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

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Trends in Food Science & Technology

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Review

New insight into umami receptor, umami/umami-enhancing peptides and T

their derivatives: A review
Jianan Zhanga,b, Dongxiao Sun-Waterhousea,b,∗, Guowan Sua,b, Mouming Zhaoa,b,∗∗
a
School of Food Science and Engineering, South China University of Technology, Guangzhou, 510640, China
b
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: Background: The structure and mechanism of umami taste receptor remain largely unclear, thus, far more re-
Umami/umami-enhancing peptide search is necessary to increase the knowledge of tasty modalities. Umami/umami-enhancing peptides and their
Derivatives derivatives are widely distributed in foods and have been reported to play important roles in food taste through
Receptor different modes of interactions with the umami receptors.
Enzymatic treatment
Scope and approach: In this review, recognition of umami taste receptor, along with the structures and possible
Maillard reaction
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 gusta-
tory 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 sub-
sequently 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 sig-
nals 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: dxsun72@hotmail.com (D. Sun-Waterhouse), femmzhao@scut.edu.cn (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.
J. Zhang, et al.
All of them are essential components of condiments and make condi-
ments 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 prop-
erties 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 world-
wide, 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 al-
losteric sites) of the umami receptors (an aspect that lacks sufficient
discussion). Then, the molecular characteristics (especially conforma-
tional 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. 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 in-
fluence 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) in-
cluding 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 phy-
siological functions in taste sensation and flavour perception
(Davaasuren et al., 2015; Freund & Lee, 2018).
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Trends in Food Science & Technology 88 (2019) 429–438
2.1. Umami receptors and their structures
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 re-
cognize umami taste stimuli with 5′-ribonucleotides as enhancers for
such a response (e.g. inosine-5-monophosphate (IMP) and guanosine-5-
monophosphate (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 transmem-
brane 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 seven-
spanning 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).
2.1.2. 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-pro-
tein 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 percep-
tion). 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 taste-
mGluR1, 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 re-
ceptors 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).
J. Zhang, et al.
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 L-
amino 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. 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 beha-
vioral models can enhance knowledge about molecular mechanisms of
the receptors.
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 sec-
tions (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 in-
complete, 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 li-
gands, 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
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Trends in Food Science & Technology 88 (2019) 429–438
report about this kind of gustatory stimulus at the present (some umami
polypeptides have been reported but the research lack receptor ex-
periments). Only a “wedge model” has been proposed for the action of
sweet proteins such as brazzein, monellin and thaumatin, which hy-
pothesizes 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). How-
ever, 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 re-
cognizing 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.
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-car-
boxylate 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).
2.2.3. 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 re-
ceptors 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 re-
garded as a hallmark of umami taste. Of particular interest is that IMP
and GMP can enhance all the mutants of the umami receptor influen-
cing 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 in-
terestingly, 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 sup-
pression 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 reg-
ulator, methional might interact with the transmembrane domain of
T1R1 at two distinct sites. This discovery confirms the umami receptor
J. Zhang, et al. Trends in Food Science & Technology 88 (2019) 429–438

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 glu-
tamate 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 re-
ferred 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

Fig. 3. The orthosteric binding sites and possible allosteric binding sites of Besides glutamic acid, other amino acids such as aspartic acid and
mGluRs or T1R1/T1R3. theanine also exhibit umami taste. Nucleotides represent another group
of typical umami monomers including inosine monophosphate, gua-
nosine monophosphate and adenylic acid with only the 5′ isomer ex-
as a multiple allosteric site-containing receptor, and the feasibility of its
hibiting umami taste. More interestingly, a range of umami/umami-
binding to various flavour compounds to tailor food taste. Similarly, the
enhancing peptides and their derivatives have been found in many
response of T1R1/T1R3 to MSG could be potentiated by a sweetener
foods like cheese, soy sauce and protein hydrolysates, and the umami
cyclamate through the interaction with the C-terminal transmembrane
taste-associated substances are essential to the pleasant taste of these
domain of T1R3 (rather than activating the T1R1/T1R3 receptor by
foods (Zhang et al., 2018).
cyclamate itself), which also indicates the presence of multiple ligand
Umami or umami-enhancing peptide are a group of peptides with
recognition sites in transmembrane domains (Xu et al., 2004). More
specific structural features and impart umami taste and/or umami-en-
recently, Li Xue et al. (2014) substantiated that locking the TM6 in-
hancing property. The findings on umami taste receptors and their li-
terface could constitutively activate mGluRs. The selectivity of ligand at
gand interaction domains would support the search for new umami
the orthosteric sites and the modulation of receptor activity at the al-
compounds including novel umami peptides. A systematic study of the
losteric sites were found to be the most essential determinants of
previously discovered umami chemical entities with orthosteric and/or
mediating the ligand specificity of mammalian T1R1/T1R3 (Toda et al.,
allosteric-binding properties for the umami receptor such as certain
2013). Large allosteric modulators such as sweet protein brazzein and
peptides and some of their derivatives would help investigate the
monellin tend to bind to a non-contiguous, multisite and multidomain
structure and specific working conformations of the umami receptor
surface, which is associated with a combined interaction of sweet
along with its orthosteric and allosteric binding sites.
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
J. Zhang, et al.
3.1. The peptides with umami taste
In 1969, the taste of amino acids and dipeptides were firstly com-
pared 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 de-
licious peptides that could improve the taste of foods. Later more and
more peptides were obtained such as those from the enzymatic hy-
drolysate 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 fun-
damental 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 regard-
less 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).
3.1.1.2. 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.
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Trends in Food Science & Technology 88 (2019) 429–438
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 (3D-
QASR) for five umami hexapeptides.
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 accu-
rately 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 be-
tween 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 pep-
tides 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
J. Zhang, et al. Trends in Food Science & Technology 88 (2019) 429–438

Table 1
Peptides showing umami-enhancing property.
Number Peptide Basic taste Umami threshold value Umami-enhancing threshold Reference
(mM) value (mM)

1 EGSEAPDGSSR umami, umami-enhancing 0.2 0.005 Su et al. (2012)

2 SSRNEQSR umami, umami-enhancing 0.17 0.052 Su et al. (2012)
3 ALPEEV Sour, astringent,umami-enhancing 0.76 ± 0.01 1.52 ± 0.03 Zhuang et al. (2016)
4 LPEEV Sour, sweet, umami, astringent,umami- 0.43 ± 0.03 3.41 ± 0.01 Zhuang et al. (2016)
enhancing
5 EAGIQ Sour, sweet, salty, astringent,umami- 0.97 ± 0.01 1.94 ± 0.05 Zhuang et al. (2016)
enhancing
6 KGDEESLA umami, bitter, sour, salt, umami- 0.53 0.16 Yamasaki & Maekawa (1978)
enhancing
7 RGENESDEQGAIVT Slight umami, astringent 0.43 0.38 Zhang et al. (2019)
8 GGITETW Flat, tasteless – 0.66 Zhang et al. (2019)
9 SFE Slight umami 1.38 1.34 Zhang et al. (2019)
10 NEY Flat, tasteless – 0.62 Zhang et al. (2019)
11 AH Sour, astrigent – 1.27 Zhang et al. (2019)
12 EP Slight umami 5.34 1.00 Zhang et al. (2019)
13 EEEQ Umami, kokumi 1.09 0.39 Zhang et al. (2019)
14 GGNP Umami, sweet 2.10 0.63 Zhang et al. (2019)
15 VDR Umami, sour, astrigent 3.66 1.02 Zhang et al. (2019)
16 DPQ Umami, astrigent 3.36 0.65 Zhang et al. (2019)
17 FT Sour, astrigent – 0.92 Zhang et al. (2019)
18 FK Slight sweet – 0.89 Zhang et al. (2019)
19 SE Umami 1.49 0.87 Zhang et al. (2019)
20 RGENESEEEGAIVT Umami, kokumi, astrigent 0.43 0.33 Zhang et al. (2019)
21 TESSSE Umami, kokumi, astrigent 0.39 0.36 Zhang et al. (2019)
22 EDG Umami 0.71 0.69 Zhang et al. (2019)
23 DQR Slight umami 1.11 0.55 Zhang et al. (2019)
24 NNP Umami, slight sweet 0.83 0.82 Zhang et al. (2019)
25 EGF Umami, bitter, kokumi 0.94 0.77 Zhang et al. (2019)
26 EE umami,umami-enhancing + ++ Maehashi, Matsuzaki, Yamamoto, &
Udaka, 1999
27 EV umami, sweet, umami-enhancing + + Maehashi et al. (1999)
28 ADE sweet, sour,bitter,umami-enhancing – + Maehashi et al. (1999)
29 AED sour,umami-enhancing – + Maehashi et al. (1999)
30 DEE salt,umami-enhancing – + Maehashi et al. (1999)
31 SPE salt, sour,umami-enhancing – + Maehashi et al. (1999)
32 EE + EV + DEE + EEN Umami-enhancing – +++ Maehashi et al. (1999)
33 DES + EE + DEE Umami-enhancing – +++ 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 Basic structure Typical substance Taste Modification Reference

Lactoyl-amino acid/ Lactoyl-glutamine Umami; Umami- Lactoyl-transferase Frerot et al. (2013); Sgarbi et al. (2013)
Lactoyl-peptide enhancing etc.

Suc-amino acid/Suc- suc-Arg Umami; Umami- Succinyl-transferase Frerot et al. (2013) etc.
peptide suc-Glu enhancing; Fullness

pGlu-peptide pGlu Umami; Taste- Glutamyl or glutamine Frerot et al. (2013); Higaki-Sato et al.
pGlu-Pro-X enhancing cyclization reaction (2003); Kiyono et al. (2013); Mucchetti
pGlu-Gly et al. (2002); Sgarbi et al. (2013) etc.

γ-Glutamyl peptide γ-Glu-Glu Umami-enhancing; γ-glutamyl transferase/γ- Zhao et al. (2016); Frerot et al. (2013);
γ-Glu-Gly Long-lasting fullness- glutamyl peptidase/γ- Kuroda et al. (2013); Suzuki et al. (2003)
γ-Glu-Cys-Gly enhancing peptide synthetase etc.
γ-Glu-Val-Gly
Maillard reaction Fru-Val Umami; Umami- or Maillard reaction Beksan et al. (2003); Iwasaki et al.
products Fru-Met sweet-enhancing (2006); Kaneko et al. (2011); Ottinger
N-glucosyl-Glu et al. (2003); Villard et al. (2003); Zhang
N-deoxyfructosyl- et al. (2018) etc.
Glu

434
J. Zhang, et al.
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 re-
ceptor, 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 pep-
tides and MSG on the umami receptor by taste receptor assays. Since a
number of publications (Zhang et al., 2017) and the commercial pro-
ducts (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/long-
chain 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 nu-
cluotides, that is, they may taste umami while enhancing the perception
of umami when being mixed with MSG.
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-D-
fructosyl-N-β-alanyl-L-glycine, are another group of umami-active spe-
cies that deserve in-depth investigations to understand their stereo-
specifity 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 proper-
ties. Using taste receptor assays to elucidate the molecular basis of the
functions for the taste-active molecules represents a feasible approach.
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
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Trends in Food Science & Technology 88 (2019) 429–438
peptides, some amino acids/peptides that initially have no or weak
umaminess may present strong umami taste and long-lasting mouth-
fulness after being modified moderately by chemical reactions like
heating or enzymatic treatment(s). Table 1 summarizes the derivatives
obtained after modification(s).
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 in-
volved 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 se-
creted 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 mouthful-
ness-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 dehydra-
tion of glutamylpeptides or condensation of glutamine and other free
amino acids. In fermented foods, some microorganisms generate pyr-
oglutamic acid cyclase to facilitate the production of pyroglutamyl
peptides. To speed up the hydrolysis of pyroglutamic acid, certain en-
zymes such as pyrrolidone carboxyl peptidase (PCP) and pyr-
ophenylpeptide hydrolyzyme (PYRase) are also needed (Mucchetti,
Locci, Massara, Vitale, & Neviani, 2002). Besides physiological activ-
ities, pyroglutamylpeptides possess desirable taste properties. Higaki-
Sato 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 commer-
cially available sake and reported that some of these peptides might be
produced from rice proteins via digestion with A. oryzae proteases. Ir-
respective of their low concentrations in the finished food systems,
pyroglutamyl peptides could enhance the taste of other food compo-
nents.
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-ethyla-
mino-L-glutamic acid (Türközü; Şanlier, 2017). The presence of L-glu-
tamic 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). Glu-
tathione (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 hydro-
lysis and microbiological fermentation, with the latter two being more
J. Zhang, et al.
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 in-
volving bacterial γ-glutamyltranspeptidase with glutamine as the γ-
glutamyl donor. They found that γ-glutamylization could suppress the
bitterness of Phe, Val, Leu, and His while initiating sourness and in-
creasing 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-ac-
tivity relation of γ-glutamyl peptides, and determined that an N-term-
inal γ-L-glutamyl residue, a moderately sized, aliphatic, neutral sub-
stituent 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 ex-
cellent umami-enhancing properties (Amino et al., 2016).
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 ma-
nipulation of Maillard reaction (Feng et al., 2015). The Maillard reac-
tion 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 com-
pounds under certain conditions.
Beksan et al. (2003) have synthesized two glycoconjugates of glu-
tamic 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 tastes-
enhancing 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) re-
ported that several Amadori rearrangement products (intermediates of
the Maillard reaction), namely Fru-Val, Fru-Met, Fru-pGlu and pGlu-
Gln, were the key compounds responsible for the umami taste of a ty-
pical 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 inter-
action with the integration of the findings in human neuroscience and
436
Trends in Food Science & Technology 88 (2019) 429–438
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 de-
rivatives 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. con-
densation/Maillard reaction or transpeptidation. However, except for γ-
glutamyl peptides, minimal research directly investigate the interaction
of peptide derivatives and the umami receptor, especially the correla-
tion for the perceptual and spatial properties of peptide derivatives and
the physichemical and structural characteristics of taste receptors.
5. Conclusion
The current review confirms the occurrence of a wealth of un-
explored 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-enhan-
cing effects, and high nutritional value. The recognization of their or-
ganoleptic 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 per-
ception 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 treat-
ment 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 re-
search should be conducted to gain insights into the sensing mechan-
isms of umami taste associated with the receptors and their ligands.
Acknowledgments
The authors are grateful to the State Key Research and Development
Plans (Project No. 2017YFD0400100) for its support. This research was
also supported by National Key R&D Program of China (No.
2016YFD0400803).
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