156 CONTROL MECHANISMS IN CELLULAR PROCESSES 



for the present discussion to adopt the views of Chance that ADP is 

 the "best candidate" for such control in vivo (cf. reviews by Slater 

 and Hiilsmann, 1959; Chance, 1959; and Lehninger et al., 1959). 

 There may, however, be factors which release the control of ADP 

 (Lehninger et al., 1959). 



In view of this prominent role of ADP in respiration rates, one is 

 tempted to seek ADP competition. However, the actual amount of 

 ADP in the cell could be mediated through parallel ATP and in- 

 organic phosphate levels. All three phospliate intermediates are in- 

 deed candidates for the causative agent of the Crabtree effect. 



That inorganic phosphate is important may be indicated by the 

 observation of Brin and McKee (1956) that high phosphate levels 

 inhibit the Crabtree effect in ascites cells. However, Wu and Racker 

 (1959b) found that such an effect was variable, while Kvamme 

 (1958a) did not find this effect at all. All agree nevertheless that 

 intracellular phosphate drops on the addition of glucose ( Kunz and 

 Schmid, 1957; Kvamme, 1958a; Wu and Racker, 1959b) . Thus phos- 

 phate as a rate-limiting compound could be involved. However, 

 even during a sustained Crabtree effect inorganic phosphate levels 

 tend to rise again (Kunz and Schmid, 1957). This indicates that 

 inorganic phospliate cannot be rate-limiting for a prolonged period 

 (cf. Ibsen et al, 1958; Seelich et al, 1956). 



The addition of iodoacetate does not inhibit the Crabtree effect 

 (Kvamme, 1958b; Wu and Racker, 1959b; Seelich and Letnansky, 

 1960). However, iodoacetic acid results in a pronounced drop of 

 adenine nucleotides (Kvamme, 1958b; Wu and Racker, 1959b; Wu, 

 1959) accompanied by a release of inosine derivatives (Wu and 

 Racker, 19591)). The effect of dinitrophenol is less clear; Kvamme 

 (1958b) found that it does not release the Crabtree effect, while 

 Wu and Racker ( 1959b) observed only partial release. Seelich et al 

 ( 1956) and Ibsen et al (1958) did find Crabtree effect release. On 

 the other hand the Crabtree effect is absent after the addition of 

 iodoacetate plus dinitrophenol or dinitrophenol at high inorganic 

 phosphate concentrations ( Kvamme, 1958b ) . The immediate ques- 

 tion arises as to how glycolvsis could exert its influence on respira- 

 tion through inorganic phosphate in the presence of iodoacetic acid, 

 which blocks the only phosphate-requiring enzyme in the glycolytic 

 sequence. Furthermore, how could inorganic phospliate influence 

 respiration in the presence of dinitrophenol? The latter difficulty 

 could be overcome if the rate of substrate phosphorylation were the 



