REGULATORY MECHANISMS IN ENERGY METABOLISM 157 



determining factor in the rate of oxidation. Evidence of the rate- 

 limiting function of a-ketoghitaric acid oxidation lias indeed been 

 obtained (Kvamme, 1958c). The iodoacetate dilemma could be 

 circumvented by asserting that the adenine nucleotide drop now 

 becomes the determining fat^;or. 



Competition for ADP between respiration and glycolvsis is a more 

 direct explanation. Gatt and Racker (1959a) found in a reconsti- 

 tuted system that the competition between glycolysis and respira- 

 tion for ADP took place at limited adenine nucleotide concentrations. 

 Tliis could be imitated by creatine kinase plus creatine phosphate. 

 Furthermore, dinitrophenol released the inhibition of respiration. 

 However, at low phosphate concentrations a Crabtree effect could 

 also be observed provdded respiration and glycolysis were main- 

 tained through hydrolysis of the formed ATP. 



Chance and Hess ( 1959 ) prefer ATP as the causative agent. 

 They envision the events as follows: upon addition of glucose to 

 the cell, a rapid release of ADP occurs which accelerates respiration 

 for a brief period. When all the ADP is phosphorylated, the intra- 

 mitochondrial ADP becomes exhausted, and the respiration slows 

 down, especially due to the compartmentation of ATP. Packer and 

 Colder ( 1960 ) sought confirmatorv evidence for this hypothesis on 

 the basis of the behavior of mitochondria inside the cell as judged 

 by lightscattering. Electron microscopy also indicates mitochondrial 

 changes after the addition of glucose to ascites cells (Merkel et al., 

 1960a). The observations, which must be interpreted in the light 

 of the theories but which pose other difficulties, are that the Crabtree 

 effect can be elicited with sugars other than glucose. Fructose and 

 mannose (Brin and McKee, 1956), as well as sugars which are 

 not readily glycolyzed, such as glucosamine (Ciinther and Greil- 

 ing, 1960), have been found to induce a Crabtree effect. Finally, 

 2-deoxyglucose gives the Crabtree effect (Ibsen et al., 1958; Packer 

 and Colder, 1960; Chance, 1960) . This sugar cannot be metabolized 

 at all. In fact it inhibits glycolysis from endogenous glycogen. The 

 only reaction the sugars have in common is the phosphorylation 

 step. In fact their relative effectiveness as Crabtree effect inducers 

 is proportional to their relative affinity for kinase reactions (Packer 

 and Colder, 1960). Acetyl glucosamine, which is not phosphory- 

 lated, does not give a Crabtree effect. ( Ciinther and Greiling, 1960) . 



The phosphorylation of these sugars does not require inorganic 

 phosphate; thus it is unlikely that inorganic phosphate per se is the 



