386 2. ANALOGS OF ENZYME REACTION COMPONENTS 



mentioning because of the implications such actions have for a feedback 

 control of carbohydrate oxidation. A rise in the levels of the inhibitory- 

 intermediates would reduce the rate of formation of pyruvate. The steady- 

 state concentrations of the cycle intermediates are certainly high enough 

 to inhibit significantly, but the problem of compartraentalization arises 

 since it is generally assumed that the tricarboxylates particularly are 

 mostly confined to the mitochondria. Whatever the significance of this 

 type of inhibition, it emphasizes the importance of compartmentalization 

 in regulatory control of metabolism, a factor which has not always been 

 taken into account. 



EFFECTS OF 2-DEOXY-D-GLUCOSE 

 ON CARBOHYDRATE METABOLISM 



An inhibitor capable of specifically blocking the glycolytic pathway 

 would not only be a valuable tool in biochemical investigation but might 

 play a role in the chemotherapy of certain neoplasms. Glucose analogs, 

 especially those entering the pathway and forming inhibitory intermediates, 

 would be the most likely candidates, and 2-deoxy-D-glucose (2-DG) is the 

 most interesting and best understood substance of this type. The volume 

 of literature during the past 10 years on this analog precludes a complete 

 discussion and emphasis will be placed on the sites and mechanisms of the 

 inhibition in the glycolytic pathway. 2-DG was first examined by Cramer 

 and Woodward (1952) at the Franklin Institute in the course of searching 

 for carcinostatic glucose analogs, and they found that it does indeed produce 

 some regression of Walker carcinoma and terminates embryonic develop- 

 ment in rats. 2-DG differs from glucose in the substitution of the 2-OH 

 group by a hydrogen atom and may be represented in the pyranose form as: 



2 -Deoxy-D -glucose 



Absorption, Distribution, and Metabolism of 2-DG 



It will be well to discuss the uptake and fate of 2-DG in cells before turn- 

 ing to the metabolic disturbance produced. 2-DG enters most cells readily; 

 this may involve a phosphorylation at the membrane in some cases, but 

 in others it is phosphorylated only after entry. Whatever the transport 

 mechanism there is usually competition between 2-DG and glucose, the 



