404 2. ANALOGS OF ENZYME REACTION COMPONENTS 



showed that fermentation of glucose and fructose by yeast is competitively 

 inhibited by 6-DFG. The apparent constants are shown in the following 

 tabulation. 6-DFG is not fermented by intact cells or yeast extracts. In 



extracts 6-DFG has essentially no effect even at 36 milf and hexokinase 

 is very weakly inhibited. Glucose utilization by rat diaphragm is not in- 

 hibited as well as yeast fermentation, and 6-DFG is not taken up as readily 

 as glucose by the muscle cells. Glucose oxidase (notatin) oxidizes 6-DFG at 

 about 3% the rate of glucose oxidation so that direct oxidation in the 

 tissues is probably negligible. It was concluded that the rate-limiting re- 

 action for glucose utilization is different in intact cells and extracts, and 

 that 6-DFG probably inhibits the membrane transport of normal hexoses. 



The uptake and metabolism of 6-DFG may vary from tissue to tissue. 

 For example, although 6-DFG is not actively transported into rat diaphragm 

 and insulin has no effect on this transfer, it is well transported across the 

 intestinal wall whereas 2-DG is not (Wick et at., 1959; Wilson and Landau, 

 1960). And, although 6-DFG is not metabolized in most tissues, a particulate 

 preparation from Aerobacter aerogenes is able to oxidize it to the corres- 

 ponding gluconate (Blakley and Ciferri, 1961). It is fairly certain that the 

 compound is quite stable and that release of fluoride does not occur suffi- 

 ciently to inhibit glycolysis (Serif et al, 1958). 



6-DFG inhibits the formation of C^^Oa from glucose-u-C^^ in liver, kidney, 

 and adipose tissue, without modifying the metabolism of acetate or lactate 

 (Serif and Stewart, 1958; Serif and Wick, 1958; Serii et al, 1958). In general 

 6-DFG is somewhat less potent than 2-DG (Fig. 2-11), but the relative 

 sensitivities depend on the tissue studied. Nevertheless, in the eviscerated 

 rat 6-DFG is able to inhibit the intracellular transport of glucose quite 

 appreciably, e. g., 42% from 200 mg/kg (Wick et al, 1959). There is no direct 

 evidence that 6-DFG acts elsewhere than on membrane transport and the 

 comparable inhibitions produced on the metabolism of glucose- 1-C^^, glu- 

 cose-6-C^*, and glucose-u-C^* would point to a block prior to the glyco- 

 lytic-pentose phosphate shunt division (Serif and Wick, 1958). However, 

 hexokinases from other than yeast have not been adequately tested. Al- 

 though the toxicities of 2-DG and 6-DFG have not been directly compared, 

 Blakley and Boyer (1955) found that 250 mg/kg 6-DFG intraperitoneally 



