TRICARBOXYLATE CYCLE 89 



genase with respect to iodoacetate inhibition, and perhaps nearly equivalent 

 to 3-PGDH in susceptibility to iodoacetamide. The degree of inhibition 

 probably depends on the method of determining the activity: the greatest 

 inhibition is probably observed when O2 uptake or methylene blue reduc- 

 tion is measured, less when ferricyanide is the acceptor, and least when 

 CO2 evohition is determined. Pyruvate decarboxylase, which does not de- 

 pend on the SH cofactors, may be less sensitive to iodoacetate, but the 

 reported results (Table 1-13) are too variable for general conclusions to 

 be drawn. 



For the purpose of evaluating the sensitivity of pyruvate oxidation to 

 iodoacetate, the most significant work is that in which the inhibition is 

 measured of the oxygen uptake resulting from pyruvate addition to tissues. 

 However, one must remember that the inhibition here need not be directly 

 on the conversion of pyruvate to acetyl-CoA but could result from suppres- 

 sing any step in the cycle. Inhibition of lactate respiration by iodoacetate 

 at 1 mM or less may be confidently attributed to an effect on the metabo- 

 lism of the pyruvate formed, since lactate dehydrogenase has been seen to 

 be relatively insensitive. The moderate inhibition of pyruvate fermentation 

 in yeast by iodoacetate around 1 niM (30-40%) reported by Yamasaki 

 (1930) and Jensen (1931) shows that it is much less sensitive than glucose 

 fermentation, but yet that some inhibition can be exerted in the intact cell, 

 probably on pyruvate decarboxylase. Meyerhof and Boyland (1931) dem- 

 onstrated that frog muscle treated for 1 hr with 0.25 mM iodoacetate 

 (this inhibiting glycolysis almost completely) can oxidize lactate and pyru- 

 vate as well as normal muscle, and Lundsgaard (1932) stated that iodo- 

 acetate-poisoned yeast can oxidize pyruvate much better than glucose, al- 

 though no data were given to indicate whether there is any inhibition at all. 

 On the other hand, Smythe (1938) found that the respiration in yeast due 

 to pyruvate is 90% inhibited by 2.1 milf iodoacetate at pH 2.5, the utiliza- 

 tion of pyruvate being reduced to the anaerobic level. At this pH the in- 

 ternal iodoacetate concentration must have been much higher than in the 

 usual experiments so that these results are perhaps not significant. The 

 oxidation of both lactate and pyruvate in guinea pig brain brei is inhib- 

 ited around 40% by 0.25 milf iodoacetate (Quastel and Wheatley, 1932); 

 although this is less than the inhibition of glucose oxidation (90%), it is 

 certainly appreciable. Very similar results were reported by Peters et at. 

 (1935) in pigeon brain treated with 0.54 mM iodoacetate, and Cohen and 

 Gerard (1937) found 92% inhibition of lactate oxidation in rat brain mince 

 by 10 mM iodoacetate. The oxidation of lactate and pyruvate by Coryne- 

 hacterium diphtkeriae is inhibited 30-40% by 1 mM iodoacetate (Fujita 

 and Kodama, 1934). This early work is thus fairly consistent in showing 

 that iodoacetate between 0.25 and 1 mM can inhibit pyruvate oxidation in 

 a variety of cells by 30-40%, and yet iodoacetate has been commonly con- 



