R: Concise Reviews

JFS R: Concise Reviews and Hypotheses in Food Science

in Food Science
Sweet Taste in Man: A Review
B. MEYERS AND M.S. BREWER

ABSTRACT: A greater understanding of the molecular mechanisms of sweet taste has profound significance for
the food industry as well as for consumers. Understanding the mechanism by which sweet taste is elicited by
saccharides, peptides, and proteins will assist science and industry in their search for sweet substances with fewer
negative health effects. The original AH-B theories have been supplanted by detailed structural models. Recent iden-
tification of the human sweet receptor as a dimeric G-protein coupled receptor comprising T1R2 and T1R3 subunits
has greatly increased the understanding of the mechanisms involved in sweet molecule binding and sweet taste
transduction. This review discusses early theories of the sweet receptor, recent research of sweetener chemorecep-
tion of nonprotein and protein ligands, homology modeling, the transduction pathway, the possibility of the sweet
receptor functioning allosterically, as well as the implications of allelic variation.
Keywords: chemoreception, protein sweeteners, saccharides, sweetness receptor, sweetness transduction

Introduction the sweet taste produced by various ligands. The AH-B theory for

F ive taste modalities have been identified in humans: sweet,

sour, bitter, salty, and umami (Temussi 2006a). Over the course
of human evolution, two of these modalities have proven most
significant to the survival of the species: sweetness provides a
means to seek out an energy source in the form of carbohy-
drates, and bitterness results in an aversion to alkaloids and
other potentially deadly toxins found in nature (Cui and others
2006).
Consuming sweet foods can have a significant effect on body
mass, overall health, and healthcare-related expenses. Over the
past 30 y, the prevalence of overweight and obese individuals in the
United States has increased significantly (Flegal and Troiano 2000).
Per capita healthcare expenditures are 81% higher for morbidly
obese adults than for adults of normal weight (Arterburn and others
2005). This increase in obesity parallels an increase in energy intake
(Salbe and others 2004). A greater understanding of the sweet taste
chemoreception mechanism, the way in which sweet molecules in-
teract with the sweet receptor, and sweet taste transduction, the
downstream signaling pathway triggered by sweetener-stimulation
of the receptor, could provide food scientists with the knowledge
required to develop new sweeteners, lower-calorie food products,
and potentially, a healthier population.
Early theories of sweetener–receptor interactions (prior to 2001)
were purely speculative because they were based on the structure of
sweeteners themselves. The discovery of the sweet taste receptor, a
dimeric G-protein coupled receptor (GPCR; Max and others 2001;
Nelson and others 2001; Li and others 2002; Zhao and others 2003),
has led to dramatic gains in recent years. This article reviews the
current and past theories of sweet taste in man focusing on sweet
taste chemoreception and transduction.
The AH-B theories and the sweetener “glycophore”
Prior to the discovery of the human sweet taste receptor, sev-
eral research groups attempted to explain the mechanism behind
MS 20080071 Submitted 1/28/2008, Accepted 4/25/2008. Author Meyers is
with The NutraSweet Co., Chicago, IL 60654, U.S.A. Author Brewer is with
the Dept. of Food Science and Human Nutrition, Univ. of Illinois, 202 ABL,
1302 West Pennsylvania Ave., Urbana, IL 61801, U.S.A. Direct inquiries to
author Brewer (E-mail: msbrewer@uiuc.edu).
sweetener/sweetener binding site interaction was one of the most
widely accepted models. Initially proposed by Shallenberger and
Acree (1967), this model proposed that a sweet-tasting compound
must contain a hydrogen bond donor (AH) as well as a hydrogen
bond acceptor (B). At a distance of 2.5 to 4 Å, the AH-B unit on the
sweet molecule (glycophore), can react with a complimentary AH-
B unit on the receptor, forming a pair of hydrogen bonds (Figure 1).
Shallenberger and Acree (1967) proposed that sweet tasting amino
acids, which greatly differ in chemical structure from saccharide
sweeteners, exhibit a spatial barrier, of given distance, perpendic-
ular to the receptor that allows for attachment of specific side-
chain conformations while excluding others. These side-chain–
receptor interactions were the suggested potentiators of the sweet
taste of these compounds (Shallenberger 1996; Eggers and others
2000).
Expanding on the work of Shallenberger and Acree (1967), Kier
(1972) proposed the addition of a 3rd component, “x” (later referred
to as “γ ”), to the glycophore model which modulates sweet potency
of the bound ligand by means of hydrophobic interactions. This
potency-modulating effect occurs due to the hydrophobic group’s
effect on the electric potential on the AH-B subunit. Although this
model expanded on the previous theory by accounting for differ-
ences in sweetener potencies, it did not specifically require the
hydrophobic component on the glycophore to trigger the transduc-
tion pathway (Eggers and others 2000).
Nofre and Tinti (1996) proposed a much more complex model
comprising 8 functional categories, organized into high affinity
and secondary sites, which contribute to sweet taste. Labeled
B-, AH-, XH-, G1-, G2-, G3-, G4-, and D, these 8 recognition sites
interact with 8 sweetener interaction sites of the same names, re-
spectively (Figure 2). This theory suggested that profound con-
formational changes occur within the receptor and its binding
site(s) due to hydrogen bonding. The number of binding sites
involved dictates the potency of the sweetener (Nofre and Tinti
1996). Goodman and others (2002) theorized that the aromatic
interactions with the D zone of the sweet receptor are responsi-
ble for the intense sweetness of peptide-based ligands (neotame,
aspartame).
The aforementioned models of the sweet receptor–binding site
interaction are inferentially based on the structure of the binding


C 2008 Institute of Food Technologists
R
Vol. 73, Nr. 6, 2008—JOURNAL OF FOOD SCIENCE R81
doi: 10.1111/j.1750-3841.2008.00832.x
Further reproduction without permission is prohibited
R: Concise Reviews Sweet taste review . . .
in Food Science
ligands, not on the structure of the sweet receptor itself (Cui and
others 2006). Each of the aforementioned models assumes a sin-
gle sweetener orthosteric (binding) site; however, more than 1 such
site has been demonstrated in the human sweet taste receptor (see
below; Dubois 2004). The commonality shared by all of the indi-
rect molecular models is the presence of the AH-B glycophore and,
in fact, these hydrogen donor/acceptor groups have been shown
to exist within 2 active sites of the sweet taste receptor (Temussi
2006a).
Discovery of the sweet taste receptor
Paving the way for elucidation of human sweet taste receptor
was the characterization of the mouse sweet taste receptor. Hoon
and others (1999) described a class of taste-specific mammalian
GPCRs. Subsequently, the Sac locus for mice, the chromosomal
region that determines the sensing of sweet taste, was identified
and genetically mapped (Li and others 2001). The specific receptor
within the mouse Sac locus responsible for sweet taste was isolated
from circumvallate papillae of the mouse tongue. The distribution
of these T1R3 receptors on the tongue differed from that of the
other T1R class receptors. Additionally, genetic mapping showed
that T1R3 resides on the mouse Sac locus (Kitagawa and others
2001). Taken together, these findings made a strong case that T1R3
was a mouse sweet taste receptor candidate.
Sainz and others (2001) validated that not only was T1R3’s
expression taste receptor cell-specific (TRC) but also alleic vari-
ation of T1R3 occurred between taster and nontaster strains of
mice. Montmayeur and others (2001) demonstrated that very
diverse T1R3 expression occurred in the mouse cirumvallate, fo-
liate, and fungiform taste papillae. More important, however, was
the observation that most cells expressing T1R3 also express T1R2,
indicating that the sweet receptor may, in fact, function as a
heterodimer.
However, the rodent sweet taste receptor does not respond to
several sweeteners that elicit responses in humans. Rat sweet taste
receptors respond to glucose, fructose, maltose, lactose, galactose,
dulcin, saccharin, acesulfame potassium, sucralose, D-tryptophan,
and glycine, but not to aspartame, cyclamate, monellin, neotame,
or thaumatin (Li and others 2002). To allow for a greater under-
standing of the human sweet receptor, it was imperative to identify
the human Sac locus.
Searching the human genome for a region syntenic to the mouse
Sac locus, Max and others (2001) identified a previously unknown
Figure 1 --- Schematic representation of the AH-B gly- Figure 2 --- The Nofre-Tinti model for the sweet receptor
cophore (adapted from Shallenberger and Acree 1967). (adapted from Nofre and Tinti 1996).
R82 JOURNAL OF FOOD SCIENCE—Vol. 73, Nr. 6, 2008
GPCR. T1R3 was identified as the likely Sac candidate as it is the
only such receptor in the identified syntenic region. In addition, it
shares a specific polymorphism that differentiates all sweet-taster
strains of mice from nontaster strains.
The T1R2 and T1R3 receptors are often co-expressed (as a
complex) in the mammalian palate. Based on changes in Ca2+ con-
centration, Nelson and others (2001) reported responses to sweet
compounds, including sucrose, fructose, saccharin, acesulfame-K,
dulcin, GA-1, and G1-2 by this complex; cells lacking either the
T1R2 or T1R3 subunit proved nonresponsive.
Subsequently, recognition of several classes of sweeteners by
the human T1R2/T1R3 receptor was demonstrated. Because the
G-protein that couples to the human T1Rs in vivo was unknown,
human T1R receptors were transfected into a human embryonic
kidney (HEK293) derived cell line, which expresses a known G-
protein. These receptors (T1R2/T1R3) responded to sugars (su-
crose, fructose, galactose, glucose, lactose, maltose), amino acids
(glycine, D-trypotophan), sweet proteins (monellin, thaumatin),
and high potency sweeteners (acesulfame potassium, aspartame,
cyclamate, dulcin, neotame, saccharin, sucralose; Li and others
2002).
Zhao and others (2003) demonstrated that sweet taste (and
concurrently umami taste) depended on the presence of T1R-
receptors. Genetically modified animals not expressing T1R sub-
units lost both taste modalities. T1R2 and T1R3 knockout mice ex-
hibited severely impaired sweet taste perception. However, high
saccharide concentrations were still able to elicit a detectable re-
sponse in both strains, indicating that T1R2 and T1R3 receptors
may be able to function independently, albeit less effectively, as
sweet taste receptors for a selective class of sweet compounds.
Taken together, the studies by Max and others (2001), Nelson and
others (2001), Li and others (2002), and Zhao and others (2003)
demonstrate that the T1R2/T1R3 complex is likely responsible for
the reception of sweet ligands in humans.
Structure of the sweet taste receptor
The sweet receptor is defined as a class C GPCR that exists as
a heterodimer of the T1R2 and T1R3 subunits (Figure 3; Cui and
others 2006). Many receptors in the human nervous system are
coupled to different classes of G-proteins. More than 50% of drugs
on the market regulate the activity of GPCRs (Fredholm and oth-
ers 2007). In mammals, there are 7 subfamilies of GPCRs: A, B,
LNB-7TM, C, Frizzled/Smoothened, taste 2, and Vomeronasal type
1. Classes A, B, C, and Vomeronasal type 1 receptors all involve
G2 G5
G4
G1 G3
XH AH

Sweet taste review . . .
activation of the coupled G-protein to trigger a signal cascade.
GPCRs are coupled to a guanosine triphosphate (GTP) binding pro-
tein that acts as an intermediary between enzymes and ion chan-
nels. Two classes of these G-proteins have been identified: het-
erotrimeric G-proteins and cytoplasmic G-proteins. Heterotrimeric
G-proteins, composed of α, β, and γ subunits, act with GPCRs in
the transduction pathway. To date, 28 α subunits, 5 β subunits, and
12 γ subunits have been identified. However, the β and γ subunits
are regarded as 1 combined functional subunit. Based on their de-
gree of similarity in the α subunits, the heterotrimeric G-proteins
fall into 1 of 4 families (Naim and others 2006)
Class C GPCRs, including the sweet receptor, are composed
of 3 domains: a large extracellular amino terminal or “N” termi-
nal domain, often referenced in the literature as the “Venus fly-
trap” domain; ATD, NTD, or VFTD (NTD), a cysteine-rich domain
(CRD); and a 7 helices transmembrane domain (7TM or TMD). The
CRD is composed of approximately 70 amino acids and acts as a
bridge between the NTD and 7TMD (Figure 3). The stability of this
dimeric complex is the result of disulphide bonds between cysteine
residues in the large extracellular domain; these cysteine residues
available for disulphide bonding do not exist in much more com-
mon class A GPCRs (Fredholm and others 2007).
The human sweet taste receptor is coupled to a G αi protein
(Ozeck and others 2004). Stimulation of bitter, sweet, and umami
receptors in HEK293 cells correlates to protein kinase phospho-
rylation and cyclic adenosine monophosphate (cAMP) concentra-
tions. Pertussis toxin, isolated from Bortaldella pertussis, is a known
inhibitor of G αi proteins. When HEK293 cells are treated with per-
tussis toxin, the signals are inhibited. Because protein kinase phos-
phorylation and cAMP are 2nd messengers of many GPCRs and
because treatment of HEK293 cells with pertusis toxin inhibit these
signals, Ozeck and others (2004) have concluded that sweet, bitter,
and umami receptor cells must be coupled to the G αi protein used
in their study.
Interestingly, the T1R2, but not the T1R3, subunit plays an im-
portant role coupling to the G α15 protein in the human sweet taste
receptor. When the C terminus domain of the rat T1R2 subunit was
substituted in place of the human C-terminus, lack of a response
to Ace-K and sucrose proved that there was no coupling of the G α15
protein (Xu and others 2004). However, replacing the same domain
of the T1R3 subunit did not result in the same response. Therefore,
although both T1R2 and T1R3 subunits are necessary for binding of
different sweet ligands, only the T1R2 subunit is required for both
ligand recognition and G-protein coupling.
R: Concise Reviews
in Food Science
Modeling the sweet taste receptor
The complete crystal structure of the human T1R2–T1R3 com-
plex has yet to be solved. Therefore, currently, the only way to ex-
amine ligand binding by this receptor is by examining homology
of models. The crystal structure of the NTD for the class C GPCR
glutamate receptor, mGluR1, has been identified (Kunishima and
others 2000). There are 5 crystalline structures of this homodimer
known. Although mGluR1 exhibits only a 20% similarity to T1R re-
ceptors (Temussi 2006b), mGluR1 homology model constructs of
T1Rs appear quite frequently in the literature. While better models
of the receptor are still required, much has been gained using the
mGluR1 homolgy model. Nie and others (2006) recently reported
expression and purification of functional ligand-binding domains
of T1R3 taste receptors. The NTD of mouse T1R3 was expressed
and purified; subsequent spectroscopic analysis confirmed that the
protein was folded and capable of binding ligands. These findings
will, no doubt, have profound effects on research into T1R3-ligand
binding. Future studies will likely use this purification method to
support or disprove current theories of T1R3 NTD ligand binding
based on homology models.
Until recently, no crystal structure had been solved for any class
C GPCR CRD. Yu and others (2004) previously proposed a homology
model based on the structure of the tumor necrosis factor receptor
(TNFR; Cui and others 2006). The amino acid sequence of TNFR
and CRDs of T1R3 share only 15% identity, yet they share 7 of 9 cys-
teine residues, indicating that the structures may have similar fold-
ing patterns. However, most recently, the entire crystal structure
of the extracellular region of the group II mGluR subtype 3 recep-
tor, which includes the CSD, was reported (Muto and others 2007).
Future studies will also likely use this crystal structure to support
or disprove current theories of CRD interactions of bound ligands
based on homology models.
The complete crystal structure of bovine rhodopsin, which falls
into subfamily A GPCR receptors, has been used extensively as
a template for homology modeling of different classes of GPCRs.
Cherezov and others (2007) recently reported the crystal struc-
ture of an engineered β 2 -adrenergic GCPR (β 2 AR), which also falls
into subfamily A. These researchers note that a number of mod-
els of β 2 AR, based on the crystal structure of bovine rhodopsin,
are reported in the literature (Bissantz and others 2003; Furse and
Lybrand 2003; Freddolino and others 2004; Gouldson and others
2004; Zhang and others 2006). However, it is further noted that all
of these models share a stronger similarity with bovine rhodopsin
than with that of β 2 AR. The authors, therefore, caution against the
Figure 3 --- Schematic representation
of the hT1R2-hT1R3 sweet taste
receptor, including the ATD, CRD,
and 7TMD regions of the
heterodimer complex (adapted from
Cui and others 2006).
Vol. 73, Nr. 6, 2008—JOURNAL OF FOOD SCIENCE R83
R: Concise Reviews Sweet taste review . . .
in Food Science
use of a single structural template for homology modeling and as-
sert that the use of a 2nd model will result in more accurate predic-
tions. Cui and others (2006) have suggested that a homology model
of bovine rhodopsin can act as a template for the 7TMD of the hu-
man sweet taste receptor. Perhaps a homology model will be pro-
posed using both bovine rhodopsin and β 2 AR as a template for the
human 7TMD and will therefore be a more accurate approximation
of its structure.
Even though a complete crystal structure of the T1R2/T1R3 re-
ceptor is not currently available, homology models for each of the
3 regions of the receptor have been proposed based on the crystal
structures of the NTD for the protein mGluR1, the TNFR, and the
7TMD of bovine rhodopsin (Cui and others 2006). Furthermore, the
crystal structures of the CRD of the group II mGluR subtype 3 recep-
tor and the GCPR β 2 AR have been solved; these discoveries should
result in even more accurate models of these 2 regions of the human
TRC in the future. By combining GPCR homology models, a tem-
plate for the human sweet taste receptor can be approximated (Cui
and others 2006). Additionally, the NTD of mouse T1R3 has been
isolated and purified.
Nonprotein ligand binding sites
of the T1R2/T1R3 receptor
Homology modeling based on the protein mGluR1 has been
used to evaluate binding mechanisms for the extracellular domain
of the T1R3 sweet taste receptor. The protein mGluR1 is a dimeric
receptor existing in open and closed conformations (Walters 2002).
In the presence of a bound glutamate ligand, the 2 monomers, or
ligand binding lobes, assume a closed formation (Figure 4). Using
in silico modeling of the mGluR1 dimeric receptor, a mechanism
for binding 3 ultra-high potency sweet compounds, neotame,
superaspartame, and SC-45647, was proposed. Polar side chains
in the cleft between the monomers readily interact with hydroxyl
groups on these sweeteners as well as on mono- and disaccharides
(Walters 2002).
The extracellular domain of the T1R2 and T1R3 subunits has
been modeled using both A and B chains of the mGluR1 template
(inactive open–open form and active closed–open form, respec-
tively). Using in silico free energy ligand binding calculations,
Morini and others (2005) identified at least 4 possible binding
sites for all classes of sweet compounds. A binding site for small
molecular weight compounds was identified in each of the 2 NTDs.
A Wedge site for high molecular weight proteins as well as a binding
site for allosteric modulators was identified in the 7TMD. The
Open Closed
Figure 4 --- The mGluR1 receptor protein in both “open: Preferential binding sites (agonist) are shown in bold. Adapted from Bishay
and “closed” conformations (adapted from Walters 2002). (2006).
R84 JOURNAL OF FOOD SCIENCE—Vol. 73, Nr. 6, 2008
identified type A binding sites were able to host only 4 compounds:
saccharin, alitame, aspartame, and 6-Cl-D-tryptophan. However,
both B type models had binding affinities for a much greater
number of small molecular weight compounds. B chain models
also had binding affinities for high molecular weight proteins in a
large wedge-like cavity. These results seem to validate the Wedge
Model first proposed by Temussi (2002) wherein high molecular
weight proteins can be bound in a large wedge-like cavity.
In contrast to the work of Walters (2002), Xu and others (2004)
have demonstrated that the N-terminal NTD of the T1R2 subunit,
not that of the T1R3, is responsible for binding the sweet peptide,
aspartame, and neotame (Table 1). When a human/rat chimera
composed of the human T1R2 subunit N-terminal domain and
rat T1R3 subunit was used, a response to both ligands occurred.
The normal rat T1R2–T1R3 complex does not respond to either
sweet compound; therefore, the N-terminal extracellular do-
main of the human T1R2 must be responsible for binding these
ligands.
In silico modeling based on the mGluR1-NTD crystal structure
predicted a binding mechanism for aspartame confirming the
hypothesis proposed by Xu and others (2004). Three primary
interactions were identified between aspartame and hT1R2 NTD:
salt bridges (Asp278 and Asp307), hydrogen bonds (Ser303, Arg383,
and Val384), and hydrophobic interactions (Tyr215, Tyr103, and
Pro277). In addition, 2 water molecules are required to bridge the
aspartame molecule in the binding pocket (Cui and others 2006).
Binding sites for the saccharide sweeteners sucrose and glucose
were proposed for the NTD of both T1R2 and T1R3 subunits. Bind-
ing affinities were determined using purified mouse NTD proteins
for both receptor subunits. Although both subunits exhibited an
affinity for these saccharides, T1R3 bound sucrose more readily
whereas T1R2 bound glucose more readily (Nie and others 2005).
Recently, a candidate-binding site for cyclamate was identi-
fied on the human sweet receptor (Jiang and others 2005c). The
human receptor (hT1R2-hT1R3) responds to cyclamate, whereas
the mouse receptor (mT1R2-mT1R3) does not. Therefore, mixed
species pairings of the 2 sweet receptor subunits were used to
determine the specific cyclamate-sensitive region. The hT1R3
subunit was required to elicit a sweet taste receptor response. Di-
rected mutagenesis, in addition to molecular modeling, identified
6 residues in the 7TMD exclusively responsible for binding cycla-
mate. Furthermore, when the cyclamate-docking site was modeled,
overlap was observed for the sweet taste inhibitor lactisole with the
binding site (see subsequently). Perhaps when lactisole is bound
to the 7TMD hT1R3 subunit, cyclamate binding is not possible due
to competition for the binding site. Using a homology model of the
hT1R3 TMD based on the bovine rhodospin crystal structure, Cui
and others (2006) demonstrated a binding pocket located among
TM-3,5,6.
Table 1 --- Summary of binding sites of nonprotein sweet-
eners commonly used in foods.
Sweetener Binding site(s)
Sucrose T1R2 NTD, T1R3 NTD
Glucose T1R2 NTD, T1R3 NTD
Sucralose T1R2 NTD, T1R3 NTD
Saccharin T1R2 NTD, T1R3 NTD
Acesulfame-K T1R2 NTD, T1R3 NTD
Cyclamate T1R3 7TMD
Aspartame T1R2 NTD
Neotame T1R2 NTD

Sweet taste review . . .
Sweet inhibitors such as lactisole are also likely to bind to the
human sweet taste receptor. Galindo-Cuspinera and Breslin (2006)
note that, based on previous research, the T1R3 subunit is required
for both umami and sweet modalities. If lactisole binds to the T1R3
subunit, it should inhibit both taste modalities. Lactisole indeed
inhibits both sweet and umami tastes in a dose-dependent manner
in humans. These findings were supported by mouse/human
chimeras, also indicating that the T1R3 subunit is responsible for
binding lactisole (Jiang and others 2005b). Galindo-Cuspinera and
Breslin (2006) proposed that the T1R1 (umami) and T1R2 (sweet)
subunits could be modulated by the T1R3 subunit and vice versa. 5
Ribonucleotides prevent lactisole’s inhibition of umami taste, but
not of sweet taste, suggesting that 5 ribonucleotides interact with
the T1R1 umami receptor but not with the T1R2 sweet receptor.
However, since it has been shown that lactisole binds to the T1R3
receptor subunit, the 5 ribonucleotides’ interaction with the
T1R1 unami receptor must affect the interaction of lactisole–T1R3
subunit in some way.
Some sweet compounds interact with other taste modalities,
as well. Saccharin and acesulfame-K trigger both sweet and bit-
ter taste modalities. These 2 ligands may cause bitter taste via a
common mechanism that differs from other known bitter com-
pounds. Both saccharin and acesulfame-K activate 2 bitter recep-
tors, hTAS2R43 and hTAS2R44, in transfected human kidney cells
(Kuhn and others 2004). These 2 receptors also exist in the taste
papillae of the tongue, further suggesting that they interact with
saccharin and acesulfame-K. The sweet protein neoculin interacts
with the sour taste modality (discussed subsequently; Shimizu-
Ibuka and others 2006; Koizumi and others 2007).
Sweet protein binding: “sweet fingers”
compared with the wedge model
Several sweet proteins can interact with the sweet taste receptor
(Temussi 2002, 2005, 2006a, 2006b; Spadacini and others 2003; Jiang
and others 2004, 2005a, 2005b; Tancredi and others 2004; Esposito
and others 2006; Shimizu-Ibuka and others 2006; Koizumi and oth-
ers 2007). Proteins are unique in their receptor interaction in that
they are much larger molecules than the other ligands that bind to
the receptor; however, the same receptor binds all classes of sweet
micro- and macromolecules.
Three sweet proteins of known 3-dimensional structure appear
frequently in the literature: brazzein, isolated from the African plant
species Pentadiplandra brazzeana; monellin, isolated from the
African plant species Dioscorephyllum cumminsii; and thaumatin,
isolated from the African plant species Thaumatococcus daniel-
lii (Kinghorn and Compadre 2001). These proteins have molecu-
lar weights 15 to 65 times greater than that of sucrose, yet all 4
molecules dock to the same sweet receptor. A small component of
the protein molecules’ structure may interact with the receptor in
the same way as do small molecular weight sweeteners. Tancredi
and others (2004) described this mechanism: small structures on
the surface of large proteins, termed “sweet fingers,” may exhibit
molecular structures similar to low molecular weight sweeteners
and can interact with the sweet receptor. These “sweet fingers,” by
definition, would have to meet 3 criteria:
1. They would have to be of sufficient length to interact with the
receptor.
2. Similar structures would have to be observed in different sweet
proteins.
3. These similar structures would have to exhibit a similar shape or
sequence as the glycophores already identified in small sweeten-
ers.
R: Concise Reviews
in Food Science
Efforts to elucidate similarities in structure between the 3 sweet
proteins brazzein, monellin, and thaumatin have failed (Temussi
2005). Three-dimensional structural modeling has revealed very lit-
tle similarity in the tertiary folds of the molecules (Tancredi and
others 2004). The only observed structural similarities occur in the
secondary β-sheet loops; therefore, they have become the only
sweet fingers candidates in these proteins.
Tancredi and others (2004) designed several cyclic peptides cor-
responding to the “hairpin” structure of the secondary β-sheet
loops of brazzein, monellin, and thaumatin; however, none elicited
sweet taste, even at high concentrations. It may be that an incor-
rect primary structure (amino acid sequence) was chosen for the
peptides, so they lacked the residues necessary to generate a re-
sponse, or that the secondary structure of the peptide lacked the
order necessary to fold into a similar 3-dimensional fold as the par-
ent protein, or a combination of the two. However, the peptides
designed for this study exhibited the same hairpin conformations
as their respective parent proteins. These researchers concluded
that these peptides were, in fact, an accurate model of the sweet
residues identified as candidate sweet fingers on brazzein, mon-
ellin, and thaumatin. The fact that the only observed similarity in
structure of these sweet proteins was the secondary β-sheet loops
and peptides designed to mimic the sweet taste of these candidate
sweet fingers, and they were unable to elicit a sweet taste, suggests
that an alternate explanation is required.
Spadacini and others (2003) reported an order of magnitude re-
duction in sweetness in a structural mutant of a single chained
monellin, G16A MNEI, compared to its parent protein, MNEI.
Structural comparison of the G16A MNEI and its parent protein
showed only a slight rotation of the β-sheets with respect to the
helix. This rotation had a profound effect on the tertiary structure
of the molecule, but had no effect on the ability of the theorized
sweet finger, Y65-D68, to interact with the sweet receptor. This sug-
gested that the area of interaction with the sweet receptor on the
protein must include more surface area than the sweet finger Y65-
D68 alone, again calling into question the sweet fingers theory for
sweet protein–receptor binding.
Using the crystal structure of mGluR1 as a homology model,
docking brazzein into the closed cleft of hT1R2 allowed identifica-
tion of several residues at the mouth of the cleft that should interact
with the sweet protein in the sweet fingers model. The disruptive
effect of mutations in these residues was examined in HEK cells.
Mutations at all 4 identified points of interaction had no effect on
the brazzein–receptor interaction, suggesting that the sweet fingers
model for brazzein is inaccurate. One of the mutations, D307N, re-
sulted in a complete loss of sweetness response when the receptor
interacted with small molecular weight sweeteners (D-tryptophan,
aspartame, sucrose; Jiang and others 2005a).
Using in silico 3-dimensional docking models, Temussi (2002)
proposed a secondary binding site on the T1R2–T1R3 receptor that
is unique to sweet proteins. Of the more than 40 preferred solutions,
most centered on a large cavity of the T1R3 promoter. Additionally,
a strong candidate-binding site that could stabilize the sweet recep-
tor was the region that acts as a bridge between the T1R2 and T1R3
promoter regions. However, this homology model construct con-
siders only 1 form of the receptor (T1R2 closed, T1R3 open; Wal-
ters and Hellekant 2006). Homology modeling of the T1R2 + T1R3
complex in both the aforementioned conformation and in the T1R2
open, T1R3 closed conformation showed brazzein to bind primar-
ily to T1R2 with contacts to T1R3 stabilizing the activated receptor
(Walters and Hellekant 2006).
The crystal homology model of the N-terminal domain of the
mGlu receptor can exist in 3 forms, a ligand-complexed (active)
Vol. 73, Nr. 6, 2008—JOURNAL OF FOOD SCIENCE R85
R: Concise Reviews Sweet taste review . . .
in Food Science
form and 2 free forms termed Free form I and Free form II. Free
form II can exist in a conformation nearly identical to that of the
active complex. If the T1R2–T1R3 receptor behaves like the mGlu
receptor, it would also exist as a mixture of these 3 forms; upon
binding a small molecular weight ligand, the receptor in Free form
I would stabilize to the active-conformation. Perhaps a 2nd mecha-
nism for sweet receptor stabilization exists via a Free form I shift to
Free form II due to external binding of a macromolecule (for exam-
ple, sweet protein; Tancredi and others 2004). Docking calculations
show that all 3 sweet proteins brazzein, monellin, and thaumatin fit
into a large cavity of the sweet receptor with wedge-shaped surfaces
of their structure. This Wedge Model is currently the most widely
accepted theoretical mechanism by which proteins can activate the
sweet receptor (Figure 5).
Jiang and others (2004) proposed an alternate binding site for
sweet proteins located in the cysteine-rich region of the T1R3 re-
ceptor. Using human/mouse chimeras of T1R3 paired with hu-
man T1R2 (hT1R2), residues 536-545 in the cysteine-rich region
were required for a response to brazzein. Two amino acid substi-
tutions (Ala-537 and Phe-540) eliminated all response. In addition,
mutations at the Phe-540 position reduced responses to brazzein
(and monellin), suggesting that, although brazzein and other sweet
proteins may interact with the T1R2 complex of the sweet recep-
tor, interactions with the T1R3 complex are crucial to elicit a sweet
response. It should be noted, however, that the validity of these
conclusions has been called into question; the same cysteine-rich
region identified in this study has a predominant structural role in
other class C receptors (Esposito and others 2006). Therefore, mu-
tations in this region could undermine the structural integrity of
the sweet receptor, causing the lack of sweet protein response as re-
ported by Jiang and others (2004). Walters and Hellekant (2006) also
propose a greater likelihood that these mutations affect the confor-
mational change required to activate downstream 2nd messengers
as opposed to the actual binding of brazzein.
Electrostatic potential is important in the sweet protein–sweet
receptor interaction in the Wedge Model (Esposito and others
2006). Seven MNEI mutants were designed, expressed, and char-
Free Form I Complexed
A
Aspartame
Free Form I Free Form II
B Margolskee (2002) proposed 2 models for sweet taste transduc-
Protein
Figure 5 --- Possible mechanisms of sweet molecule–
sweet receptor interactions (adapted from Tancredi and
others 2004). (A) Binding of aspartame transforms inac-
tive, ligand-free form I into the active complexed form.
(B) A sweet protein binding to a surface site of the ligand-
free form II shifts the equilibrium to favor active free form
II. Long-lasting signal transmission is due to stabilization
for form II by protein complexation.
R86 JOURNAL OF FOOD SCIENCE—Vol. 73, Nr. 6, 2008
acterized with specific electrostatic changes in several neutrally
charged residues. Docking calculations showed that the proposed
interaction surface of MNEI with the wedge site of the sweet re-
ceptor was positively charged. If monellin indeed interacts with
the wedge site of the sweet receptor, changes in MNEI uncharged
residues into either acidic or basic states would affect the surface
that interacts with the sweet protein, and thus perceived sweet-
ness of the molecule. Sensory studies, a more direct confirma-
tion of the validity of the Wedge Model for sweet protein–sweet
receptor interaction than studies using human/mouse chimeras,
confirm this hypothesis. In addition, it offers insight into the im-
portance of the electrostatic potential of sweet protein–receptor
interactions.
Recently, the crystal structure of the sweet heterodimeric pro-
tein neoculin, found in the fruit of Curculigo latifolia, was solved
(Shimizu-Ibuka and others 2006). Neoculin elicits a sweet response
in humans and also has taste-modifying activity in that it converts
sour taste to sweet taste. This is the 1st tertiary structure identi-
fied for a protein of this nature. Neoculin exists in pH-dependent
open and closed conformations. It may be that in the presence
of acid, the protein shifts into the open conformation, then in-
teracts with the T1R2–T1R3 receptor. This would account for the
protein’s taste modifying activity. Using human/mouse chimeras
of the T1R3 subunit, Koizumi and others (2007) demonstrated
that the NTD of human T1R3 (hT1R3) is required for the recep-
tion of neoculin; a positive neoculin response occurred in hu-
man T1R2–human T1R3 (hT1R2-hT1R3) cells, whereas a negative
response occurred in human T1R2–mouse T1R3 (hT1R2-mT1R3)
cells.
Sweet taste transduction
Transduction refers to the cascade of chemical signals occur-
ring downstream from chemoreception that ultimately stimulates
the nervous system to signal the brain of an incoming stimulus.
Although transduction pathways are generally similar for all senses,
there are unique differences in the pathway of sweet taste, and
there is some debate as to the exact mechanism by which it occurs.
Prior to the discovery of the sweet taste receptor, several studies
showed changes in chemicals thought to be 2nd messengers (cAMP
and inositol 1,4,5-triphosphate [IP 3 ]) in signal transduction path-
ways of TRCs in response to sweet ligands because these chemicals
increase in rats, hamster, and frog taste cells in response to a variety
of sweet stimuli (Brand and Feign 1996; Kinnamon and Margolskee
1996). Increases in IP 3 in response to nonsaccharide ligands, but
not in response to sucrose, suggested that 2 different sweet taste
transduction mechanisms may exist for saccharide and nonsaccha-
ride sweeteners. A far greater increase in IP 3 concentration occurs
in response to the high potency sweeteners saccharin and SC-45647
than to sucrose, whereas a greater concentration of cAMP occurs in
response to sucrose (Bernhardt and others 1996).
tion. In the first, a saccharide sweetener activates G s via the GPCR,
which activates adenyl cyclase (AC) generating cAMP. The cAMP
then acts directly, via an ion channel, or indirectly, via activation
of a protein kinase, to depolarize the taste cell via a release of
Ca2+ . Depolarization then triggers neurotransmitter release. The
2nd model describes a transduction pathway for nonsaccharide
sweeteners. Upon binding to the GPCR, the nonsaccharide sweet-
ener activates phospholipase (PLCβ2) generating IP 3 and diacyl-
glycerol (DAG), which induce Ca2+ release from internal stores. As
in the 1st proposed transduction pathway, Ca2+ release causes cell
depolarization and neurotransmitter release. Both mechanisms are
theorized to exist in the same TRC (Figure 6).

Sweet taste review . . .
Ca2+ and ion channels are crucial to the sweet taste transduction
pathway. Changes in Ca2+ concentration in TRCs occur in response
to several classes of sweeteners (Bernhardt and others 1996). The
mammalian transient receptor potential channel 5 (TRPM5), a
cationic ion channel believed to regulate Ca2+ entry into cells, is
present in TRCs (Perez and others 2002, 2003). Several downstream
taste signaling molecules are coexpressed with TRPM5, supporting
the theory that this receptor regulates sweet (and/or bitter) trans-
duction. In mice, the absence of TRPM5 results in loss of sensitivity
to saccharide and nonsaccharide sweeteners as well as bitter and
umami tastants (Zhang and others 2003). These observations high-
light the importance of Ca2+ and ion channel regulation for trans-
duction of sweet taste and for bitter and umami tastes as well.
Research by Sugimoto and others (2002) further supports the im-
portance of ion channel activity in sweet taste transduction. Leptin,
a hormone released by adipose tissue, inhibits food intake and in-
creases energy expenditure. In the taste cells of healthy mice, leptin
decreases sensitivity to sweet compounds by enhancing K+ influx
into the cell limiting sweet-induced depolarization. Genetically di-
abetic db/db mice, which are deficient in the leptin receptor Ob-
Rb gene, do not respond similarly to leptin. Sugimoto and others
(2002) argued that leptin’s interaction with Ob-Rb is essential to
K+ ion channel activation that inhibits sweet taste through hyper-
polarization of the taste cell.
A recent hypothesis that nonsaccharide sweeteners interfere
with downstream elements of the transduction pathway (Zubare-
Samuelov and others 2005) is supported by characteristic sweet
aftertaste of many of compounds (Schiffman and others 2007), sug-
gesting possible interference with signal termination. G-protein re-
ceptor signaling is reduced as a result of phosphorylation mediated
by 2 types of protein kinases: 2nd messenger-dependent protein ki-
nases (PKA) and GPCR kinases (GRK). Phosphorylation inhibition
could delay signal termination. Membrane permeability of several
A enyl
Adenyl GPCR
Cyclase
? ? ? ?
cAMP
Protein
Kinase A
Na +
K+
K+ K+ Na +
Ion Channels
Figure 6 --- Schematic representation of transduction mechanisms leading to taste cell depolarization (adapted from
Margolskee 2002).
R: Concise Reviews
in Food Science
sweet and bitter compounds has been demonstrated in rat taste
bud cells in vivo showing that the tastants can physically interact
with the PKA and GRKs in taste cells (Zubare-Samuelov and others
2005). The sweet tastants cyclamate, saccharin, and neohesperidin
dihydrochalcone (NHD), and several bitter compounds, inhibited
GRK-phosphorylated rhodopsin and PKA-phosphorylated casein.
Interaction with protein kinases in the taste receptor might be the
mechanism behind characteristic sweet and bitter aftertastes in a
variety of compounds.
Possible allosteric modulation of the sweet receptor
The possibility that the class C GPCRs function allosterically has
been proposed (Pin and others 2005; Galindo-Cuspinera and oth-
ers 2006). Different domains of the receptor exist in different con-
formations and may alter its activity. The NTD exists in both open
and closed conformations, and in 2 orientations: resting “R” and
active “A”. Oscillations between these conformations and orienta-
tions provide potential allosteric modulation of the taste receptor
in response to ligand binding. This may explain unique sweetener
taste properties such as sweetener synergy and cross-adaptation
(Pin and others 2005).
Galindo-Cuspinera and others (2006) pointed to an allosteric
model of the T1R1/T1R3 complex to explain the phenomenon of
sweet “water-taste.” Water-tastes are elicited by water after the
tastant chemical has been removed from the mouth; this effect
occurs for several gustatory sensations. To identify the mecha-
nism for this sensation in human sweet TRCs, hT1R1-hT1R3 cell
cultures have been used to replicate the action of rinsing with water
in vitro. The known sweet water-taste stimuli, sodium saccharin,
and acesulfame-K, have been used to model the interaction. When
cells were exposed to 50 mM concentrations of the sweet com-
pounds, a minimal response was observed; however, upon rins-
ing, a strong response occurred. However, when exposed to 3 mM
GPCR
Phospholipase ? ? ?
IP 3
DAG
Ca 2
Ca 2
Ca 2
Ca 2
Ca 2
Ca 2
Ca 2
K+ Ca 2
Vol. 73, Nr. 6, 2008—JOURNAL OF FOOD SCIENCE R87
R: Concise Reviews Sweet taste review . . .
in Food Science
concentrations, the opposite effect was observed in that a strong
initial response occurred followed by no after-rinsing effect. The
authors suggest an allosteric model for the sweet taste receptor
wherein high-affinity and low-affinity binding sites for saccharin
and acesulfame-K occur. At low concentrations, these sweeten-
ers bind preferentially to the high-affinity site; at high concen-
trations, additional binding to the low-affinity site allostericallly
shifts the receptor into an inactive conformation, inhibiting sweet
taste. As the compounds are washed from the low-affinity binding
site, the receptor again assumes the active conformation and the
sweet taste returns. They concluded that sweet water-taste could
be used as predictor of sweet-taste blockers such as saccharin and
acesulfame-K at high concentrations.
Effect of allelic variation of the T1R3 receptor
Citing discrepancies between previously observed sweetener in-
teractions in mice and rat species, an attempt to design a more
accurate system for measuring the sweetener response of the
T1R3 subunit was undertaken by Bachmanov (2005). Many strains
of inbred, hybrid high sweetener-preferring and low sweetener-
preferring and 129.B6-Sac congenic mice were used because of
the genetic variations in their T1R3 alleles. Varying responses to
a variety of sweet compounds were observed among the different
strains of mice, leading the author to conclude that allelic variation
of the T1R3 gene affected response to some, but not all sweeten-
ers. An effect occurred in response to the sugars sucrose, glucose,
maltose, and fructose; a sugar alcohol, erythritol; the amino acids
D-phenylalanine, D-tryptophan, and L-proline; and the artificial
sweeteners saccharin, acesulfame, sucralose, and SC45647, but not
to the sweet amino acids glycine and L-alanine. Mice lacking or
expressing allelic variation in the T1R3 receptor genes responded
to several sweeteners (sucrose, saccharin, D-phenylalanine, D-
tryptophan, SC-45647, glycine, L-proline, L-alanine, L-glutamine),
indicating that many of these sweeteners interact with another
taste receptor, namely, the T1R2 subunit (Inoue and others 2004).
Allelic differences within species can result in observable pheno-
typic differences in taste, which must be considered when evaluat-
ing the sweet taste receptor.
Conclusions
T he accepted theory of the mechanism by which the human
sweet taste receptor functions has undergone many changes
in recent times. Early theories were inferentially based on the struc-
ture of the sweeteners, not on the receptor itself. With the discov-
ery of the T1R2/T1R3 receptor complex, understanding advanced
as to how such a variety of sweet ligands, falling into such a wide
range of chemical classes, are able to bind to the same receptor.
Although most transduction pathways in humans show very sim-
ilar mechanisms, there are some mechanisms unique to the sweet
receptor. Although much has been gained in recent years, as with
any new research, it seems that more questions have been created
than answers provided: Are the current homology models sufficient
for describing the human sweet receptor? Do sweeteners interfere
with downstream transduction signal pathways? Do bound ligands
change the shape of the sweet receptor allowing it to be allosteri-
cally modified? How important is allelic variation?
While work remains to be done, discovery of the sweet taste re-
ceptor and application of homology models allow for a far greater
understanding of sweet taste than was available only a few years
ago, making this a particularly exciting time for research in this
field. It appears that it is only a matter of time until a complete
picture of the sweet taste pathway in humans from chemore-
ception through transduction is realized. However, this begs the
R88 JOURNAL OF FOOD SCIENCE—Vol. 73, Nr. 6, 2008
question—What impact will this knowledge have on the future of
sweet taste? Will new, better tasting sweeteners and food products
be developed? Will this research lead to a healthier population of
adults in the world? A world in which people no longer enjoy sweet
tastes is hardly imaginable; therefore, it seems that the burden of
making it possible to continue to enjoy this pleasure while helping
to create a healthier population falls squarely on the shoulders of
food scientists. Further research in this field should provide food
scientists with the tools necessary to meet this challenge.
Glossary of Terms
Acesulfame-K: Acesulfame potassium is the potassium salt of a
dihydrooxathiazinone dioxide, which is approximately 200 times
sweeter than sugar (von Rymon Lipinski and Hanger 2001).
Adenyl cyclase (AC): An enzyme involved in the manufacture of
cAMP.
Aspartame: A dipeptide sweetener composed of L-aspartic acid and
the methyl ester of L-phenylalanine, which is approximately 200
times sweeter than sugar (Butchko and others 2001).
ATD: Amino terminal domain of the T1R2–T1R3 receptor complex,
also referred to as NTD.
Brazzein: One of 2 sweet proteins found in the African plant species
Pentadiplandra brazzeana ranging from 500 to 2000 times sweeter
than sugar.
CRD: Cysteine-rich domain of the T1R2–T1R3 receptor complex.
Cross adaptation: The phenomenon of adaptation to a sweetener
resulting in the subsequent decreased sweet response to another
sweetener (Schiffman and others 2008).
Cyclamate: Cyclamic acid often produced as a sodium or calcium
salt is a high potency sweetener approximately 30 times sweeter
than sugar (Bopp and Price 2001).
Cyclic adenosine monophosphate (cAMP): A 2nd messenger in sig-
nal transduction that is a derivative of ATP and is manufactured by
the enzyme adenyl cyclase.
Diacylglycerol (DAG): A 2nd messenger in the signal transduction
pathway produced by the enzyme phopholipase.
Dulcin: p-ethoxyphenylurea, a urea derivative, is a high potency
sweetener approximately 200 times sweeter than sugar (Kinghorn
and Compadre 2001).
GA-1: Guanidinoacetic acid 1, a high potency sweetener estimated
to be > 200000 sweeter than sugar when compared to 2% sucrose
(Nagarajan and others 1996).
G1-2: Guanidinoacetic acid 2, a high potency sweetener estimated
to be > 200000 sweeter than sugar when compared to 2% sucrose
(Nagarajan and others 1996).
Glycophore: The original term used by Schallenberger and Acree to
describe the theorized sweet receptor/sweet ligand complex.
GPCR: G-protein coupled receptor.
HEK293: A strain of Human Embroytic Kidney Cells often used for
in vitro testing.
Heterodimer: A dimer composed of 2 different subunits.
Inositol 1,4,5-triphosphate (IP 3 ): A 2nd messenger in signal trans-
duction made by the enzyme phopholipase C.
Lactisole: An aralkyl carboxylic acid that inhibits sweet and umami
taste perception by humans but not by rats (Jiang and others
2005b).
Ligand: A molecule that binds to a receptor.
Monellin: The sweet protein found in the African plant species
Dioscorephyllum cumminsii ranging from 1500 to 2000 times
sweeter than sugar.
mGluR1: A G-protein coupled glutamate receptor. The crystal
structure of the NTD has been solved and is often used as a homol-
ogy model for the sweet receptor.

Sweet taste review . . .
Neohesperidin dihydrochalcone (NHD): A glycosidic flavonoid that
is approximately 1800 times sweeter than sugar (Borrego and Mon-
tijano 2001).
Neotame: A structural derivative of the peptide sweetener aspar-
tame formed by alkylation of the molecule ranging from 7000 to
13000 times sweeter than sugar (Stargel and others 2001).
NTD: N-terminal domain of the T1R2-T1R3 receptor complex.
Sac locus: The gene locus responsible for sweet taste originally
named for the chemical compound saccharin.
Saccharin: Acid saccharin is a high potency sweetener approxi-
mately 300 times sweeter than sugar which is typically available as
a sodium, calcium, or potassium salt (Pearson 2001).
SC-45647: A guanidine-aliphatic acid several thousand times
sweeter than sugar (Walters and Hinds 1994).
Sucralose: A high potency sweetener resulting from the chlorina-
tion of sucrose in the 1 and 6 positions of the fructose moiety and
the inversion and chlorination of the 4 position of the glucose moi-
ety that is approximately 600 times sweeter than sugar (Goldsmith
and Merkel 2001).
Sweetener synergy: The phenomenon of the combined sweetness
of 2 or more sweeteners within a matrix being perceived as higher
than the sum of each individual sweetener.
T1R: A class of mammalian taste receptors for sweet and umami
taste modalities.
Thaumatin: A class of sweet proteins found in the arils of the fruits
of the West African plant species Thaumatococcus daniellii ranging
from 1600 to 3000 times sweeter than sugar (Kinghorn and Com-
padre 2001).
TMD (7TM): 7-transmembrane domain of the T1R2–T1R3 receptor
complex.
TRC: Taste receptor cell.
Tumor necrosis factor receptor (TNFR): A family of receptors that
bind to a tumor necrosis factor.
VFTD: “Venus Flytrap” domain of the T1R2–T1R3 receptor complex
also referred to as NTD.
References
Arterburn DE, Maciejewski ML, Tsevat J. 2005. Impact of morbid obesity on medical
expenditures in adults. Int J Obes 29:334–9.
Bachmanov AA. 2005. Genetic approach to characterize interaction of sweeteners
with the sweet taste receptors in vivo. Chem Senses 30(Suppl 1):i82–3.
Bernhardt SJ, Naim M, Zehavi U, Lindemann B. 1996. Changes in IP 3 and cytosolic
Ca2+ in response to sugars and non-sugar sweeteners in transduction of sweet taste
in the rat. J Physiol 4902:325–36.
Bishay IE. 2006. The biology and chemistry of taste. Presented at the Illinois Inst. Tech-
nology, Chicago, Ill.
Bissantz C, Bernard P, Hibert M, Rognan D. 2003. Protein-based virtual screening of
chemical databases. II. Are homology models of G-protein coupled receptors suit-
able targets? Proteins: Struct Function Genet 50:5–25.
Bopp BA, Price P. 2001. Cyclamate. In: O’Brien Nabors L, editor. Alternative sweeten-
ers. 3rd ed., revised and expanded. New York: Marcel Dekker. p 63–85.
Borrego F, Montijano H. 2001. Neohesperidin dihydrochalcone. In: O’Brien Nabors
L, editor. Alternative sweeteners. 3rd ed., revised and expanded. New York: Marcel
Dekker. p 87–104.
Brand JG, Feign AM. 1996. Biochemistry of sweet taste transduction. Food Chem
563:199–207.
Butchko HH, Stargel WW, Comer CP, Mayhew DA, Andress SE. 2001. Aspartame. In:
O’Brien Nabors L, editor. Alternative sweeteners. 3rd ed., revised and expanded.
New York: Marcel Dekker. p 41–61.
Cherezov V, Rosenbaum DM, Hanson MA, Rasmussen SGF, Thian FS, Kobilka TS,
Choi HJ, Kuhn P, Weis WI, Kobilka BK, Stevens RC. 2007. High-resolution crystal
structure of an engineered human β 2 -adrenergic G protein-coupled receptor. Sci-
ence 318:1258–65.
Cui M, Jiang P, Maillet E, Max M, Margolskee RF, Osman R. 2006. The heterodimeric
sweet taste receptor has multiple potential ligand binding sites. Curr Pharmaceut
Des 12:4591–600.
Dubois GE. 2004. Unraveling the biochemistry of sweet and umami tastes. Proc Natl
Acad Sci USA 10139:13972–3.
Eggers SC, Acree TE, Schallenberger RS. 2000. Sweetness chemoreception theory and
sweetness transduction. Food Chem 68:45–9.
Esposito V, Gallucci R, Picone D, Saviano G, Tancredi T, Temussi TA. 2006. The impor-
tance of electrostatic potential in the interaction of sweet proteins with the sweet
taste receptor. J Mol Biol 360:448–56.
Flegal KM, Troiano RP. 2000. Changes in the distribution of body mass index of adults
and children in the US population. Int J Obes 24:807–18.
R: Concise Reviews
in Food Science
Freddolino PL, Yashar M, Kalani S, Vaidehi N, Floriano WB, Hall SE, Trabanino RJ, Kam
VWT, Goddard WA III. 2004. Predicted 3D structure for the human β2 adrenergic
receptor and its binding site for agonists and antagonists. Proc Natl Acad Sci USA
101:2736–41.
Fredholm BB, Hökfelt T, Miligan G. 2007. G-protein-coupled receptors: an update.
Acta Physiol 190:3–7.
Furse KE, Lybrand TP. 2003. Three-dimensional models for β-adrenergic receptor
complexes with agonists and antagonists. J Med Chem 46:4450–62.
Galindo-Cuspinera V, Breslin PAS. 2006. The liaison of sweet and savory. Chem Senses
31:221–5.
Galindo-Cuspinera V, Winning M, Bufe B, Meyerhof W, Breslin PAS. 2006. A TAS1R
receptor-based explanation of sweet ‘water-taste.’ Nature 441:354–7.
Goldsmith LA, Merkel CM. 2001. Sucralose. In: O’Brien Nabors L, editor. Alternative
sweeteners. 3rd ed., revised and expanded. New York: Marcel Dekker. p 185–207.
Goodman M, Del Valle JR, Amino Y, Benedetti E. 2002. Molecular basis of sweet taste
in dipeptide ligands. Pure Appl Chem 747:1109–16.
Gouldson PR, Kidley NJ, Bywater RP, Psaroudakis G, Brooks HD, Diaz C, Shire D,
Reynolds CA. 2004. Toward the active conformations of rhodopsin and the β 2 -
adrenergic receptor. Proteins 56:67–84.
Hoon M, Adler E, Lindemeier J, Battey JF, Ryba NJP, Zuker CS. 1999. Putative mam-
malian taste receptors: a class of taste-specific GPCRs with distinct topographic
selectivity. Cell 96:541–51.
Inoue M, Reed DR, Li X, Tordoff MG, Beauchamp GK, Bachmanov AA. 2004. Allelic
variation of the Tas1r3 taste receptor gene selectively affects behavioral and neural
taste responses to sweeteners in the F 2 hybrids between C57BL/6ByJ and 129P3/J
Mice. J Neurosci 249:2296–303.
Jiang P, Ji Q, Liu Z, Snyder LA, Benard LM, Margolskee RF, Max M. 2004. The cysteine-
rich region of T1R3 determines responses to intensely sweet proteins. J Biol Chem
27943:45068–75.
Jiang P, Cui M, Ji Q, Snyder L, Liu Z, Bernard L, Margolskee RF, Osman R, Max M.
2005a. Molecular mechanisms of sweet receptor function. Chem Senses 30(Suppl
1):i17–8.
Jiang P, Cui M, Zhao B, Liu Z, Snyder LA, Benard LMJ, Osman R, Margolskee RF, Max
M. 2005b. Lactisole interacts with the transmembrane domains of human T1R3 to
inhibit sweet taste. J Biol Chem 28015:15238–46.
Jiang P, Cui M, Zhao B, Snyder LA, Benard LM, Osman R, Max M, Margolskee RF.
2005c. Identification of the cyclamate interaction site within the transmembrane
domain of the human sweet taste receptor subunit T1R3. J Biol Chem 28040:34296–
305.
Kier LB. 1972. Molecular theory of sweet taste. J Pharmacy Sci 61:1394–7.
Kinghorn D, Compadre C. 2001. Less common high-potency sweeteners. In: O’Brien
Nabors L, editor. Alternative sweeteners. 3rd ed., revised and expanded. New York:
Marcel Dekker. p 209–33.
Kinnamon SC, Margolskee RF. 1996. Mechanisms of taste transduction. Curr Opin
Neurobiol 6:506–13.
Kitagawa M, Kusakabe Y, Miura H, Ninomiya Y, Hino A. 2001. Molecular genetic iden-
tification of a candidate receptor gene for sweet taste. BioChem Biophys Res Comm
2831:236–42.
Koizumi A, Nakajima K, Asakura T, Morita Y, Ito K, Shimizu-Ibuka A, Misaka T, Abe K.
2007. Taste-modifying sweet protein, neoculin, is received at human T1R3 amino
terminal domain. Biochem Biophys Res Comm 358:585–9.
Kuhn C, Bufe B, Winnig M, Hofmann T, Frank O, Behrens M, Lewtschenko T, Slack JP,
Ward CD, Meyerhof W. 2004. Bitter taste receptors for saccharin and acesulfame-K.
J Neurosci 244:10260–5.
Kunishima N, Shimada Y, Tsuji Y, Sato T, Yamamoto M, Kumasaka T, Nakanishi S,
Jingami H, Morikawa K. 2000. Structural basis of glutamate recognition by a dimeric
metabotropic glutamate receptor. Nature 407:971–7.
Li X, Inoue M, Reed DR, Huque T, Puchalski RB, Tordoff MG, Ninomiya Y, Beauchamp
GK, Bachmanov AA. 2001. High-resolution genetic mapping of the saccharin pref-
erence locus Sac and the putative sweet taste receptor T1R1 gene Gpr70 to mouse
distal chromosome 4. Mammal Genome 12:13–6.
Li X, Staszewski L, Xu H, Durick K, Zoller M, Adler. 2002. Human receptors for sweet
and umami taste. Proc Natl Acad Sci USA 997:4692–6.
Margolskee RF. 2002. Molecular mechanisms of taste transduction. Pure Appl Chem
747:1125–33.
Max M, Shanker YG, Huang L, Rong M, Liu Z, Campagne F, Weinstein H, Damak S,
Margolskee RF. 2001. Tas1r3, encoding a new candidate taste receptor, is allelic to
the sweet responsiveness locus Sac. Nat Genet 281:58–63.
Montmayeur JP, Liberles SD, Matsunami H, Buck LB. 2001. A candidate taste receptor
gene near a sweet taste locus. Nat Neurosci 4:492–8.
Morini G, Bassoli A, Temussi PA. 2005. From small sweeteners to sweet proteins:
anatomy of the binding sites of the human T1R2˙T1R3 receptor. J Med Chem
48:5520–9.
Muto T, Tsuchiya D, Morikawa K, Jingami H. 2007. Structures of the extracellular re-
gions of the group II/III metabotropic glutamate receptors. Proc Natl Acad Sci USA
104:3759–64.
Naim H, Huang L, Spielman AI, Shaul ME, Aliluiko A. 2006. Stimulation of taste cells
by sweet taste compounds. In: Spillane WJ, editor. Optimizing sweet taste in foods.
Boca Raton, Fla.: CRC Press. p 3–29.
Nagarajan S, Kellogg MS, DuBois GE. 1996. Understanding the mechanism of sweet
taste: synthesis of ultrapotent guanidinoacetic acid photoaffinity labeling reagents.
J Med Chem 3921:4167–72.
Nelson G, Hoon MA, Chandrashekar J, Zhang Y, Ryba NJ, Zuker CS. 2001. Mammalian
sweet taste receptors. Cell 106:381–90.
Nie Y, Hobbs J Vigues S, Olson WJ, Conn CL, Munger SD. 2006. Expression and purifi-
cation of functional ligand-binding domains of T1R3 taste receptors. Chem Sense
31:505–13.
Nie Y, Vigues S, Hobbs JR, Conn GL, Munger SD. 2005. Distinct contributions of
T1R2 and T1R3 taste receptor subunits to the detection of sweet stimuli. Curr Biol
15:1948–52.
Nofre C, Tinti J. 1996. Sweetness reception in man: the multipoint attachment theory.
Food Chem 563:263–74.
Vol. 73, Nr. 6, 2008—JOURNAL OF FOOD SCIENCE R89
R: Concise Reviews Sweet taste review . . .
in Food Science
Ozeck M, Brust P, Xu H, Servant G. 2004. Receptors for bitter, sweet and umami taste
couple to inhibitory G protein signaling pathways. Eur J Pharm 489:139–49.
Pearson RL. 2001. Saccharin. In: O’Brien Nabors L, editor. Alternative sweeteners. 3rd
ed., revised and expanded. New York: Marcel Dekker. p 147–65.
Perez CA, Huang L, Rong M, Kozak A, Preuss AK, Zhang H, Max M, Margolskee RF.
2002. A transient receptor potential channel expressed in taste receptor cells. Nat
Neurosci 511:1169–76.
Perez CA, Margolskee RF, Kinnamon SC, Ogura T. 2003. Making sense with TRP chan-
nels: store-operated calcium entry and the ion channel Trpm5 in taste receptor
cells. Cell Calcium 33:541–9.
Pin JP, Kniazeff J, Liu J, Binet V, Goudet C, Rondard P, Prezéau L. 2005. Allosteric
functioning of dimeric class C G-protein-coupled receptors. Fed Exp Biol Soc Lett
272:2947–55.
Sainz E, Korley JN, Battey JF, Sullivan SL. 2001. Identification of a novel member of the
T1R family of putative taste receptors. J Neurochem 77:896–903.
Salbe AD, DelParigi A, Pratley RE, Drewnowski A, Tataranni PA. 2004. Taste prefer-
ences and body weight changes in an obesity-prone population. Am J Clin Nut 79:
372–8.
Shallenberger RS. 1996. The AH-B glycophore and general taste chemistry. Food
Chem 563:209–14.
Schallenberger RS, Acree TE. 1967. Molecular theory of sweet taste. Nature 216:
480–2.
Schiffman SS, Sattely-Miller EA, Bishay IE. 2007. Time to maximum sweetness
intensity of binary and ternary blends of sweeteners. Food Qual Pref 18:405–
15.
Schiffman SS, Sattely-Miller E, Bishay IE. 2008. Sensory properties of neotame: com-
parison with other sweeteners. In: Weerasinghe DK, Dubois GE, editors. Sweetness
and sweeteners: biology, chemistry, and psychophysics. Washington, D.C.: Ameri-
can Chemical Society. p 511–29.
Shimizu-Ibuka A, Morita Y, Terada T, Asakura T, Nakajima K, Iwata S, Misaka T,
Sorimachi H, Arai S, Abe K. 2006. Crystal structure of neoculin: insights into its
sweetness and taste-modifying activity. J Mol Biol 359:148–58.
Spadacini R, Trabucco F, Saviano G, Picone D, Crescenzi O, Tancredi T, Temussi
PA. 2003. The mechanism of interaction of sweet proteins with the T1R2-T1R3 re-
ceptor: evidence from the solution structure of G16A-MNEI. J Mol Biol 328:683–
92.
Stargel WW, Mayhew DA, Comer CP, Andress SE, Butchko HH. 2001. Neotame. In:
O’Brien Nabors L, editor. Alternative sweeteners. 3rd ed., revised and expanded.
New York: Marcel Dekker. p 129–45.
R90 JOURNAL OF FOOD SCIENCE—Vol. 73, Nr. 6, 2008
Sugimoto K, Shigemura N, Yasumatsu K, Ohta R, Nakashima K, Kawai K, Ninomiya Y.
2002. Ion channels and second messengers involved in transduction and modula-
tion of sweet taste in mouse taste cells. Pure Appl Chem 747:1141–51.
Tancredi T, Pastore A, Salvadori S, Esposito V, Temussi PA. 2004. Interaction of sweet
proteins with their receptor: a conformational study of peptides corresponding to
loops of brazzein, monellin and thaumatin. Eur J Biochem 271:2231–40.
Temussi PA. 2002. Why are sweet proteins sweet? Interaction of brazzein, monellin
and thaumatin with the T1R2-T1R3 receptor. Fed Exp Biol Soc Lett 526:1–4.
Temussi P. 2005. From oligopeptides to sweet proteins. J Pept Sci 111:262–4.
Temussi P. 2006a. The history of sweet taste: not exactly a piece of cake. J Mol Recognit
19:188–99.
Temussi PA. 2006b. Natural sweet macromolecules: how sweet proteins work. Cell Mol
Life Sci 63:1876–88.
von Rymon Lipinski GW, Hanger LY. 2001. Acesulfame-K. In: O’Brien Nabors L, editor.
Alternative sweeteners. 3rd ed., revised and expanded. New York: Marcel Dekker.
p 13–30.
Walters DE. 2002. Homology-based model of the extracellular domain of the taste re-
ceptor T1R3. Pure Appl Chem 74:1117–23.
Walters DE, Hellekant G. 2006. Interactions of the sweet protein brazzein with the
sweet taste receptor. J Agric Food Chem 54:10129–33.
Walters DE, Hinds M. 1994. Genetically evolved receptor models: a computational
approach to construction of receptor models. J Med Chem 37:2527–36.
Xu H, Staszewski L, Tang H, Adler E, Zoller M, Li X. 2004. Different functional
roles of T1R subunits in the heteromeric taste receptors. Proc Nat Acad Sci USA
10139:14258–63.
Yu L, Liang S, Liu X, He Q, Studholme DJ, Wu Q. 2004. NCD3G: a novel nine-cysteine
domain in family 3 GPCRs. Trends Biochem Sci 29:458–61.
Zhao GQ, Zhang Y, Hoon MA, Chandrashekar J, Erlenbach I, Ryba NJ, Zuker CS. 2003.
The receptors for mammalian sweet and umami taste. Cell 115:255–66.
Zhang Y, Hoon M, Chandrashekar J, Mueller KL, Cook B, Wu D, Zuker CS, Ryba NJP.
2003. Coding of sweet bitter and umami tastes: different receptor cells sharing sim-
ilar signaling pathways. Cell 112:293–301.
Zhang Y, Devries ME, Skolnick J. 2006. Structure modeling of all identified G protein–
coupled receptors in the human genome. PLoS Comput Biol 2:88–99.
Zubare-Samuelov M, Shaul ME, Peri I, Aliluiko A, Tirosh O, Naim M. 2005. Inhibition
of signal termination-related kinases by membrane-permeant bitter and sweet tas-
tants: potential role in taste signal termination. Am J Physiol Cell Physiol 289:483–
92.