AEROBIC METABOLISM OF CARBOHYDRATE 125 



Action of lodoacetate as Related to Alternate Pathways for Glucose Oxidation 



The experimental evidence that oxidation of ghicose in some tissues can 

 proceed when the EM pathway is blocked by iodoacetate led some early 

 investigators to conclude that a ]iathway existed alternate to the EM path- 

 way and not necessarily involving 3-PGDH. We have seen above that there 

 are several explanations for this phenomenon, and incomplete inhibition by 

 iodoacetate cannot alone establish that an alternate pathway is operative. 

 In fact, the cells in which the early evidence was obtained (mainly yeast 

 and muscle) are now known to be rather deficient in these alternate path- 

 ways (e.g., yeast normally oxidizes approximately 3% of the glucose taken 

 up via the pentosiJ-P pathway). However, since it is now demonstrated 

 beyond doubt that many cells possess an active pentose-P pathway, we 

 must consider its role in the effects of iodoacetate on carbohydrate oxidation. 



Scheme 2 shows some of the carbohydrate pathways. The relationships 

 of the direct oxidation of glucose, the pentose-P pathway, and the Entner- 

 Doudoroff pathway to the EM pathway are such that both COg formation 

 and O2 uptake can occur in the presence of a block at the 3-PGDH step. 

 The direct oxidation of glucose and the Entner-Doudoroff sequence are 

 probably of importance only in certain cells, mostly microorganisms; e.g., 

 the latter pathway is very important in the pseudomonads but perhaps not 

 elsewhere. However, Ramachandran and Gottlieb (1963) have recently 

 found that Caldariomyces fumago possesses not only the EM and pentose-P 

 pathways but also the Entner-Doudoroff pathway and an active glucose 

 oxidase of the notatin type. lodoacetate at 1 mM inhibits the glucose res- 

 piration 50% in whole cells but only 9% in extracts; indeed, the cellular 

 O2 uptake is reduced to that of the extract, so that apparently the glucose 

 oxidation in the extract is mediated through iodoacetate-resistant pathways. 

 Glucose dehydrogenase occurs in liver but is usually not very active in 

 other tissues, while glucose oxidases are confined to bacteria, fungi, and 

 algae. We shall thus be particularly concerned with the pentose-P pathway, 

 which is apparently more widespread than any other route alternate to the 

 EM pathway. The operation of the pentose-P cycle leads to the formation 

 of NADPH, CO2, and 3-phosphoglyceraldehyde. The NADPH can reduce 

 a variety of substances (directly or through transhydrogenation with NAD) 

 or be oxidized by O2 through electron transport systems. It is thus evident 

 that, in cells in which the pentose-P pathway is active, respiration and 

 aerobic CO2 formation could occur in the presence of iodoacetate, providing 

 iodoacetate does not block this pathway. Table 1-19 presents the available 

 data on the inhibition of enzymes involved in the pentose-P pathway and 

 certain other pathways of pentose metabolism. It is seen that none of these 

 enzymes is markedly inhibited by iodoacetate and at concentrations of 

 1 mM and below there is likely to be very little if any effect on the pentose-P 

 pathway, so that essentially a complete block of the EM pathway could 



