TRICARBOXYLATE CYCLE 87 



TRICARBOXYLATE CYCLE 



The effects of iodoacetate on pyruvate oxidation and the tricarboxylate 

 cycle will be considered preparatory to a discussion of the effects on res- 

 piration and aerobic carbohydrate metabolism. The end product of the EM 

 pathway as here defined is pyruvate, and the most important aspect of 

 exergonic carbohydrate oxidation is the disposal pathways for this pyruvate, 

 the commonest being the cycle (as previously, "cycle" will refer only to the 

 Krebs tricarboxylate cycle). The central role of the cycle in energy produc- 

 tion and the multiplicity of the types of enzyme it contains always make 

 the cycle a fascinating subject for the study of inhibitors. Several cycle en- 

 zymes are usually classed as SH enzymes and two cofactors, coenzyme A 

 and lipoate, also contain SH groups, so that the cycle would not be expected 

 to be immune to iodoacetate. 



Antagonism of Iodoacetate Inhibition by Pyruvate, Lactate, and Acetate 



The early workers were more concerned with the ability of lactate and 

 related substrates to counteract metabolic depression by iodoacetate than 

 with the direct effects of iodoacetate on the oxidation of these substrates. 

 Fundamentally, the increase in respiration previously inhibited by iodoace- 

 tate (in the presence of glucose or endogenous substrates) brought about by 

 the addition of C2-C4 acids is not a true antagonism of the iodoacetate inhi- 

 bition, but shows only that iodoacetate does not inhibit the oxidation of 

 these added substrates as readily as the endogenous or glucose respiration. 

 Since little quantitative information can be obtained from such studies, they 

 will be summarized very briefly. They are mainly of historical interest. 



Krebs (1931) reported that 0.3 niM iodoacetate inhibits anaerobic gly- 

 colysis and respiration markedly, and that the addition of lactate reduces 

 the inhibition (see accompanying tabulation). Tartrate, citrate, /^-hydroxy- 



butyrate, and glycine do not alter the respiratory inhibition. However, it 

 should be noted that some inhibition remained, especially in the tumor 

 tissue, but whether this indicates depression of lactate oxidation is not 



