EFFECTS OF 2-DEOXY-D-GLUCOSE 389 



accumulation of 2-DG-6-P (Barban, 1962 a, b). How much of the 2-DG is 

 oxidized directly is generally unknown, but the glucose oxidase from 

 As'pergillus niger oxidizes it fairly well: the relative rates of oxidation are 

 glucose (100), 2-DG (20), 3-DG (1), 4-DG (2), 5-DG (0.05), and 6-DG (10) 

 (Pazur and Kleppe, 1964). The direct oxidation of 2-DG is apparently 

 catalyzed by a variety of enzymes, some of the notatin type (Sols and de 

 la Fuente, 1957) and some of the glucose dehydrogenase type (Williams 

 and Eagon, 1959). The further metabolism of 2-deoxy-D-gluconate probably 

 varies with the tissue and has been shown in the scheme above for skin 

 (Brooks et at., 1960). Other pathways for 2-DG metabolism may occur in 

 plants, since Kocourek et al. (1963) have provided evidence for (1) /?- 

 glucosidation probably on C-6, (2) oxidation on C-1 to form 2-deoxyhexo- 

 nate lactone, and (3) epimerization to 2-deoxygalactose in tobacco plants 

 taking up 2-DG through the roots. The last reaction involves three enzymes 

 and the epimerization occurs in a complex with UDP. The abnormal di- 

 saccharide, /5-D-fructofuranosyl-2-deoxy-D-glucose, has been insolated from 

 the excised leaves of several plants following incubation with 2-DG (Barber, 

 1959). It is possible that a number of abnormal polysaccharides containing 

 2-DG will eventually be found. 



Effects of 2-DG and 2-DG-6-P on Glycolytic Enzymes 



2-DG inhibits the utilization of glucose and other sugars in many organ- 

 isms and tissues, and we shall now attempt to localize the site of this 

 inhibition in the early phases of glycolysis. We must consider not only 

 2-DG but also its primary metabolic product, 2-DG-6-P, as inhibitors. 

 The most likely sites for inhibition would be (1) 2-DG on hexokinases, or 

 (2) 2-DG-6-P on phosphoglucose isomerase, 6-phosphofructokinase, or al- 

 dolase with respect to glucose metabolism. Since 2-DG is phosphorylated 

 about as well as glucose by hexokinases it is clear that some competitive 

 inhibition would be observed under certain circumstances, a suggestion first 

 made by Cramer and Woodward (1952). However, this would appear to 

 be generally an unimportant factor in the over-all glycolytic inhibition, 

 since 2-DG equimolar with glucose does not inhibit the glucokinase of ascites 

 cells (Nirenberg and Hogg, 1958) and at 10 times the glucose concentration 

 does not inhibit HeLa cell glucokinase (Barban and Schulze, 1961). The 

 situation may be somewhat more complex in certain tissues, however, in- 

 asmuch as rat liver contains two glucose-phosphorylating enzymes, called 

 glucokinase and hexokinase (Walker and Rao, 1963). The sensitivities of 

 these enzymes are quite different (see accompanying tabulation) and a 

 kinetic analysis was made, the hexokinase being studied without interfer- 

 ence by the glucokinase since fetal liver contains only the former. The 

 effect of the various inhibitors, which are all competitive, varies in a com- 

 plex fashion as the glucose concentration is changed because of the vary- 



