The Nitrogen-Sparing Effect of Glucose 177 



increased as to promote further than before the synthesis of glutamic 

 acid from ammonia and a-ketoglutaric acid. 



The alternative hypothesis proposes that the nitrogen-sparing ac- 

 tion of carbohydrates is a consequence of the inhibition of one or more 

 reactions of the Krebs-Henseleit cycle. In step I of the urea cycle 

 the synthesis of citrulline is accomplished in the enzyme-catalyzed 

 reaction between ornithine and carbamyl phosphate, the latter com- 

 pound being formed enzymatically from stoichiometric amounts of 

 NH 3 , C0 2 , and ATP. 9 Siekevitz and Potter 10 have observed that the 

 synthesis of citrulline by washed rat-liver mitochondria may be com- 

 pletely inhibited in the presence of a sufficiently high concentration of 

 hexokinase and glucose. Since it was also noted that the concentration 

 of ATP in the medium declined to low levels, the authors concluded 

 that the hexokinase reaction competes for ATP with the citrulline- 

 synthesizing system. It is conceivable also that step II of the urea 

 cycle is similarly blocked in the competition for ATP between the 

 arginme-synthesizing system and the hexokinase reaction. Clearly, 

 serious consideration must be given to the competition for ATP as a 

 factor of physiological significance in regulating the rate of synthesis 

 of urea. 



In rat-liver homogenates the synthesis of urea from ammonia and 

 a-ketoglutaric acid is not as rapid as from glutamic acid. 11 To account 

 for this finding it has been suggested that a high concentration of 

 a-ketoglutaric acid inhibits transaminations from glutamic acid, thus 

 restricting the amount of aspartic acid available to the arginine- 

 synthesizing system. This is still another way in which the formation 

 of urea may be regulated by interactions between the Krebs-Henseleit 

 cycle and the intermediary metabolism of carbohydrates. 



Referring once more to the sequence of reactions leading to the syn- 

 thesis of urea from amino acids, it may be seen that, if the concept 

 of interaction between the intermediary metabolism of carbohydrates 

 and the aminophorase-glutamic dehydrogenase system is correct in 

 accounting for the nitrogen-sparing effect of carbohydrates, it may be 

 expected that the specific rate of utilization of ammonia in the forma- 

 tion of amino acids will be increased in the presence of dietary carbo- 

 hydrate and that the concentration of hepatic ammonia will decline. 

 On the other hand, if nitrogen retention results from the blocking of 

 step I of the urea cycle, it may be anticipated that the specific rate 

 of utilization of ammonia in the synthesis of citrulline will decline 

 and the concentration of ammonia in the liver will increase. In the 

 event that the intermediary metabolism of carbohydrates invokes a 



