Structure-CaSR-Activity Relation of Kokumi γ-Glutamyl Peptides.

Modulation of the calcium sensing receptor (CaSR) is one of the physiological activities of gamma-glutamyl peptides such as glutathione (gamma-glutamylcysteinylglycine). gamma-Glutamyl peptides also possess a flavoring effect, i.e., sensory activity of kokumi substances, which modifies the five basic tastes when added to food. These activities have been shown to be positively correlated, suggesting that kokumi gamma-glutamyl peptides are perceived through CaSRs in humans. Our research is based on the hypothesis that the discovery of highly active CaSR agonist peptides will lead to the creation of practical kokumi peptides. Through continuous study of the structure-CaSR-activity relation of a large number of gamma-glutamyl peptides, we have determined that the structural requirements for intense CaSR activity of gamma-glutamyl peptides are as follows: existence of an N-terminal gamma-L-glutamyl residue; existence of a moderately sized, aliphatic, neutral substituent at the second residue in an L-configuration; and existence of a C-terminal carboxylic acid, preferably with the existence of glycine as the third constituent. By the sensory analysis of gamma-glutamyl peptides selected by screening using the CaSR activity assay, gamma-glutamylvalylglycine was found to be a potent kokumi peptide. Furthermore, norvaline-containing gamma-glutamyl peptides, i.e., gamma-glutamylnorvalylglycine and gamma-glutamylnorvaline, possessed excellent sensory activity of kokumi substances. A novel, practical industrial synthesis of regiospecific gamma-glutamyl peptides is also required for their commercialization, which was achieved through the ring opening reaction of N-a-carbobenzoxy-L-glutamic anhydride and amino acids or peptides in the presence of Nhydroxysuccinimide.