AEROBIC METABOLISM OF CARBOHYDRATE 123 



against the unitary concept of glucose oxidation, wherein gkicose is broken 

 down through an anerobic pathway to pyruvate (lactate in the early work) 

 and then oxidized through another pathway. On the other hand, Krebs 

 (1931) found in rat tissues that anaerobic glycolysis and glucose respiration 

 are inhibited comparably by iodoacetate, and favored the unitary concept. 

 Similar results were reported by Crabtree and Cramer (1933 a) on rat sar- 

 coma, and by Fujita and Kodama (1934) on Corynebacterium diphtheriae, 

 in both cases anaerobic glycolysis and respiration with glucose being inhi- 

 bited to about the same degree. These conflicting results and the incomplete 

 knowledge of the pathways of glucose oxidation created a confusion which 

 has been completely resolved. We can now summarize the experimental 

 results by saying that in most cells under the usual conditions the anaerobic 

 glycolysis is inhibited more readily than respiration by iodoacetate, although 

 very seldom can a completely differential effect be observed, and in some 

 instances there may be very little difference in susceptibility. It should also 

 be pointed out that only with a carefully chosen range of iodoacetate con- 

 centrations can significantly different inhibitions on glycolysis and respira- 

 tion be obtained. Some tissues in which a very clear differential effect is 

 observed are frog muscle (Wright, 1932; Saslow, 1936; Stannard, 1938 a), 

 cat and dog heart (Shorr et al., 1938), rat and guinea pig brain (Heald, 

 1953; Lisovskaya, 1956; McMurray et al., 1957 a), and Ehrlich ascites car- 

 cinoma cells (Holzer et al., 1955 c, 1958; Maizels et al., 1958), as well as in 

 yeast (Lundsgaard, 1930 c; Jensen, 1931; Nilsson et al., 1931; Stier and 

 Stannard, 1936; Stickland, 1956 b). 



A discussion of the reasons for the different susceptibilities of glycolysis 

 and respiration to iodoacetate will bring out a number of the factors in- 

 volved in the inhibition of carbohydrate metabolism. There is not one but 

 several explanations for a differential effect. 



(a) Oxidation of noncarbohydrate substrates. The oxidation of fats, amino 

 acids, and other substrates may proceed in the presence of iodoacetate 

 (providing the concentration is not too high) and may account for part 

 of the iodoacetate-resistant respiration. A determination of the R.Q.'s for 

 normal and poisoned cells will sometimes give information on this point 

 (see page 133). 



(b) Oxidation of intermediates from carbohydrate breakdown. We have seen 

 that lactate and pyruvate can be oxidized appreciably in tlie presence of 

 glycolysis-blocking concentrations of iodoacetate, and Lundsgaard (1932) 

 and others have shown this to hold also for ethanol. Much of the iodoace- 

 tate-resistant respiration of yeast, for example, arises from the oxidation 

 of ethanol formed before glycolytic inhibition is complete. Lundsgaard 

 showed that the longer the fermentation proceeds before iodoacetate inhi- 

 bition, the greater the differential effect on fermentation and respiration, 

 more ethanol having accumulated. If the yeast is washed immediately be- 



