Amino Yusuke, Nakazawa Masakazu, Kaneko Megumi, Miyaki Takashi, Miyamura Naohiro, Maruyama Yutaka, Eto Yuzuru
Institute for Innovation, Ajinomoto Co., Inc.
Chem Pharm Bull (Tokyo). 2016;64(8):1181-9. doi: 10.1248/cpb.c16-00293.
Modulation of the calcium sensing receptor (CaSR) is one of the physiological activities of γ-glutamyl peptides such as glutathione (γ-glutamylcysteinylglycine). γ-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 γ-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 γ-glutamyl peptides, we have determined that the structural requirements for intense CaSR activity of γ-glutamyl peptides are as follows: existence of an N-terminal γ-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 γ-glutamyl peptides selected by screening using the CaSR activity assay, γ-glutamylvalylglycine was found to be a potent kokumi peptide. Furthermore, norvaline-containing γ-glutamyl peptides, i.e., γ-glutamylnorvalylglycine and γ-glutamylnorvaline, possessed excellent sensory activity of kokumi substances. A novel, practical industrial synthesis of regiospecific γ-glutamyl peptides is also required for their commercialization, which was achieved through the ring opening reaction of N-α-carbobenzoxy-L-glutamic anhydride and amino acids or peptides in the presence of N-hydroxysuccinimide.
钙敏感受体（CaSR）的调节是γ-谷氨酰肽（如谷胱甘肽，γ-谷氨酰半胱氨酰甘氨酸）的生理活性之一。γ-谷氨酰肽还具有调味作用，即味丰物质的感官活性，当添加到食物中时会改变五种基本味道。这些活性已被证明呈正相关，表明味丰γ-谷氨酰肽在人体内是通过CaSRs被感知的。我们的研究基于这样一个假设，即发现高活性的CaSR激动剂肽将导致实用味丰肽的产生。通过对大量γ-谷氨酰肽的结构-CaSR-活性关系的持续研究，我们确定了γ-谷氨酰肽具有强烈CaSR活性的结构要求如下：存在N端γ-L-谷氨酰残基；在第二个残基处存在中等大小的L构型脂肪族中性取代基；以及存在C端羧酸，最好第三个组成部分是甘氨酸。通过对使用CaSR活性测定筛选出的γ-谷氨酰肽进行感官分析，发现γ-谷氨酰缬氨酰甘氨酸是一种有效的味丰肽。此外，含正缬氨酸的γ-谷氨酰肽，即γ-谷氨酰正缬氨酰甘氨酸和γ-谷氨酰正缬氨酸，具有优异的味丰物质感官活性。味丰γ-谷氨酰肽的商业化还需要一种新颖、实用的区域特异性γ-谷氨酰肽的工业合成方法，这是通过在N-羟基琥珀酰亚胺存在下N-α-苄氧羰基-L-谷氨酸酐与氨基酸或肽的开环反应实现的。
