INHIBITORS OF CARBOHYDRATE METABOLISM 405 



in rats produces toxic symptoms with recovery. Since the LD50 for 2-DG 

 is probably around 10 times this, it would indicate that 6-DFG must af- 

 fect the central nervous system more than the other tissues which have 

 been studied. 



VARIOUS ANALOG INHIBITORS 

 OF CARBOHYDRATE METABOLISM 



Numerous inhibitions of enzymes in the glycolytic and pentose phosphate 

 pathways by analogs have been reported. Some of these may be important 

 in attempts to block carbohydrate metabolism specifically and some are 

 undoubtedly significant in mechanisms regulating the rates in these path- 

 ways. We shall discuss a few of the more important enzymes and inhibi- 

 tions, no effort being made to include all of the observations. 



Phosphorylases 



The enzymes involved in the synthesis and phosphorolysis of polysac- 

 charides, such as starch or glycogen, are very stereospecific with respect 

 to substrates and inhibitors. The fairly potent inhibition of glycogen phos- 

 phorolysis by the product glucose- 1-P in preparations from rabbit muscle 

 was reported by Cori et al. (1939), 7 mM inhibiting 93%, whereas glucose- 

 6-P at the same concentration inhibits only 17%. The reverse reaction of 

 glycogen synthesis from glucose-1-P is inhibited competitively by glucose, 

 and to a lesser extent by mannose, galactose, and maltose, but the ajffinity 

 of the enzyme for these sugars is low since 30% inhibition occurs when 

 glucose and substrate are approximately equimolar at 17 m.M (Cori and 

 Cori, 1940). However, the lobster muscle phosphorylase is inhibited only 

 25% by 250 mM glucose when glucose-1-P is 100 mM (Cowgill, 1959). 



The only known substrate for rabbit muscle phosphorylase is a-D-glu- 

 cose-l-P with respect to glycogen synthesis, and Cori and Cori (1940) had 

 found that only a-D-glucose inhibits, /?-D-glucose having little if any ef- 

 fect, so the question of a, /5-specificity was studied in detail on the crystal- 

 line enzyme by Campbell et al. (1952). It was found that /?-D-glucose-l-P 

 is neither a substrate nor an inhibitor, and that whereas a-methyl glucoside 

 inhibits, /?-metliylglucoside is without activity. The /?-anomers appear to 

 have no affinity for the enzyme. Furthermore, a large number of sugars 

 and derivatives at 50 mM were found to be inactive. The configurations of 

 the hydroxyl groups on all the positions of glucose seem to be necessary 

 for combination with the enzyme. A pyranose structure seems also to be 

 a requirement for inhibition, since sorbitol and inositol are without effect, 

 and a primary alcohol group on C-5 is necessary since D-xylose is inactive. 

 The failure of fructose to inhibit might be explained in several ways: (1) 

 the more planar furanose form is dominant, (2) the configurations on the 



