TRYPTOPHAN METABOLISM 321 



TRYPTOPHAN METABOLISM 



Tryptophan is involved in several important metabolic pathways, form- 

 ing active substances as well as being incorporated into proteins, so that 

 many attempts to block these pathways specifically with analogs have 

 been made. Growth inhibition and physiological disturbances are readily 

 produced by many of these analogs. (See scheme on page 322). 



Synthesis of Tryptophan 



L-Tryptophan is a potent feedback inhibitor of the conversion of 5- 

 phosphoshikimate to anthranilate, an early reaction in tryptophan biosyn- 

 thesis, and 5-methyltryptophan also inhibits, although not so strongly, 

 a phenomenon (i.e., inhibition of a biosynthetic step by an analog) termed 

 false feedback inhibition by Moyed (1960). It is likely that this mechanism 

 explains the bacteriostatic activity of this analog. The condensation of 

 anthranilate and 5-phosphoribosyl-l-pyrophosphate is not inhibited by 

 5-methyltryptophan, but 6-fiuorotryptophan is inhibitory. A later reac- 



COO 



NH, 



Tryptophan Anthranilate 



tion in this sequence, the conversion of anthranilic deoxyribonucleotide to 

 indoleglycerol-3-phosphate, is inhibited by a variety of anthranilate de- 

 rivatives, especially the 3- and 4-methyl analogs (Gibson and Yanofsky, 

 1960). The final reaction, the condensation of indole and serine to form 

 tryptophan, catalyzed by tryptophan synthetase, is a major site of the 

 attack by 4-methyltryptophan, which is a bacterial growth inhibitor 

 (Trudinger and Cohen, 1956). The 5- and 6-methyl indoles are fairly potent 

 competitive inhibitors, with K^ values near 0.1 roM (Hall et al., 1962). 

 They are also antibacterial. The growth depression of E. coli is counteracted 

 by tryptophan (Fig. 2-6). At least two sites for the inhibition have been 

 demonstrated. Tryptophan synthetase is inhibited competitively, but there 

 is also a block of the much earlier formation of anthranilate. There are no 

 effects on the immediate metabolism of anthranilate or on tryptophanase, 

 which indeed readily splits the analog to 4-methylindole. The bacteriostatic 

 action is probably due mainly to suppression of tryptophan synthesis rather 

 than to a disturbance of tryptophan utilization. Thus several steps in the 

 biosynthesis are susceptible to analogs and it is quite possible that other 



