umami-enhancing peptides and their derivatives: A review

Trends in Food Science & Technology 88 (2019) 429–438

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Review

New insight into umami receptor, umami/umami-enhancing peptides and their derivatives: A review

T

Jianan Zhanga,b, Dongxiao Sun-Waterhousea,b,∗, Guowan Sua,b, Mouming Zhaoa,b,∗∗ a b

School of Food Science and Engineering, South China University of Technology, Guangzhou, 510640, China Guangdong Food Green Processing and Nutrition Regulation Technologies Research Center, Guangzhou, 510640, China

A R T I C LE I N FO

A B S T R A C T

Keywords: Umami/umami-enhancing peptide Derivatives Receptor Enzymatic treatment Maillard reaction

Background: The structure and mechanism of umami taste receptor remain largely unclear, thus, far more research is necessary to increase the knowledge of tasty modalities. Umami/umami-enhancing peptides and their derivatives are widely distributed in foods and have been reported to play important roles in food taste through different modes of interactions with the umami receptors. Scope and approach: In this review, recognition of umami taste receptor, along with the structures and possible binding sites (orthosteric and allosteric sites) of umami/umami-enhancing peptides and their derivatives, was firstly described. The validation of the structural characteristics of umami and umami-enhancing substances and their binding sites to the receptors allows better understanding of the sensing mechanisms of umami taste. Key findings and conclusions: There are several receptors responsible for the recognition of umami substances and each receptor may be activated through different mechanisms. Besides orthosteric sites, allosteric binding sites are also found and being emphasized as it may explain why complementary interactions among umami or umami-enhancing peptides and their derivatives as well as an increase in hydrophilicity of compounds may promote food acceptance. Unlike di-/tri-peptides, the spatial structure is the most critical factor for the taste modality of long-chain umami peptides besides amino acid composition. Quite a few of these peptides and derivatives can also act as taste enhancing agents. Multiple polar moieties in peptides and their derivatives may trigger the umami/umami-enhancing property. Maillard reaction and treatment with certain enzymes could facilitate the yield of umami/umami-enhancing peptide derivatives with increased hydroxyl or amino groups.

1. Introduction Taste is the sensation produced as a response of the human gustatory system to molecules and ions from the ingested food dissolved in the saliva. A good deal of research has been conducted on taste sensing and cell biology in the last decade. The dissolved molecules and/or ions can bind to the surface proteins (‘taste receptors’) distributed throughout the whole tongue or interact with pore-like proteins (‘ion channels’), inducing electrical changes within the taste cells and subsequently chemical signals via the seventh, ninth and tenth cranial nerves to the brain where the perception of taste takes place (Roper & Chaudhari, 2017). Taste is different from flavor. Taste perception is based on gustatory responses triggered by water-soluble substances via contacting sensory taste end organs in the oral cavity. Flavor perception combines sensory experience of olfaction and gestation. Olfactory signals are produced by neurons in a specialised patch of the nasal

∗

epithelium upon the exposure to volatile substances. Both gustatory and olfactory signals are integrated in the orbitofrontal and other areas of the cerebral cortex to generate the taste or flavor perception. Umami taste has long been perceived in many traditional foods such as soy sauce, cheese and fermented Asian foods, although this taste quality was officially recognized only a while ago (Zhang, Venkitasamy, Pan, Liu, & Zhao, 2017). The word “umami” came from a Japanese word (うま味) which means a “pleasant savory taste”, “mouthfulness” or “delicious”. Umami was recognized as the fifth basic taste in 2002 (after salty, sweet, sour and bitter) to describe a pleasant savory or MSG-like taste (Temussi, 2012). Two important characteristics of umami are synergism and interactions with other tastes e.g. suppression of bitterness (Kim, Son, Kim, Misaka, & Rhyu, 2015). Besides MSG, a range of substances were found to elicit umami taste including some free L-amino acids, bi-functional acids, peptides and their derivatives or reaction products (Winkel et al., 2008; Zhao, Schieber, & Gänzle, 2016).

Corresponding author. School of Food Science and Engineering, South China University of Technology, Guangzhou, 510640, China. Corresponding author. School of Food Science and Engineering, South China University of Technology, Guangzhou, 510640, China. E-mail addresses: [email protected] (D. Sun-Waterhouse), [email protected] (M. Zhao).

∗∗

https://doi.org/10.1016/j.tifs.2019.04.008 Received 18 January 2018; Received in revised form 22 March 2019; Accepted 12 April 2019 Available online 17 April 2019 0924-2244/ © 2019 Elsevier Ltd. All rights reserved.

Trends in Food Science & Technology 88 (2019) 429–438

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2.1. Umami receptors and their structures

All of them are essential components of condiments and make condiments delicious and healthy. In particular, certain peptides and some derivatives are indispensable elements to achieving superior products, therefore, the knowledge of the structure and physicalchemical properties of these tastants is important both in scientific and nonscientific fields including the food industry. A number of studies on umami taste have been conducted worldwide, mainly focused on umami receptors (Behrens et al., 2018), taste perception or gene expression (Banerjee, Tudu, Bandyopadhyay, & Bhattacharyya, 2016), discovery of novel umami substances and the structure-taste relationship (Zhang et al., 2017). In this review, we firstly provide an overview of the established modes of action of taste receptors. A focus is placed on the active sites (i.e. orthosteric and allosteric sites) of the umami receptors (an aspect that lacks sufficient discussion). Then, the molecular characteristics (especially conformational versatility), taste attributes and producing pathways of the identified umami/umami-enhancing peptides and their derivatives were summarized into two aspects, i.e. umami property (for orthosteric sites) and umami-enhancing ability (for allosteric sites), followed by discussion on the functions of these binding sites of the umami receptor in sensing and enhancing the umami taste sensation. The ultimate goal of this review is to elucidate the structure–umami taste relationship to support the design and production of pleasant umami taste agents.

2.1.1. T1R1/T1R3 T1R1, T1R2 and T1R3 are members of the family of GPCRs and function in forms of heterodimers. Either T1R1 or T1R2 is co-expressed with T1R3. T1R1/T1R3 heteromer in human is activated selectively by L-amino acids including glutamate, aspartic acid and theanine, and recognize umami taste stimuli with 5′-ribonucleotides as enhancers for such a response (e.g. inosine-5-monophosphate (IMP) and guanosine-5monophosphate (GMP)). T1R2/T1R3 heteromer responses to a range of natural and artificial sweeteners such as sugars and sweet proteins (Roper et al., 2017). All members of T1Rs class have similar structures (i.e. membrane proteins with large and complicated structures containing N-terminal ligand binding domains) to collect information from the extracellular environment (Nango et al., 2016). T1Rs receptors contain three regions (Fig. 1): the large extracellular region, the seven-spanning transmembrane region and the cytoplasmic region. The extracellular fragment, where orthosteric agonists bind consists of a large “venus flytrap” (VFT) domain and a small cysteine-rich domain (CRD), with the former as the ligand binding module to distinguish and recognize taste modalities, and the latter as a bridge between the VFT domain and the sevenspanning transmembrane region (7TM) (which is responsible for the receptor activation to transmit the signal elicited by structural changes in VFT domain). An equilibrium exists between resting and active forms of the receptor in the absence or presence of a ligand. Both the T1R1/ T1R3 and T1R2/T1R3 receptors have many active sites (Nuemket et al., 2017).

2. Umami taste receptors and its vital orthosteric/allosteric sites Distinct receptors recognize the five basic tastes. Taste receptors for the taste qualities including sweet, bitter and umami tastes are a family of G Protein Coupled Receptors (GPCRs). Each taste modality may influence receptor cells via distinct mechanisms because of the different structures of the receptors and corresponding downstream effectors (Chandrashekar, Hoon, Ryba, & Zuker, 2006; Roper et al., 2017). Umami taste is initiated by the binding of tastants to GPCRs. So far, eight candidate umami taste receptors were reported (see Fig. 1) including the heterodimer T1R1/T1R3 (Greg et al., 2002), metabotropic glutamate receptors mGluR1 (brain-mGluR1) (Toyono et al., 2003), mGluR4 (brain-mGluR4) (Takashi et al., 2002), taste-specific isoforms of metabotropic glutamate receptors taste-mGluR1 (San Gabriel, Uneyama, Yoshie, & Torii, 2005), taste-mGluR4 (Chaudhari, Landin, & Roper, 2000), extracellular-calcium-sensing receptor (CaSR) (Bystrova, Romanov, Rogachevskaja, Churbanov, & Kolesnikov, 2010), GPCR, class C and group 6 subtype A receptor (GPRC6A) (Wellendorph & Bräuner-Osborne, 2004), and a rhodopsin-like GPCR class A (GPR92, also named GPR93 or LPAR5) (Haid et al., 2013). They all belong to class C GPCRs except for GPR92, and spread all over the tongue and even along the digestive tract and upper airway, suggesting their physiological functions in taste sensation and flavour perception (Davaasuren et al., 2015; Freund & Lee, 2018).

2.1.2. Metabotropic glutamate receptor (brain/taste-mGluR1 and brain/ taste-mGluR4) Besides the above-mentioned T1R1/T1R3 heterodimer, the umami receptors also include some metabotropic glutamate receptors (mGluRs), which comprise 8 different subsets, mGluRn (n = 1–8), and can be divided into three groups based on sequence homology, G-protein coupling and ligand selectivity i.e. mGluRs 1 and 5 as Group I, mGluRs 2 and 3 as Group II, and mGluRs, 4, 6, 7, and 8 as Group III (Ribeiro, Vieira, Pires, Olmo, & Ferguson, 2017). mGluRs spread widely in the central nervous system and are activated to initiate initiating actions on neuronal excitability and synaptic transmission (e.g. cell signal transduction including umami taste transmission and perception). The identified metabotropic glutamate receptors involved in the recognition of umami substance(s) include taste/brain-mGluR1 (San Gabriel et al., 2005; Toyono et al., 2003) and taste/brain-mGlu4 (Chaudhari et al., 2000; Takashi et al., 2003). Brain-mGluRs in taste buds have the same forms as corresponding mGluRs in the brain, and possess high sensitivity to L-glutamate. Taste-mGluRs are novel mGluRs variant with truncated extracellular domains thus exhibit a low binding Fig. 1. The basic structures of eight candidate umami taste receptors: T1R1/T1R3, brain and tastemGluR1, brain and taste-mGluR4, CaSR and GPRC6A belong to class C GPCR; GPR92 belongs to class A GPCR. CaSR, GPRC6A and GPR92 have a relatively broad ligand spectrum and are regarded as the receptors detecting L-amino acids or peptides (Bystrova et al., 2010; Chaudhari et al., 2000; Lee et al., 2001; Nelson et al., 2002; San Gabriel et al., 2005; Toyono et al., 2002, 2003).

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report about this kind of gustatory stimulus at the present (some umami polypeptides have been reported but the research lack receptor experiments). Only a “wedge model” has been proposed for the action of sweet proteins such as brazzein, monellin and thaumatin, which hypothesizes that the proteins fit a large cavity of the active VFT domain of the sweet receptors T1R2 and T1R3, aided by the wedge-shaped parts of their surfaces and charge complementarity to trigger consequent reactions (Gabriella, Angela, & Temussi, 2005; Temussi, 2002). However, it remains unclear whether such a “wedge model” can be applied perfectly to umami substances. This uncertainty arises because of the paucity of known umami ligands, even though T1R2-T1R3 heteromer responses to sweet taste substances while T1R1-T1R3 heteromer recognizing umami taste stimuli and the sequences (Behrens et al., 2018), and likely the VFT domain sites (Zhang et al., 2008) of T1R1 and T1R2 are similar.

affinity to L-glutamate and dismissed association and potentiation with nucleotide. mGluRs function as taste receptors owing to their structural features in a way resembling T1Rs: the presence of VFD, CRD, 7TM and C-Terminus to modulate G protein coupling (Ribeiro et al., 2017). 2.1.3. Other candidate umami taste receptors CaSR and GPRC6A (Fig. 1), as members of class C GPCRs, have the same structures as T1Rs (Shigemura & Ninomiya, 2016). Unlike T1Rs and mGluRs, CaSR responds to broad and diverse ligands including Ca2+, L-amino acids and peptides. GPRC6A is a group of receptors that specifically recognize certain amino acids. Their expression in mouse taste bud cells suggests that they might be involved in the gustatory Lamino acid sensing. GPR92 is a heptahelical transmembrane protein without any extracellular regions (Haid et al., 2013). Being expressed in gustatory T1R1-expressing cells, GPR92 might respond to not only the amino acids but also the peptides in protein hydrolysates. This finding supports the hypothesis that there might be different sorts of receptors being involved in the umami taste transduction stimulated by various kinds of umami-tastants.

2.2.2. Orthosteric binding sites of umami substance The active sites located in T1R1 and T1R3 correspond, in a similar manner, to the Glu sites in mGluR1 (Zhang et al., 2008). L-glutamate acid binds to the pocket of VFT domain of T1R1 either directly through ionic hydrogen bond interaction or through a bridging water molecule (López Cascales et al., 2010). As shown in Fig. 2B and C, α-carboxylate and amine nitrogen group of glutamate interact simultaneously with the orthosteric binding sites. In comparison, the interaction of γ-carboxylate of the glutamate with this site seems less firmly and requires water molecule as a bridge to link Arg151 and Arg277. These findings were mostly consistent with the results of Zhang et al. (2008), and the importance of the above-mentioned functional groups has been proved by chemical reactions. Notably, for human, additional residues are also critical (Toda et al., 2013).

2.2. The activation of umami receptor and associated modes of action Despite active efforts have recently been made on the identification of umami substances and elucidation of the sensing mechanisms of umami taste, there is still insufficient understanding in this field due to bottleneck issues such as limitation related to recombinant expression and difficulties encountered during protein purification for analysis of T1Rs (Nango et al., 2016). The key ligand-binding residues for T1Rs were found to be conserved in mGluRs whose structures have been determined (López Cascales, Oliveira Costa, de Groot, & Walters, 2010). Therefore, it is feasible to build reliable homologe models of T1R1/ T1R3. The applications of mutation testing, mathematical modelling, molecular docking, electrophysiology techniques and animal behavioral models can enhance knowledge about molecular mechanisms of the receptors.

2.2.3. The modulation of umami taste receptor by allosteric tastants Allosteric modulators of GPCR have attracted increasing attention in the past decades because of the complex structure of GPCR and greater structural diversity of allosteric sites than orthosteric sites. Umami receptors likely possess many different sites for the ligand interaction, indicating opportunities for multiple taste-enhancing compounds bound to the umami receptors (see Fig. 3). The synergism between MSG and 5′-ribonucleotides has been regarded as a hallmark of umami taste. Of particular interest is that IMP and GMP can enhance all the mutants of the umami receptor influencing the glutamate effect, suggesting that 5′-ribonucleotides have bound to different sites adjacent to the glutamate binding domain. Rather than 5′-ribonucleotides, peptides have also been proposed as allosteric modulators for the action of MSG on T1R3 within VFT (where is not the binding site of 5′-ribonucleotides) (Dang et al., 2019). In terms of other allosterc sites, only a few studies mentioned their working mechanism for T1R1+T1R3, with more studies reporting the other possible allosteric sites for homologous receptors (i.e. mGluRs) (Leach & Gregory, 2017). Sufficient dimerization is mandatory for the activation of a receptor, therefore, the adjustment of this action to bring the two domains into close proximity contribute to or even become crucial for controlling the receptor activity (Zhang, Liu, & Jiang, 2014). Indeed, the intersubunit movement of the two CRDs is a determinant for C class GPCR activation (Huang et al., 2011). Assadi-Porter, Tonelli, Maillet, Markley, and Max (2010) identified the binding residues in the CRD of T1R3 that interact with the sweet protein brazzein. Most interestingly, it was corroborated that, without VFT and CRD, 7TM could also fold independently and oscillate between active and inactive state in response to specific allosteric modulators. The difference only lies in that contacting in 7TM would likely lead to activation as well as suppression of the receptor (Feng, Ma, Hu, & Xie, 2015). A striking example is the recent discovery by Yasuka Toda et al. (2018) that methional could allosterically modulate T1R1/T1R3. As a positive allosteric regulator, methional might interact with the transmembrane domain of T1R1 at two distinct sites. This discovery confirms the umami receptor

2.2.1. The activation of the umami receptor by umami substances It has been proven that the binding of MSG to the pocket of VFT domain on T1Rs would change the structure of umami taste receptor into an active conformation to allow the sense of umami taste (Zhang et al., 2008). The well-known synergistic effect of glutamate and 5′nucleotide on the VFT domain is via a two-step mechanism (see Fig. 2A), i.e. glutamate binds quickly to the binding sites of VFT domain to induce domain closure (by which electric signals are triggered and the brain is made aware of umami substances); while the nucleotide located at the opening site of VFT domain enhances the stability of such a closed conformation (by which the intensity of umami perception is strengthened) (Mouritsen & Khandelia, 2012; Zhang et al., 2008). Upon the binding of glutamate to the hinge of VFT domain, T1R1 receptor protein exists in the closed conformation whist T1R3 receptor in the open conformation in the heterodimer (as illustrated in Fig. 2A) (López Cascales et al., 2010). Other umami compounds (e.g. L-theanine and umami peptides) also elicit a conformational change of T1R1+T1R3 but to a different extent, which will be further discussed in latter sections (see Sections 2.2.2 and 3.1.2). For homodimers brain-mGluRs, at least one closed conformation of VFT is required for receptor activation (Ribeiro et al., 2017). The VFT structures of taste-mGluRs are incomplete, resulting in a lower sensitivity to MSG as compared to the brain-mGluRs. The ligand affinity to the receptor is related to the number of binding sites along with the equilibrium between the open and closed patterns of the bilobate protein (Behrens et al., 2018). This relationship, however, provide opportunities for some long-chain ligands, as it allows them bind well to the exposed binding sites in the pocket without steric hindrance. For the large-size ligands (polypeptides and their derivatives or proteins), the binding modes might be different. However there is no 431

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Fig. 2. Different conformations of the T1R1/T1R3 hinge of venus flytrap domains (VFTs) when glutamate binds to the VFTs in the presence of IMP/GMP (A) or umami-enhancing peptides (B). Important binding interactions maintained over the course of simulation (C). The left side shows the binding of glutamate in the closed T1R1 site. The right side shows the binding of glutamate in the open T1R3 site. The bound glutamate is shown in blue (López Cascales et al., 2010; Dang et al., 2019; F. Zhang et al., 2008). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

to identify diverse umami tastants. Besides orthosteric binding sites, allosteric binding sites also influence receptor modulation, interactions between these two kinds of binding sites are possible. For example, it was found that the number of positive allosteric modulator binding sites increased without affinity fluctuation when glutamate (orthosteric agonist) was bound (Doornbos et al., 2016). However, there still exist many unanswered questions related to taste receptor and other GPCRs: What is the exact crystal structure and conformations of T1R1/T1R3 along with the binding sites for individual taste-active substance? How the extracellular domain allosteric binding sites of the receptor (as compared with the more thoroughly studied orthosteric binding sites) might influence the taste sensation or taste enhancement, especially given the large number of unidentified allosteric sites in the receptor ?

3. Umami/umami-enhancing peptides Besides glutamic acid, other amino acids such as aspartic acid and theanine also exhibit umami taste. Nucleotides represent another group of typical umami monomers including inosine monophosphate, guanosine monophosphate and adenylic acid with only the 5′ isomer exhibiting umami taste. More interestingly, a range of umami/umamienhancing peptides and their derivatives have been found in many foods like cheese, soy sauce and protein hydrolysates, and the umami taste-associated substances are essential to the pleasant taste of these foods (Zhang et al., 2018). Umami or umami-enhancing peptide are a group of peptides with specific structural features and impart umami taste and/or umami-enhancing property. The findings on umami taste receptors and their ligand interaction domains would support the search for new umami compounds including novel umami peptides. A systematic study of the previously discovered umami chemical entities with orthosteric and/or allosteric-binding properties for the umami receptor such as certain peptides and some of their derivatives would help investigate the structure and specific working conformations of the umami receptor along with its orthosteric and allosteric binding sites.

Fig. 3. The orthosteric binding sites and possible allosteric binding sites of mGluRs or T1R1/T1R3.

as a multiple allosteric site-containing receptor, and the feasibility of its binding to various flavour compounds to tailor food taste. Similarly, the response of T1R1/T1R3 to MSG could be potentiated by a sweetener cyclamate through the interaction with the C-terminal transmembrane domain of T1R3 (rather than activating the T1R1/T1R3 receptor by cyclamate itself), which also indicates the presence of multiple ligand recognition sites in transmembrane domains (Xu et al., 2004). More recently, Li Xue et al. (2014) substantiated that locking the TM6 interface could constitutively activate mGluRs. The selectivity of ligand at the orthosteric sites and the modulation of receptor activity at the allosteric sites were found to be the most essential determinants of mediating the ligand specificity of mammalian T1R1/T1R3 (Toda et al., 2013). Large allosteric modulators such as sweet protein brazzein and monellin tend to bind to a non-contiguous, multisite and multidomain surface, which is associated with a combined interaction of sweet protein with both the VFT of T1R2 and the CRD of T1R3 (Assadi-Porter et al., 2010). Taken together, multiple receptors are involved in umami sensation 432

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published studies on an octapeptide indicated the importance of position and sequence of acidic amino acids in a peptide, and the interaction between the cations of a basic unit and the anions of its adjacent acidic unit within a peptide (Cutts, Howlin, Mulholland, & Webb, 1996). However, the findings not apply to other peptides such as decapeptides and pentapeptides, even though a number of conformations co-exist in the majority of short linear peptides including delicious peptides. Such exceptions probably result from the variations in umami receptors' binding sites as discussed above or the dynamic changes of peptide's three dimensional (3D) structures in liquid systems. Yu, Zhang, Miao, Li, and Liu (2017) found that the amino acid composition and sequence accounted for the differences in peptide spatial conformation and surface charge distribution through establishing a 3D quantitative structure-activity relationship (3DQASR) for five umami hexapeptides.

3.1. The peptides with umami taste In 1969, the taste of amino acids and dipeptides were firstly compared and grouped into sour, sweet and bitter groups. In addition the small peptides showing umami taste, Lys-Gly-Asp-Glu-Glu-Ser-Leu-Ala (identified in a beef hydrolysate in 1978) represents a hallmark of delicious peptides that could improve the taste of foods. Later more and more peptides were obtained such as those from the enzymatic hydrolysate of deamidated wheat gluten which were proven as MSG-like and taste-enhancing agents with abilities to intensify the corresponding tastes of salt, glutamate and acidulant (Schlichtherle-Cerny & Amadò, 2002). 3.1.1. Structure features of umami peptides 3.1.1.1. Primary structure of umami peptides. There are about 98 peptides with umami taste, among which dipeptide and tripeptide account for around 29.6% and 30.6% respectively. Thus, over a half of identified umami peptides are short linear peptides. A number studies also reported that umami peptides isolated usually had a molecular weight distribution less than 5000 Da. Although isolation and identification of a long chain peptide are more difficult than dipeptides or tripeptides, long linear peptides have also been found possessing strong umami intensity (Su et al., 2012; Zhang, Zhao, Su, & Lin, 2019; Zhuang et al., 2016). Fig. 4 shows the proportions of 98 identified umami peptides grouped based on the number of amino acid residues. Di- or tri-peptides with umami taste generally consist of glutamic acid, aspartic acid and/ or other hydrophilic amino acids. An amino acid accounting for about 20% of the required hydrophobic amino acid is alanine, which is very different from other bitter hydrophobic amino acids and mostly occurs as a typical sweet amino acid. Long chain tasty peptides do not have the same compositional characteristics of amino acid as the short linear peptides: the proportions of umami amino acids and hydrophilic amino acids drop from 52.0% to 18.2%, respectively for di- and tri-peptides, to 33.7% and 25.9%. For long linear peptides, amino acid composition is no longer the most critical factor to influence their umami properties. Instead, spatial structure as well as the presence of umami amino acids, hydrophilic amino acids and hydrophobic amino acids form the fundamental requirements for their umami taste. This structure-umami taste relationship is quite different from the relationship between the bitterness of peptides and their chemical structures. The amino acids in a peptide chain can independently contribute to the bitterness regardless of the sequence and configuration of amino acids, although amino acid sequence and configuration still play important roles in bitter perception e.g. C-terminal sequence (Iwaniak, Hrynkiewicz, Bucholska, Minkiewicz, & Darewicz, 2019; Jianbo, Lingxiao & Kangnan, 2017).

3.1.2. Interactions between umami peptides and taste receptors Different types of receptors are involved in the sensing of umami taste caused by various umami-tatants including amino acids and peptides (both often co-exist in protein-rich foods). Peptone receptor GPR92 is one of the receptors expressed in T1R1-positive taste cells and can be activated by protein-hydrolysates (Haid et al., 2013). Dang, Gao, Xie, Wu, and Ma (2014) also found interactions between several umami peptides and T1R1/T1R3, but no rule to follow in summarizing accurately the binding sites and four interactive forces involved (including electrostatic interaction, hydrogen bonding, van der Waals interactions and hydrophobic interactions). Unlike the simplicity of amino acid molecules, more influencing factors such as molecular weight and chain flexibility of a peptide should be considered for the studies on the binding mechanism for umami peptide and the receptor. 3.2. The peptides with umami-enhancing ability 3.2.1. Structures of umami-enhancing peptides It is worth noting the ability of (umami) peptides to increase the umami intensity of solutions containing umami molecules like MSG, IMP and GMP etc. While umami-enhancing properties of nucleotides are well recognized, little attention has been given to such properties of umami peptides. High-quality condiments contain higher amounts of peptides than nucleotides, suggesting potential synergistic effect between peptids and nucleotides. As shown in Table 1, there are much fewer umami-enhancing peptides reported in the literature than umami peptides. Many umami-enhancing peptides are umami peptides with some being tasteless or slightly bitter. Thus the relationship between structure and umami-enhancing ability of the umami-enhancing peptides may be more complicated as compared to umami peptides. Umami-enhancing peptides can significantly increase the intensity of the umami taste of MSG or IMP solution at a very low concentration. Further, a mixture of several umami peptides could enhance the taste

3.1.1.2. Spatial structure of umami peptides. Few studies thoroughly investigated the spatial structure of umami peptides. Several

Fig. 4. The pie chart of the identified umami peptides. The numbers next to or on the pie indicate the percentage for a specific type of peptide out of the sum for all umami peptides. 433

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Table 1 Peptides showing umami-enhancing property. Number

Peptide

Basic taste

Umami threshold value (mM)

Umami-enhancing threshold value (mM)

Reference

1 2 3 4

EGSEAPDGSSR SSRNEQSR ALPEEV LPEEV

0.2 0.17 0.76 ± 0.01 0.43 ± 0.03

0.005 0.052 1.52 ± 0.03 3.41 ± 0.01

Su et al. (2012) Su et al. (2012) Zhuang et al. (2016) Zhuang et al. (2016)

5

EAGIQ

0.97 ± 0.01

1.94 ± 0.05

Zhuang et al. (2016)

6

KGDEESLA

0.53

0.16

Yamasaki & Maekawa (1978)

7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26

RGENESDEQGAIVT GGITETW SFE NEY AH EP EEEQ GGNP VDR DPQ FT FK SE RGENESEEEGAIVT TESSSE EDG DQR NNP EGF EE

umami, umami-enhancing umami, umami-enhancing Sour, astringent,umami-enhancing Sour, sweet, umami, astringent,umamienhancing Sour, sweet, salty, astringent,umamienhancing umami, bitter, sour, salt, umamienhancing Slight umami, astringent Flat, tasteless Slight umami Flat, tasteless Sour, astrigent Slight umami Umami, kokumi Umami, sweet Umami, sour, astrigent Umami, astrigent Sour, astrigent Slight sweet Umami Umami, kokumi, astrigent Umami, kokumi, astrigent Umami Slight umami Umami, slight sweet Umami, bitter, kokumi umami,umami-enhancing

0.43 – 1.38 – – 5.34 1.09 2.10 3.66 3.36 – – 1.49 0.43 0.39 0.71 1.11 0.83 0.94 +

0.38 0.66 1.34 0.62 1.27 1.00 0.39 0.63 1.02 0.65 0.92 0.89 0.87 0.33 0.36 0.69 0.55 0.82 0.77 ++

27 28 29 30 31 32 33

EV ADE AED DEE SPE EE + EV + DEE + EEN DES + EE + DEE

umami, sweet, umami-enhancing sweet, sour,bitter,umami-enhancing sour,umami-enhancing salt,umami-enhancing salt, sour,umami-enhancing Umami-enhancing Umami-enhancing

+ – – – – – –

+ + + + + +++ +++

Zhang et al. (2019) Zhang et al. (2019) Zhang et al. (2019) Zhang et al. (2019) Zhang et al. (2019) Zhang et al. (2019) Zhang et al. (2019) Zhang et al. (2019) Zhang et al. (2019) Zhang et al. (2019) Zhang et al. (2019) Zhang et al. (2019) Zhang et al. (2019) Zhang et al. (2019) Zhang et al. (2019) Zhang et al. (2019) Zhang et al. (2019) Zhang et al. (2019) Zhang et al. (2019) Maehashi, Matsuzaki, Yamamoto, & Udaka, 1999 Maehashi et al. (1999) Maehashi et al. (1999) Maehashi et al. (1999) Maehashi et al. (1999) Maehashi et al. (1999) Maehashi et al. (1999) Maehashi et al. (1999)

1-6: The peptides were tasted at the corresponding concentration with MSG (0.03 mg/L). 7-12: The peptides were tasted as a 0.5% solution containing 0.02% of IMP. 13-14: The peptides were tasted as a mixture of 0.5% of each peptide containing 0.02% of IMP. Umami taste were scored: not tasted; + weaker than average; ++ average; +++ strong than average.

Table 2 The derivatives of umami amino acids and peptides. Name

Typical substance

Taste

Modification

Reference

Lactoyl-amino acid/ Lactoyl-peptide

Lactoyl-glutamine

Umami; Umamienhancing

Lactoyl-transferase

Frerot et al. (2013); Sgarbi et al. (2013) etc.

Suc-amino acid/Sucpeptide

suc-Arg suc-Glu

Umami; Umamienhancing; Fullness

Succinyl-transferase

Frerot et al. (2013) etc.

pGlu-peptide

pGlu pGlu-Pro-X pGlu-Gly

Umami; Tasteenhancing

Glutamyl or glutamine cyclization reaction

Frerot et al. (2013); Higaki-Sato et al. (2003); Kiyono et al. (2013); Mucchetti et al. (2002); Sgarbi et al. (2013) etc.

γ-Glutamyl peptide

γ-Glu-Glu γ-Glu-Gly γ-Glu-Cys-Gly γ-Glu-Val-Gly Fru-Val Fru-Met N-glucosyl-Glu N-deoxyfructosylGlu

Umami-enhancing; Long-lasting fullnessenhancing

γ-glutamyl transferase/γglutamyl peptidase/γpeptide synthetase

Zhao et al. (2016); Frerot et al. (2013); Kuroda et al. (2013); Suzuki et al. (2003) etc.

Umami; Umami- or sweet-enhancing

Maillard reaction

Beksan et al. (2003); Iwasaki et al. (2006); Kaneko et al. (2011); Ottinger et al. (2003); Villard et al. (2003); Zhang et al. (2018) etc.

Maillard reaction products

Basic structure

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peptides, some amino acids/peptides that initially have no or weak umaminess may present strong umami taste and long-lasting mouthfulness after being modified moderately by chemical reactions like heating or enzymatic treatment(s). Table 1 summarizes the derivatives obtained after modification(s).

intensity to a remarkably greater extent than a peptide alone at the same concentration. For this reason, the influence of the synergistic effect arising from (umami) peptides and other taste substances on the taste of real food systems deserves greater attention (see Table 2). 3.2.2. Interactions between umami-enhancing peptides and the taste receptors Almost no reports have explained the synergistic mechanism of peptide and MSG towards the umami receptor. Recently, Dang et al. (2019) proposed a novel two-step model (see Fig. 2B) for T1R1/T1R3 to depict the potentiating effect of an umami peptide in the presence of MSG by means of molecular docking: 1) MSG may firstly bind to the pocket of T1R1, enlarging the size of the binding cavity of T1R3 due to dimerization; 2) the addition of MSG likely makes it easier for peptides to bind with T1R3. During the interacting process, there may be five residues (Glu-429, Gln-302, Gly-304, Try-107 and His-364) that exhibit strong binding interactions with MSG located at the VFT of T1R3. Their cooperations would consolidate the conformational change of the receptor, leading to an enhanced perception of umami taste. Another receptor that involves the umami-enhancement by peptides is CaSR. It has been observed that CaSR-expressing taste cells would be primary detectors of kokumi and taste-enhancing substances (e.g. γ-Glutamyl peptides) (Maruyama, Yasuda, Kuroda, & Eto, 2012). However, more work is required to further ascertain the interactive effects of the peptides and MSG on the umami receptor by taste receptor assays. Since a number of publications (Zhang et al., 2017) and the commercial products (U.S. Patent No. 2,009,143,488; U.S. Patent No. 20,170,145,360), showed significant synergistic effect of MSG and small peptides/longchain peptides, one may assume the occurrence of other modulation mechanisms for long-chain peptides. In summary, (umami) peptides may exhibit simultaneously bivariate organoleptic properties like nucluotides, that is, they may taste umami while enhancing the perception of umami when being mixed with MSG.

4.1. Lactoyl-X and Suc-X Lactoyl-glutamine and lactoyl-peptide were firstly identified in cheese with N-lactoyl-X as the basic structure (where X represents the residues of amino acid or peptide). These substances are commonly found in fermented foods and generated through the interaction of endogenous enzymes or enzyme(s) produced by microorganisms involved in fermentation such as lactase, and can impart remarkable fullness and mouthfeel (Sgarbi et al., 2013). Succinic acid can react with amino acids to form suc-amino acids and suc-amino acids can also be produced using transsuccinylase secreted by microorganisms like Aspergillusoryzae etc. Frerot et al. (2013) isolated six suc-derivatives (Suc-Arg, Suc-Glu, Suc-His, Suc-Ser, Suc-Leu and Suc-Val) from the acidic fraction of soy sauce and reported their sensory characteristics as umami-imparting, umami- and/or mouthfulness-enhancing abilities. 4.2. pGlu-X Glutamine is the direct precursor of pyroglutamic acid (pGlu) and prepared via dehydration at room temperature (higher temperatures would accelerate this process) (Weiss, Muth, Drumm, & Kirchner, 2018). Pyroglutamylpeptides can also be produced through dehydration of glutamylpeptides or condensation of glutamine and other free amino acids. In fermented foods, some microorganisms generate pyroglutamic acid cyclase to facilitate the production of pyroglutamyl peptides. To speed up the hydrolysis of pyroglutamic acid, certain enzymes such as pyrrolidone carboxyl peptidase (PCP) and pyrophenylpeptide hydrolyzyme (PYRase) are also needed (Mucchetti, Locci, Massara, Vitale, & Neviani, 2002). Besides physiological activities, pyroglutamylpeptides possess desirable taste properties. HigakiSato et al. (2003) isolated several pGlu-X substances (X represents one of six amino acids) from the enzymatic hydrolysate of wheat gluten. Kiyono et al. (2013) identified 19 pyroglutamyl peptides in commercially available sake and reported that some of these peptides might be produced from rice proteins via digestion with A. oryzae proteases. Irrespective of their low concentrations in the finished food systems, pyroglutamyl peptides could enhance the taste of other food components.

3.3. The challenges related to umami/umami-enhancing peptides The positively charged and negatively charged groups of tasty peptide backbones or residues are essential to their taste properties, although spatial construction and position of charged groups may also be important contributors especially for long linear peptides. Accordingly using a raw material rich in umami and hydrophilic amino acids for ingredient development would increase the possibility and efficiency of obtaining high quality umami ingredient(s). Adding or generating moieties like hydroxyl and carboxylate groups or an amine nitrogen in the chemical structure of an ingredient may facilitate the connection of new tastants and the umami receptors. For the peptides lacking target moiety, grafting a polar group (via Maillard reaction and enzyme treatment) such as a hydroxyl group may be a feasible way to initiate or promote its umami taste. Likewise, amino acids and peptide derivatives, such as glycoconjugates of glutamic acid and 1-deoxy-Dfructosyl-N-β-alanyl-L-glycine, are another group of umami-active species that deserve in-depth investigations to understand their stereospecifity for the umami taste receptor binding site. In terms of precise tuning of umami taste-imparting properties, there exists a huge gap in the knowledge about the influence of umami-enhancing peptides on the receptor and the structure-function relationship of these peptides especially with both umami-imparting and umami-enhancing properties. Using taste receptor assays to elucidate the molecular basis of the functions for the taste-active molecules represents a feasible approach.

4.3. γ-Glutamyl peptides Glutamic acid has two carboxyl groups, namely α-carboxyl group and γ-carboxyl group. Thus, both α-glutamylpeptides and γ-glutamyl peptides are available depending on which carboxyl group participate in peptide binding, with α-glutamylpeptides being the more common type of peptide. The simplest γ-glutamyl substance is theanine. It is a non-protein amino acid with a unique chemical structure as γ-ethylamino-L-glutamic acid (Türközü; Şanlier, 2017). The presence of L-glutamic acid and γ-glutamyl residues in theanine is likely responsible for its exotic and slightly sweet taste and the umami taste, indicating its potential for masking bitterness and promoting the general flavor of food (Narukawa, Toda, Nakagita, Hayashi, & Misaka, 2014). Glutathione (GSH) is the most typical γ-glutamyl tripeptide. It is very popular because GSH possesses multiple biological functions to almost all the systems in the body, such as antioxidant ability, reinforcement of immunity, and it also exhibits excellent tasty-enhancing and extending properties in foods (Rae & Williams, 2017). The production methods for GSH are generally divided into chemical synthesis, enzymatic hydrolysis and microbiological fermentation, with the latter two being more

4. Derivatives of umami amino acids and peptides Peptides showing umami/umami-enhancing property are presented at high levels in industrial products such as processed meat products, products of plant-/animal-based proteolysis, yeast extract, soy sauce and other fermented products (Zhang et al., 2019). Besides umami 435

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esthematology prove to be important, but are out of the scope of this review. In summary, a number of amino acid/peptide derivatives founded in food exhibit umami taste and/or kokumi property irrespective of their own tastes (whether being tasteless or not) and synergistic effects with other substances (glutamate, sugar and nucleotide). Most of these derivatives in foods, although having a concentration lower than their corresponding threshold, can act as essential contributors to the taste of foods through imparting, promoting, enriching and prolonging basic tastes. Appropriate thermal processing and enzymatic treatments are desired for facilitating the production of these derivatives e.g. condensation/Maillard reaction or transpeptidation. However, except for γglutamyl peptides, minimal research directly investigate the interaction of peptide derivatives and the umami receptor, especially the correlation for the perceptual and spatial properties of peptide derivatives and the physichemical and structural characteristics of taste receptors.

comprehensive. Likewise, enzymatic hydrolysis and microbiological fermentation can also generate other γ-glutamyl peptides. Kuroda et al. (2013) discovered a novel γ-tripeptide, γ-Glu-Val-Gly, which resembles GSH with only one amino acid different, but could exhibit umami taste/ kokumi sensation almost 12.8 times stronger than GSH. Suzuki et al. (2003) developed a method to synthesize γ-glutamyl compounds involving bacterial γ-glutamyltranspeptidase with glutamine as the γglutamyl donor. They found that γ-glutamylization could suppress the bitterness of Phe, Val, Leu, and His while initiating sourness and increasing food preference. What's more, it was discovered that CaSR might be responsible for the detection of taste-active γ-glutamyl peptides. It was reported that a large number of γ-glutamyl peptides including GSH and γ-Glu-Val-Gly were CaSR agonists, evoking the release of calcium ions in gustation cells (Maruyama et al., 2012). The discovery of highly active CaSR agonist peptides is beneficial to the design of practical taste-enhancing peptides. Yusuke Amino et al. (2016) studied the structure-CaSR-activity relation of γ-glutamyl peptides, and determined that an N-terminal γ-L-glutamyl residue, a moderately sized, aliphatic, neutral substituent at the second residue and a C-terminal carboxylic acid were required for a intense CaSR agonist. The γ-glutamyl peptides obtained via screening with the CaSR activity assay were found to possess excellent umami-enhancing properties (Amino et al., 2016).

5. Conclusion The current review confirms the occurrence of a wealth of unexplored novel umami-imparting and/or umami-enhancing substances. The sensing mechanisms of umami taste are complicated, involving several umami taste receptors and different downstream effectors. Many orthosteric and positive allosteric binding sites exist for binding both the umami and the tasteless molecules (which can enhance the agonist-dependent taste receptor activity). Umami/umami-enhancing peptides and relevant derivatives may exhibit desirable sensory and nutritional properties e.g. intense umami taste, strong umami-enhancing effects, and high nutritional value. The recognization of their organoleptic and structural characteristics and associated mechanisms of receptor activation, supports the understanding of favorable umami taste. The validation of binding sites of receptors provides a scientific basis for recognizing the roles of umami-active peptides in the perception of food's umaminess. Accordingly, choosing food materials rich in umami amino acids and hydrophilic amino acids likely favors the production of delicious protein ingredients. Proper selection and manipulation of processing methods including enzymatic hydrolysis, fermentation and heat treatment can enable the improvement of the overall flavor of food products, through inducing the generation of more species and higher amounts of umami and umami-enhancing peptides and their derivatives. More research should be conducted to gain insights into the sensing mechanisms of umami taste associated with the receptors and their ligands.

4.4. Maillard reaction products Maillard reaction involves condensation between a carbonyl group of reducing sugars, aldehydes or ketones and an amine group of amino acids (such as free amino acids, peptides and proteins), and takes place in almost all the food manufacturing processes. A lot of previous studies made efforts on producing unique aromas and tastes through the manipulation of Maillard reaction (Feng et al., 2015). The Maillard reaction has been reported as an effective method to promote the umami intensity of peptides via generating more delicious peptide/peptide derivatives and/or substances capable of enhancing other taste compounds under certain conditions. Beksan et al. (2003) have synthesized two glycoconjugates of glutamic acid (which are intermediates of the Maillard reaction and exhibit intense umami taste). Ottinger H. and Hofmann (Ottinger & Hofmann, 2003) isolated a so-called universal taste enhancer (Alapyridaine) that is formed in thermally processed beef broth. This enhancer, although being tasteless, was found to exhibit sweet, umami and salty tastesenhancing activities (Soldo, Blank, & Hofmann, 2003; Villard et al., 2003). In fermented products, the Maillard reaction occurs even at an ambient temperature. Kaneko, Kumazawa, and Nishimura (2011) reported that several Amadori rearrangement products (intermediates of the Maillard reaction), namely Fru-Val, Fru-Met, Fru-pGlu and pGluGln, were the key compounds responsible for the umami taste of a typical Japanese soy sauce. Ajinomoto or Givaudan also generated a number of patents related to the Maillard reaction products that possess a good umami/umami-enhancing ability (European Patent Application EP20,040,728,395). In addition to the above-mentioned non-volatile Maillard reaction products, volatile Maillard products of amino acids/peptides may be another group of umami-enhancing derivatives, given the occurrence of taste-aroma interactions and taste-aroma-food matrix interactions (Niimi et al., 2014). Under certain conditions, the presence of certain volatile compounds at a sub-threshold level may cause an increase in the detected threshold of some non-volatile compounds (Linscott & Lim, 2016). A recent study directly demonstrated that the flavour compound methional could positively modulate T1R1/T1R3 via binding to the transmembrane domain of T1R1 with two allosteric binding positions (Toda et al., 2018). This discovery confirms the feasibility of T1R1's binding to various flavour compounds and the interaction between odour compounds and tastants. Further investigations on such interaction with the integration of the findings in human neuroscience and

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