EFFECTS OF 2-DEOXY-D-GLUCOSE 391 



dehydrogenase is inhibited noncompetitively by 2-DG-6-P (Barban and 

 Schulze, 1961), 2-DG-6-P competitively inhibits the activation of rat liver 

 glycogen synthetase by glucose-6-P (Steiner et al., 1961), and UDP6: 

 a- l,4-glucan-o;-4-glucosy transferase from dog muscle is inhibited by 2-DG- 

 6-P with Kj =1.3 mM (Rosell-Perez and Larner, 1964). The importance 

 of these inhibitions in the interference produced by 2-DG on glucose me- 

 tabolism is not understood. 



The block of fructose utilization by 2-DG may well present a different 

 problem. Fructose phosphorylation is inhibited much more readily than 

 glucose phosphorylation, presumably due to the lower affinity of the hexo- 

 kinases for fructose (Sols, 1956; Nirenberg and Hogg, 1958; Barban and 

 Schulze, 1961). The inhibition of phosphoglucose isomerase could not explain 

 the suppression of fructose utilization inasmuch as the fructose pathway 

 bypasses this step. In rat adipose tissue 2-DG has very little effect on the 

 metabolism of fructose although glucose metabolism is quite strongly 

 depressed (Fain, 1964). With glucose at 2.8 mM and 2-DG at 1.4 mM, the 

 formation of COg is reduced 70% and of fatty acids 89%. Nevertheless, the 

 stimulatory effect of insulin on fructose utilization is blocked by 2-DG 

 whereas the effects of insulin on glucose are unaltered. Certainly different 

 tissued and organisms must have various transport and enzyme systems for 

 the metabolism of fructose, so one should not expect a uniform action of 

 2-DG. The enzymes involved in the metabolism of fructose- 1-P or fruc- 

 tose-6-P have not been studied with respect to 2-DG inhibition. 



Effects of 2-DG on Carbohydrate Metabolism and Respiration 



Investigations on isolated enzymes have indicated an important block 

 of phosphoglucose isomerase by 2-DG-6-P and contributory inhibition of 

 hexokinases under certain conditions. Let us now turn to studies on carbo- 

 hydrate metabolism in intact cells and tissues in order to determine if the 

 effects of 2-DG can be explained adequately on this basis, or to accumulate 

 evidence of blocks elsewhere. Anaerobic glycolysis, aerobic glycolysis, 

 and glucose respiration are inhibited by 2-DG but to very different degrees 

 (Fig. 2-10). Indeed, respiration is inhibited only with high concentrations, 

 usually 30-100 times that required to inhibit anaerobic glycolysis compara- 

 bly (Woodward and Hudson, 1954; Tower, 1958), so that some workers 

 have reported that respiration is not inhibited (Fridhandler, 1959; Taylor, 

 1960). In the case of sea urchin eggs, the inhibition can be almost completely 

 counteracted by increasing glucose concentration (Bernstein and Black, 

 1959). However, glucose must be present when the 2-DG is added and is 

 ineffective when the inhibition has developed. The respiration of guinea pig 

 skin in the presence of various substrates is inhibited by 2-DG moderately 

 and progressively (see accompanying tabulation) (Carney et al., 1962). 

 All substrates and 2-DG were 20 mM. There is no effect on the endogenous 



