6 1. lODOACETATE AND lODOACET AMIDE 



glycolytic pathway is especially sensitive to iodoacetate and may be inhib- 

 ited without greatly affecting other fractions of the O2 uptake, if the proper 

 conditions are established. Meyerhof and Boyland (1931) showed that lac- 

 tate oxidation is not markedly interfered with in iodoacetate-poisoned 

 muscle, and found that pyruvate stimulates the respiration even more ef- 

 fectively in the presence of iodoacetate. Muscle poisoned with iodoacetate 

 will contract longer when lactate is provided and the lactate disappears 

 (Mawson, 1932); this showed that lactate can be used for the resynthesis 

 of phosj^hagen. In Bacterium delbriickii 0.17 milf iodoacetate inhibits glu- 

 cose respiration 61% and lactate respiration not at all. All recent work, if 

 properly done, has confirmed these original general conclusions. Pyruvate 

 or lactate oxidation may thus proceed in the presence of iodoacetate but, 

 if their formation depends on glycolysis, the respiration will be depressed. 

 The determination of the site of iodoacetate action in the glycolytic path- 

 way proceeded concurrently with the elucidation of the sequence. The em- 

 phasis on the fact that fluoride and iodoacetate inhibit at different loci 

 (Lohmann, 1931) was very important in the analysis. Meyerhof and Kies- 

 sling (1933) showed that whereas fluoride blocks the formation of pyruvate 

 from P-glycerate, iodoacetate is inactive; iodoacetate, on the other hand, 

 blocks the reduction of pyruvate to lactate when coupled with the oxidation 

 of phosphoglyceraldehyde. Furthermore, in the presence of iodoacetate an 

 easily hyrolyzable ester appears during the breakdown of glucose or hexose 

 phosphates and, after isolating phosphoglyceraldehyde from muscle, they 

 showed that its metabolism is blocked by iodoacetate. Embden and Deu- 

 ticke (1934) found that fructose-diP no longer forms P-glycerate and glyc- 

 ero-P in poisoned muscle, and believed they could isolate some phospho- 

 glyceraldehyde as a result of the block. The reaction coupling pyruvate 

 reduction with phosphoglyceraldehyde oxidation is inhibited potently by 

 iodoacetate but the site of the block was not known. Green and Brosteaux 

 (1936) found lactate dehydrogenase to be quite resistant to iodoacetate, so 

 that the sensitive reaction seemed to be the phosphoglyceraldehyde dehy- 

 drogenase. However, the picture was temporarily confused by the report of 

 Dixon (1937) that phosphoglyceraldehyde dehydrogenase is not very sensi- 

 tive to iodoacetate; indeed, he found alcohol dehydrogenase (which plays 

 a role comparable to the lactate dehydrogenase in alcoholic fermentation) 

 to be more sensitive and felt this to be the site of inhibition in yeast fer- 

 mentation. That the principal point of attack is the phosphoglyceraldehyde 

 dehydrogenase in all cases was finally proved by Adler et al. (1938), al- 

 though the demonstration of inhibition of the purified enzyme had to await 

 the work of Cori et al. (1948). The inhibition of glucose utilization, lactate 

 or ethanol formation, and respiration due to glucose, as well as the accu- 

 mulation of certain phosphate esters, could now be readily explained on 

 the basis of a fairly specific block of the step in which phosphoglyceraldehyde 



