84 1. lODOACETATE AND lODOACETAMIDE 



tate, in most cases the rise in pH being around 0.5-1 unit. There is thus 

 adequate evidence from a variety of organisms and tissues that the predict- 

 ed changes in pH actually occur. However, since there are several factors 

 which determine these pH changes and the interrelationships are rather 

 complex, it should not be concluded that such changes as have been ob- 

 served will invariably occur. 



The importance of the effects of iodoacetate on pH cannot be overlooked. 

 The penetration of iodoacetate into cells depends on the external and inter- 

 nal pH's so that modification of these can secondarily affect the inhibition 

 produced by iodoacetate, as pointed out by Beevers and Simon (1949). 

 Furthermore, cell function can be altered through the pH changes induced 

 by iodoacetate. Sandow and Karczmar (1950) have discussed the latency 

 phenomena of muscle as related to normal pH changes on stimulation and 

 the changes brought about by iodoacetate. It is probably worthwhile to 

 remember that the internal pH of cells treated with iodoacetate may rise, 

 and that this can be a factor in the metabolic or functional changes observed. 



Chronological Sequence of Events brought About Anaerobically 

 by Iodoacetate 



The effects of iodoacetate on the EM pathway will be summarized by 

 discussing the sequence of changes which would be predicted if iodoacetate 

 blocked completely and specifically 3-PGDH under anaerobic conditions 

 (the aerobic situation will be treated on page 139). The simphfied scheme 

 of anaerobic glycolysis (Scheme 1) will help to visualize these effects. The 

 phosphatase reactions have also been included since they may be important 

 in relation to accumulation of hexose phosphates. The over-all reaction is 

 the generation of 2 moles of ATP from each mole of glucose utilized. This 

 scheme also indicates the major controls of the glycolytic rate. One should 

 perhaps also include the following reactions: 



ATP -^ ADP + P, (ATPase or functional utilization) 

 ATP + creatine ^ ADP + creatine-P 



As the (ATP)/(ADP) ratio increases from to 1, the glycolytic rate will 

 increase and then decrease, there being an optimal ratio for the operation 

 of the EM pathway. The (NAD)/(NADH) ratio is similarly important. 



It is impossible to describe the changes consequent to complete block 

 of 3-PGDII in entirely sequential fashion, inasmuch as many things occur 

 simultaneously but, broadly speaking, there is a changing pattern. 



(A) There is a simultaneous cessation of (1) oxidation of 3-phosphoglyc- 

 eraldehyde, (2) formation of 1.3-diphosphoglycerate, (3) generation of ATP, 

 and (4) reduction of NAD. 



