MISCELLANEOUS ANALOG INHIBITIONS 613 



brane. Durham and Hubbard (1959, 1960) favor competition for a transport 

 system in the inhibition by p- aminosalicylate of the oxidative assimilation 

 of p-aminobenzoate in Flavobacterium. In the presence of ^-aminosalicylate 

 there is more p-aminobenzoate remaining in the medium and almost com- 

 plete inhibition of uptake is seen at a p-AS/p-AB ratio of 10. p-Aminoben- 

 zoate may be not only a necessary metabolite for folate synthesis, but also 

 the principal source of energy for growth. It is very difficult in such cases 

 to determine whether the inhibition is on a surface transport or an intra- 

 cellular enzyme until the enzymes responsible for the metabolism have been 

 isolated and examined. 



Inhibition of Acetate and Fat Metabolism by Propionate 



The original work in this field was done by Jowett and Quastel (1935 a,b). 

 The transformation of butyrate into acetoacetate in guinea pig liver slices 

 is inhibited strongly by benzoate, /9-phenylpropionate, and cinnamate. Pro- 

 pionate also inhibits but more weakly (59% at 10 mM). Much later Felts 

 et al. (1956) reported that 4 mM propionate almost completely depresses 

 the incorporation of acetate- 1-C^* into fatty acids in rat liver slices. The 

 formation of C^Og is also suppressed. Propionate is known to be inhibitory 

 to the growth of many bacteria and fungi, so the question of the mechanism 

 of its action is of some importance. It has often been attributed to a com- 

 bination with and depletion of coenzyme A. This inhibition has been studied 

 most thoroughly by Pennington (1956, 1957), who found that the reaction 

 acetate- 1-C^* -^ C^^Og in rat liver can be inhibited readily and almost com- 

 pletely, while simultaneously the total amount of acetate disappearing is 

 reduced. This also occurs in kidney, heart, and diaphragm, but to a lesser 

 extent. Even concentrations as low as 0.5 mM are 40% inhibitory in the 

 liver. It was felt that propionate blocks both the uptake of acetate and the 

 formation of acetyl-CoA. The oxidation of pyruvate is inhibited much less 

 and that of butyrate not at all. However, most of the action must be on 

 the intracellular metabolism inasmuch as marked inhibition is seen in liver 

 homogenates (Pennington and Appleton, 1958). Addition of coenzyme A 

 in the presence of propionate increases the amount of COg formed from 

 acetate slightly but does not reverse the inhibition, indicating that a simple 

 depletion of coenzyme A is not the mechanism. It was postulated that 

 perhaps propionate inhibits after being metabolically altered, possibly to 

 propionyl-CoA, or directly inhibits acetyl-CoA synthetase. This is an in- 

 teresting and metabolically important inhibition so that one looks forward 

 to studies on the enzymes involved in acetate metabolism. 



A few instances of the inhibition of acyl-CoA metabolism by analogs have 

 been reported. Tetrolyl-CoA and propiolyl-CoA, the acetylenic analogs of 

 butyryl-CoA and propionyl-CoA, respectively, are potent noncompetitive 

 inhibitors of fatty acid synthesis in brain and liver extracts (Brady, 1963; 



