HISTORICAL DEVELOPMENT 5 



At the same time, Lundsgaard (1930 c) believed that iodoacetate could 

 effect a separation of anaerobic glycolysis and respiration, since 1.1 mM 

 iodoacetate inhibits the former completely and has no effect on yeast respi- 

 ration, a point which received much attention later, as we shall see. Iodo- 

 acetate also acts more potently to suppress the CO2 production under an- 

 aerobic conditions than aerobically. Lundsgaard also first demonstrated the 

 fall in R.Q. (1.38 to 0.99) brought about by iodoacetate as the utilization 

 of glucose is inhibited in yeast. A rather specific effect on glycolysis was 

 indicated in the work of Yamasaki (1930), who showed that iodoacetate 

 strongly inhibits the fermentation of hexose diphosphate and has little effect 

 on pyruvate fermentation. A similar result was obtained by Krebs (1931) 

 in mammalian tissues in which iodoacetate at 0.3 mM inhibits anaerobic 

 glycolysis and respiration in the presence of glucose while inhibiting the O2 

 uptake from lactate relatively little (see accompanying tabulation). Two 



basic problems thus existed: (1) can iodoacetate separate glycolysis from 

 respiration as Lundsgaard had believed, and (2) can lactate counteract the 

 inhibitory effect of iodoacetate on respiration? These problems were quite 

 important at that time and much work was done to elucidate the com- 

 plexities; knowing what we do today about metabolism, the answers being 

 fairly clear, it is often difficult to appreciate the concern over these matters. 

 Krebs in finding that iodoacetate inhibits the respiration in animal tissues 

 in the presence of glucose opposed the idea that separation of glycolysis 

 and respiration could be achieved, and believed there to be two phases in 

 glucose metabolism: (1) a first anaerobic phase in which glucose is metab- 

 olized to lactate, and (2) a second aerobic phase wherein the lactate is 

 utilized. Substitution of pyruvate for lactate in this formulation would 

 accord with modern concepts. Thus if iodoacetate inhibits the first phase, 

 it should also inhibit the respiration or second phase, since it is dependent 

 on the first phase for the supply of oxidizable substrate. This would be true 

 if glucose were the sole source for the respiration, but many cells oxidize 

 various endogenous substrates even in the presence of glucose and this 

 could account for an iodoacetate-resistant fraction of respiration. One can 

 say that the respiration ultimately due to the formation of pyruvate by the 



