetoacetate found after the 

 administration of malonate is probably derived mainly from liver. In heart, 

 on the other hand, the enzyme balance is such as to favor the rapid me- 

 tabolism of acetoacetate and it does not accumulate. Acetate rather than 

 acetoacetate accumulates in some cells, for example in heart mitochondrial 

 suspensions metabolizing pyruvate in the presence of 8.8 mM malonate 

 (Fuld and Paul, 1952). 



(Malonate) 

 a -Ketoglutorate ^ Succmyl- Co A Succinate -X"^ Fumorcte — ^ —^Citrate 



Fatty acids Pyruvate 



Fig. l-l.'j. Diagram of some pathways involved in the effects 

 of malonate on the metabolism of acetoacetate. 



One would predict that fumarate should counteract the ketogenic activi- 

 ty of malonate because, by supplying oxalacetate, acetyl-CoA will again be 

 able to enter the cycle. However, it may be noted that fumarate may lead 

 to an even greater accumulation of succinate and if the formation of aceto- 

 acetate by the transfer of coenzyme A from acetoacetyl-CoA to succinate is 

 important, fumarate will only augment the malonate effect. Administration 

 of fumarate with malonate to rabbits abolishes the appearance of acetone 

 that arises with malonate alone (Huszak, 1935). Addition of fumarate to 

 malonate-inhibited minces of rat sarcoma likewise prevents the accumula- 

 tion of acetone bodies (Boyland and Boyland, 1936). However, fumarate 

 has very little effect on the appearance of acetoacetate in rat liver slices 

 inhibited by malonate (Edson, 1936), and this might indicate a mechanism 

 for malonate action other than the inhibition of succinate oxidation, or the 

 importance of the coenzyme A transfer reaction. 



It is now easy to see how malonate can reduce the oxygen uptake and 

 the CO2 production from fatty acid oxidation without necessarily decreasing 

 the utilization of the fatty acids. A fraction that would normally be com- 

 pletely oxidized is diverted into acetoacetate (or acetate, acetone, and other 

 products). One of the best indications that malonate does not inhibit the 

 helix directly is the fact that the C^Oo appearing in the end products from 

 labeled fatty acid is not reduced by malonate. To illustrate this it will be con- 

 venient to turn to the excellent studies of Geyer and his group at Harvard. 



