HOWARD M. LENHOFF 211 



glycine, S-acetyl glutathione, S-succinimido glutathione, and 

 oxidized glutathione ) when at high concentrations inhibit the action 

 of glutathione (3, 13). These inhibitions are overcome by increasing 

 the glutathione concentration. Thus, those analogs which retain the 

 tripeptide backbone of glutathione act as competitive inhibitors in 

 the activation of the feeding reflex. 



Another tripeptide which acts as a competitive inhibitor is 

 asparthione (/?-aspartylcysteinylglycine) (13). This compound is 

 nearly identical to reduced glutathione except that it lacks one 

 methylene group, having aspartic acid substituted for glutamic 

 acid. Loomis first showed that asparthione fails to activate the feed- 

 ing reflex ( 17 ) . These characteristics of asparthione point out the 

 importance of the y-glutamyl moiety of the tripeptide for the acti- 

 vation process, as well as providing additional proof that the pres- 

 ence of a sulfhydryl group on a tripeptide similar to glutathione 

 is not sufficient for activity. Contrastingly, glyoxylase, another glu- 

 tathione-requiring system, functions with asparthione (1). 



Further evidence that the y-glutamyl moiety is of special impor- 

 tance in the active structure of glutathione is the action of both 

 glutamic acid and glutamine as competitive inhibitors of gluta- 

 thione, while neither cysteine nor glycine have this efi^ect ( 13 ) . 

 The importance of the a-amino group of the glutamyl moiety is 

 emphasized by the failure of a-keto glutaric acid and of glutaric 

 acid to inhibit. Also, as might l)e anticipated, neither aspartic acid 

 nor asparagine were inhibitory (13). 



These data indicate that the receptor has a high affinity for the 

 y-glutamyl group, that the sulfhydryl group is important only 

 in that it conforms to certain size limitations, and that the glycine 

 is needed to complete the fit of the tripeptide into the receptor 

 (Loomis has shown that y-glutamylcysteine does not activate a 

 response. Ref. 17). As more analogs become available, we hope to 

 determine the exact structural requirements for the stimulatory 

 activity of glutathione. In addition, it should be possible by com- 

 paring the Ki's of the different inhibitors to determine the relative 

 affinities of the receptor for the different parts of the glutathione 

 molecule. 



No other system known to require glutathione has such exacting 

 requirements for the peptide backbone of glutathione. Regardless 



