TRYPTOPHAN METABOLISM 325 



by serotonin (Frieden et al., 1961). The K/s in the following tabulation 

 indicate 3-indolylacrylate to be the most effective inhibitor. Other inhibi- 

 tions observed when (S) = (I) = 3 mM are: indole 69%, tryptazan 50%, 



5-methyltryptophan 38%, and 6-methyltryptophan 33%. The analogs with 

 altered side chains are competitive while the others are mainly noncompeti- 

 tive. The roughly equivalent binding of tryptamine and 3-indolylpropionate, 

 and of serotonin and 5-hydroxytryptophan, might indicate that the binding 

 is primarily with the indole ring, the side chains contributing little, and this 

 is substantiated by the fact that indole is bound approximately as well 

 as 3-indolylpropionate. The stronger binding of 3-indolylacrylate compared 

 to 3-indolylpropionate (about 2 kcal/mole) is thus difficult to account for 

 unless there is a modification of the interaction of the indole N. Tryptophan 

 pyrrolase is an inducible enzyme in the rat but none of these analogs is 

 active, although Sourkes and Townsend (1955) found a-methyltryptophan 

 to induce after subcutaneous injection. 



Tryptophan Hydroxylase (Phenylalanine Hydroxylase) 



Excessive feeding of phenylalanine leads to low blood serotonin, a low 

 excretion of 5-hydroxyindoleacetate, and a decrease in brain serotonin, 

 and this has usually been attributed to an inhibition of 5-hydroxytrypto- 

 phan decarboxylase. However, no accumulation of 5-hydroxytryptophan 

 has been demonstrated and it is possible that the site of the inhibition might 

 be earlier, perhaps on the hydroxy lation of tryptophan (Freedland et al., 

 1961). Hydroxylating preparations from rat liver are indeed quite potently 

 inhibited by L-phenylalanine, and also by phenylpyruvate and phenyUac- 

 tate (K,„ for L-tryptophan is 29 mM, and K^ for L-phenylalanine is 0.22 mM). 



