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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 identification 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 chemoreception 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
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 carbohydrates, 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 interact 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, several 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: email@example.com).
the sweet taste produced by various ligands. The AH-B theory for 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 A, the AH-B unit on the sweet molecule (glycophore), can react with a complimentary AHB 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, perpendicular to the receptor that allows for attachment of specific sidechain 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 differences in sweetener potencies, it did not specifically require the hydrophobic component on the glycophore to trigger the transduction 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, respectively (Figure 2). This theory suggested that profound conformational 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 responsible 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 doi: 10.1111/j.1750-3841.2008.00832.x
Vol. 73, Nr. 6, 2008—JOURNAL OF FOOD SCIENCE
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R: Concise Reviews in Food Science
taste 2. sucralose. the studies by Max and others (2001). (adapted from Nofre and Tinti 1996). was the observation that most cells expressing T1R3 also express T1R2. B. The commonality shared by all of the indirect molecular models is the presence of the AH-B glycophore and. Nr. Each of the aforementioned models assumes a single sweetener orthosteric (binding) site. Cui and others 2006). neotame. Subsequently. R82 JOURNAL OF FOOD SCIENCE—Vol. monellin. thaumatin). . Zhao and others (2003) demonstrated that sweet taste (and concurrently umami taste) depended on the presence of T1Rreceptors. acesulfame-K. Because the G-protein that couples to the human T1Rs in vivo was unknown. The specific receptor within the mouse Sac locus responsible for sweet taste was isolated from circumvallate papillae of the mouse tongue. B. and G1-2 by this complex. In addition. maltose). dulcin. dulcin. it was imperative to identify the human Sac locus. However. human T1R receptors were transfected into a human embryonic kidney (HEK293) derived cell line. the chromosomal region that determines the sensing of sweet taste. Nelson and others (2001). . but not to aspartame. Sainz and others (2001) validated that not only was T1R3’s expression taste receptor cell-specific (TRC) but also alleic variation of T1R3 occurred between taster and nontaster strains of mice. galactose. 2008 . Max and others (2001) identified a previously unknown 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. sucralose. fructose. neotame. including sucrose. GA-1. recognition of several classes of sweeteners by the human T1R2/T1R3 receptor was demonstrated. Li and others (2002). Frizzled/Smoothened. To allow for a greater understanding of the human sweet receptor. indicating that T1R2 and T1R3 receptors may be able to function independently. these findings made a strong case that T1R3 was a mouse sweet taste receptor candidate. Hoon and others (1999) described a class of taste-specific mammalian GPCRs. lactose. however. however.Figure 2 --. D-tryptophan. and fungiform taste papillae. in fact. Searching the human genome for a region syntenic to the mouse Sac locus. dulcin. maltose. cyclamate. glucose. function as a heterodimer. not on the structure of the sweet receptor itself (Cui and others 2006). cyclamate. 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.R: Concise Reviews in Food Science Sweet taste review . 6. T1R3 was identified as the likely Sac candidate as it is the only such receptor in the identified syntenic region. Rat sweet taste receptors respond to glucose. and Vomeronasal type 1 receptors all involve G2 G1 G3 G4 G5 XH AH B Figure 1 --. D-trypotophan). Classes A. GPCR. Additionally. fructose. Taken together. However. foliate. saccharin. saccharin. it shares a specific polymorphism that differentiates all sweet-taster strains of mice from nontaster strains. These receptors (T1R2/T1R3) responded to sugars (sucrose. these hydrogen donor/acceptor groups have been shown to exist within 2 active sites of the sweet taste receptor (Temussi 2006a). Subsequently. More than 50% of drugs on the market regulate the activity of GPCRs (Fredholm and others 2007). The distribution of these T1R3 receptors on the tongue differed from that of the other T1R class receptors. and high potency sweeteners (acesulfame potassium. in fact. Nelson and others (2001) reported responses to sweet compounds. cells lacking either the T1R2 or T1R3 subunit proved nonresponsive. In mammals. there are 7 subfamilies of GPCRs: A. indicating that the sweet receptor may. 73. or thaumatin (Li and others 2002). Genetically modified animals not expressing T1R subunits lost both taste modalities. as sweet taste receptors for a selective class of sweet compounds. The T1R2 and T1R3 receptors are often co-expressed (as a complex) in the mammalian palate. sweet proteins (monellin. Dubois 2004). aspartame.Schematic representation of the AH-B gly. saccharin. C. and glycine. More important. Taken together. Montmayeur and others (2001) demonstrated that very diverse T1R3 expression occurred in the mouse cirumvallate. Based on changes in Ca2+ concentration. T1R2 and T1R3 knockout mice exhibited severely impaired sweet taste perception. which expresses a known Gprotein. galactose. LNB-7TM. Li and others 2002). fructose. high saccharide concentrations were still able to elicit a detectable response in both strains. more than 1 such site has been demonstrated in the human sweet taste receptor (see below. the rodent sweet taste receptor does not respond to several sweeteners that elicit responses in humans. and Zhao and others (2003) demonstrate that the T1R2/T1R3 complex is likely responsible for the reception of sweet ligands in humans.The Nofre-Tinti model for the sweet receptor cophore (adapted from Shallenberger and Acree 1967). was identified and genetically mapped (Li and others 2001). and Vomeronasal type 1. acesulfame potassium. lactose. ligands. Many receptors in the human nervous system are coupled to different classes of G-proteins. C. genetic mapping showed that T1R3 resides on the mouse Sac locus (Kitagawa and others 2001). albeit less effectively. amino acids (glycine. the Sac locus for mice.
. yet they share 7 of 9 cysteine residues. which also falls into subfamily A. and 7TMD regions of the heterodimer complex (adapted from Cui and others 2006). subsequent spectroscopic analysis confirmed that the protein was folded and capable of binding ligands. the entire crystal structure of the extracellular region of the group II mGluR subtype 3 receptor. ATD. have profound effects on research into T1R3-ligand binding. 6. The amino acid sequence of TNFR and CRDs of T1R3 share only 15% identity. has been used extensively as a template for homology modeling of different classes of GPCRs. However. Pertussis toxin. These findings will. act with GPCRs in the transduction pathway. are composed of 3 domains: a large extracellular amino terminal or “N” terminal domain. However. including the sweet receptor. indicating that the structures may have similar folding patterns. The complete crystal structure of bovine rhodopsin.Schematic representation of the hT1R2-hT1R3 sweet taste receptor. no doubt. Ozeck and others (2004) have concluded that sweet. Future studies will likely use this purification method to support or disprove current theories of T1R3 NTD ligand binding based on homology models. a cysteine-rich domain (CRD). Based on their degree of similarity in the α subunits. NTD. composed of α. 73. Interestingly. and umami receptors in HEK293 cells correlates to protein kinase phosphorylation and cyclic adenosine monophosphate (cAMP) concentrations. 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. Nr. only the T1R2 subunit is required for both ligand recognition and G-protein coupling. . However. Until recently. The CRD is composed of approximately 70 amino acids and acts as a bridge between the NTD and 7TMD (Figure 3). no crystal structure had been solved for any class C GPCR CRD. Therefore. are reported in the literature (Bissantz and others 2003. and γ subunits. Although mGluR1 exhibits only a 20% similarity to T1R receptors (Temussi 2006b). or VFTD (NTD). The NTD of mouse T1R3 was expressed and purified. was reported (Muto and others 2007). Heterotrimeric G-proteins. Cherezov and others (2007) recently reported the crystal structure of an engineered β 2 -adrenergic GCPR (β 2 AR). and umami receptor cells must be coupled to the G αi protein used in their study. replacing the same domain of the T1R3 subunit did not result in the same response. subunit plays an important role coupling to the G α15 protein in the human sweet taste receptor. β. activation of the coupled G-protein to trigger a signal cascade. These researchers note that a number of models of β 2 AR. based on the crystal structure of bovine rhodopsin. Nie and others (2006) recently reported expression and purification of functional ligand-binding domains of T1R3 taste receptors. The human sweet taste receptor is coupled to a G αi protein (Ozeck and others 2004). lack of a response to Ace-K and sucrose proved that there was no coupling of the G α15 protein (Xu and others 2004). mGluR1 homology model constructs of T1Rs appear quite frequently in the literature. Yu and others (2004) previously proposed a homology model based on the structure of the tumor necrosis factor receptor (TNFR. To date. is a known inhibitor of G αi proteins. much has been gained using the mGluR1 homolgy model. but not the T1R3. The stability of this dimeric complex is the result of disulphide bonds between cysteine residues in the large extracellular domain. and a 7 helices transmembrane domain (7TM or TMD). When HEK293 cells are treated with pertussis toxin. 5 β subunits. caution against the Figure 3 --. isolated from Bortaldella pertussis. Two classes of these G-proteins have been identified: heterotrimeric G-proteins and cytoplasmic G-proteins. the β and γ subunits are regarded as 1 combined functional subunit. the heterotrimeric G-proteins fall into 1 of 4 families (Naim and others 2006) Class C GPCRs. including the ATD. most recently. Freddolino and others 2004. 2008—JOURNAL OF FOOD SCIENCE R83 R: Concise Reviews in Food Science . The crystal structure of the NTD for the class C GPCR glutamate receptor. Cui and others 2006). bitter. CRD. However. Zhang and others 2006). mGluR1. Gouldson and others 2004. Because protein kinase phosphorylation and cAMP are 2nd messengers of many GPCRs and because treatment of HEK293 cells with pertusis toxin inhibit these signals. While better models of the receptor are still required. although both T1R2 and T1R3 subunits are necessary for binding of different sweet ligands. 28 α subunits. Stimulation of bitter. sweet. often referenced in the literature as the “Venus flytrap” domain. and 12 γ subunits have been identified. currently. Modeling the sweet taste receptor The complete crystal structure of the human T1R2–T1R3 complex has yet to be solved. the only way to examine ligand binding by this receptor is by examining homology of models. has been identified (Kunishima and others 2000). Vol. the T1R2. the signals are inhibited. Furse and Lybrand 2003. which falls into subfamily A GPCR receptors. GPCRs are coupled to a guanosine triphosphate (GTP) binding protein that acts as an intermediary between enzymes and ion channels. There are 5 crystalline structures of this homodimer known. therefore. these cysteine residues available for disulphide bonding do not exist in much more common class A GPCRs (Fredholm 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. which includes the CSD.Sweet taste review . Therefore. When the C terminus domain of the rat T1R2 subunit was substituted in place of the human C-terminus.
and hydrophobic interactions (Tyr215. Sweetener Sucrose Glucose Sucralose Saccharin Acesulfame-K Cyclamate Aspartame Neotame Binding site(s) T1R2 NTD. B chain models also had binding affinities for high molecular weight proteins in a large wedge-like cavity.R: Concise Reviews in Food Science Sweet taste review . Cui and others (2006) have suggested that a homology model of bovine rhodopsin can act as a template for the 7TMD of the human sweet taste receptor. T1R3 NTD T1R3 7TMD T1R2 NTD T1R2 NTD Open Closed Figure 4 --. whereas the mouse receptor (mT1R2-mT1R3) does not. 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). identified 6 residues in the 7TMD exclusively responsible for binding cyclamate. the TNFR. when the cyclamate-docking site was modeled. a template for the human sweet taste receptor can be approximated (Cui and others 2006). Nr. therefore. and 6-Cl-D-tryptophan. (2006).6. and Pro277). a candidate-binding site for cyclamate was identified on the human sweet receptor (Jiang and others 2005c). hydrogen bonds (Ser303. overlap was observed for the sweet taste inhibitor lactisole with the binding site (see subsequently). When a human/rat chimera composed of the human T1R2 subunit N-terminal domain and rat T1R3 subunit was used. alitame. The hT1R3 subunit was required to elicit a sweet taste receptor response. The protein mGluR1 is a dimeric receptor existing in open and closed conformations (Walters 2002). these discoveries should result in even more accurate models of these 2 regions of the human TRC in the future. T1R3 NTD T1R2 NTD. Directed mutagenesis. Binding affinities were determined using purified mouse NTD proteins for both receptor subunits. Using a homology model of the hT1R3 TMD based on the bovine rhodospin crystal structure. mixed species pairings of the 2 sweet receptor subunits were used to determine the specific cyclamate-sensitive region. T1R3 NTD T1R2 NTD. 2 water molecules are required to bridge the aspartame molecule in the binding pocket (Cui and others 2006). not that of the T1R3. the NTD of mouse T1R3 has been isolated and purified. a response to both ligands occurred. However. 2008 . use of a single structural template for homology modeling and assert that the use of a 2nd model will result in more accurate predictions. Tyr103.5. Additionally. Three primary interactions were identified between aspartame and hT1R2 NTD: salt bridges (Asp278 and Asp307). Although both subunits exhibited an affinity for these saccharides. 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. 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. or ligand binding lobes. in addition to molecular modeling. the crystal structures of the CRD of the group II mGluR subtype 3 receptor and the GCPR β 2 AR have been solved. 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. Even though a complete crystal structure of the T1R2/T1R3 receptor is not currently available. the 2 monomers. and Val384). neotame. Perhaps when lactisole is bound to the 7TMD hT1R3 subunit. is responsible for binding the sweet peptide. The Table 1 --. A binding site for small molecular weight compounds was identified in each of the 2 NTDs. Furthermore. the N-terminal extracellular domain of the human T1R2 must be responsible for binding these ligands. superaspartame. and neotame (Table 1). identified type A binding sites were able to host only 4 compounds: saccharin. By combining GPCR homology models. Using in silico modeling of the mGluR1 dimeric receptor. A Wedge site for high molecular weight proteins as well as a binding site for allosteric modulators was identified in the 7TMD. In addition. Using in silico free energy ligand binding calculations. Perhaps a homology model will be proposed 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. and SC-45647. respectively).and disaccharides (Walters 2002). both B type models had binding affinities for a much greater number of small molecular weight compounds. 6. aspartame. Furthermore. Recently. Binding sites for the saccharide sweeteners sucrose and glucose were proposed for the NTD of both T1R2 and T1R3 subunits. T1R3 NTD T1R2 NTD. . Arg383. Adapted from Bishay and “closed” conformations (adapted from Walters 2002). Polar side chains in the cleft between the monomers readily interact with hydroxyl groups on these sweeteners as well as on mono. Therefore.Summary of binding sites of nonprotein sweeteners commonly used in foods. Cui and others (2006) demonstrated a binding pocket located among TM-3. In the presence of a bound glutamate ligand. T1R3 NTD T1R2 NTD. a mechanism for binding 3 ultra-high potency sweet compounds. aspartame. assume a closed formation (Figure 4). The human receptor (hT1R2-hT1R3) responds to cyclamate. Xu and others (2004) have demonstrated that the N-terminal NTD of the T1R2 subunit. 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. The normal rat T1R2–T1R3 complex does not respond to either sweet compound. and the 7TMD of bovine rhodopsin (Cui and others 2006). R84 JOURNAL OF FOOD SCIENCE—Vol.The mGluR1 receptor protein in both “open: Preferential binding sites (agonist) are shown in bold. 73. was proposed. In contrast to the work of Walters (2002). Morini and others (2005) identified at least 4 possible binding sites for all classes of sweet compounds. cyclamate binding is not possible due to competition for the binding site. . T1R3 bound sucrose more readily whereas T1R2 bound glucose more readily (Nie and others 2005).
the same receptor binds all classes of sweet micro. monellin. Lactisole indeed inhibits both sweet and umami tastes in a dose-dependent manner in humans. termed “sweet fingers. a ligand-complexed (active) Vol. They would have to be of sufficient length to interact with the receptor. none elicited sweet taste. isolated from the African plant species Pentadiplandra brazzeana. Sweet inhibitors such as lactisole are also likely to bind to the human sweet taste receptor. a strong candidate-binding site that could stabilize the sweet receptor was the region that acts as a bridge between the T1R2 and T1R3 promoter regions. The disruptive effect of mutations in these residues was examined in HEK cells.” by definition. again calling into question the sweet fingers theory for sweet protein–receptor binding. 6. but not of sweet taste. sucrose. These 2 receptors also exist in the taste papillae of the tongue. aspartame. Koizumi and others 2007). Galindo-Cuspinera and Breslin (2006) proposed that the T1R1 (umami) and T1R2 (sweet) subunits could be modulated by the T1R3 subunit and vice versa. monellin. Tancredi and others (2004) designed several cyclic peptides corresponding to the “hairpin” structure of the secondary β-sheet loops of brazzein. Three sweet proteins of known 3-dimensional structure appear frequently in the literature: brazzein. since it has been shown that lactisole binds to the T1R3 receptor subunit.Sweet taste review . therefore. in transfected human kidney cells (Kuhn and others 2004). and thaumatin. Galindo-Cuspinera and Breslin (2006) note that. 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. they have become the only sweet fingers candidates in these proteins. in fact. Proteins are unique in their receptor interaction in that they are much larger molecules than the other ligands that bind to the receptor. Similar structures would have to be observed in different sweet proteins. T1R3 closed conformation showed brazzein to bind primarily to T1R2 with contacts to T1R3 stabilizing the activated receptor (Walters and Hellekant 2006). or that the secondary structure of the peptide lacked the order necessary to fold into a similar 3-dimensional fold as the parent protein. Koizumi and others 2007). Y65-D68. however. D307N. and thaumatin. Additionally. The sweet protein neoculin interacts with the sour taste modality (discussed subsequently. Nr. Walters and Hellekant 2006). further suggesting that they interact with saccharin and acesulfame-K. . Three-dimensional structural modeling has revealed very little similarity in the tertiary folds of the molecules (Tancredi and others 2004). hTAS2R43 and hTAS2R44. Shimizu-Ibuka and others 2006. monellin. 3. also indicating that the T1R3 subunit is responsible for binding lactisole (Jiang and others 2005b). If lactisole binds to the T1R3 subunit. 2005b. 2006a. Some sweet compounds interact with other taste modalities. These similar structures would have to exhibit a similar shape or sequence as the glycophores already identified in small sweeteners. and thaumatin. However. based on previous research. 5 Ribonucleotides prevent lactisole’s inhibition of umami taste. 2005a. monellin. to interact with the sweet receptor. 2005. It may be that an incorrect primary structure (amino acid sequence) was chosen for the peptides.and macromolecules. . One of the mutations. Of the more than 40 preferred solutions. Using the crystal structure of mGluR1 as a homology model. suggesting that 5 ribonucleotides interact with the T1R1 umami receptor but not with the T1R2 sweet receptor. These proteins have molecular weights 15 to 65 times greater than that of sucrose. 73. The only observed structural similarities occur in the secondary β-sheet loops. R: Concise Reviews in Food Science . These 2 ligands may cause bitter taste via a common mechanism that differs from other known bitter compounds. T1R3 open. even at high concentrations. suggesting that the sweet fingers model for brazzein is inaccurate. MNEI. Tancredi and others 2004. an accurate model of the sweet residues identified as candidate sweet fingers on brazzein. 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. These findings were supported by mouse/human chimeras. ShimizuIbuka and others 2006. the peptides designed for this study exhibited the same hairpin conformations as their respective parent proteins. suggests that an alternate explanation is required. The crystal homology model of the N-terminal domain of the mGlu receptor can exist in 3 forms. These researchers concluded that these peptides were. Both saccharin and acesulfame-K activate 2 bitter receptors. 2. the T1R3 subunit is required for both umami and sweet modalities. However. most centered on a large cavity of the T1R3 promoter. isolated from the African plant species Dioscorephyllum cumminsii. G16A MNEI. Spadacini and others (2003) reported an order of magnitude reduction in sweetness in a structural mutant of a single chained monellin. however. yet all 4 molecules dock to the same sweet receptor. However. Efforts to elucidate similarities in structure between the 3 sweet proteins brazzein. This rotation had a profound effect on the tertiary structure of the molecule. or a combination of the two. isolated from the African plant species Thaumatococcus daniellii (Kinghorn and Compadre 2001). and thaumatin have failed (Temussi 2005). it should inhibit both taste modalities. Temussi (2002) proposed a secondary binding site on the T1R2–T1R3 receptor that is unique to sweet proteins. 2006b. resulted in a complete loss of sweetness response when the receptor interacted with small molecular weight sweeteners (D-tryptophan. Homology modeling of the T1R2 + T1R3 complex in both the aforementioned conformation and in the T1R2 open. Esposito and others 2006. would have to meet 3 criteria: 1. the 5 ribonucleotides’ interaction with the T1R1 unami receptor must affect the interaction of lactisole–T1R3 subunit in some way. Spadacini and others 2003. Jiang and others 2005a). 2008—JOURNAL OF FOOD SCIENCE R85 Sweet protein binding: “sweet fingers” compared with the wedge model Several sweet proteins can interact with the sweet taste receptor (Temussi 2002. This suggested that the area of interaction with the sweet receptor on the protein must include more surface area than the sweet finger Y65D68 alone. as well. Using in silico 3-dimensional docking models.” may exhibit molecular structures similar to low molecular weight sweeteners and can interact with the sweet receptor. compared to its parent protein. but had no effect on the ability of the theorized sweet finger. Saccharin and acesulfame-K trigger both sweet and bitter taste modalities. Structural comparison of the G16A MNEI and its parent protein showed only a slight rotation of the β-sheets with respect to the helix. These “sweet fingers. this homology model construct considers only 1 form of the receptor (T1R2 closed. docking brazzein into the closed cleft of hT1R2 allowed identification of several residues at the mouth of the cleft that should interact with the sweet protein in the sweet fingers model. Mutations at all 4 identified points of interaction had no effect on the brazzein–receptor interaction. so they lacked the residues necessary to generate a response. Jiang and others 2004. and they were unable to elicit a sweet taste.
which activates adenyl cyclase (AC) generating cAMP The cAMP . via an ion channel. Recently. there are unique differences in the pathway of sweet taste. In the first. In addition. suggesting that. but not in response to sucrose. Two amino acid substitutions (Ala-537 and Phe-540) eliminated all response. several studies showed changes in chemicals thought to be 2nd messengers (cAMP and inositol 1. (B) A sweet protein binding to a surface site of the ligandfree form II shifts the equilibrium to favor active free form II. 73. It may be that in the presence of acid. monellin. Sweet taste transduction Transduction refers to the cascade of chemical signals occurring downstream from chemoreception that ultimately stimulates the nervous system to signal the brain of an incoming stimulus. 2008 . Both mechanisms are theorized to exist in the same TRC (Figure 6). to depolarize the taste cell via a release of Ca2+ . This would account for the protein’s taste modifying activity. ligand-free form I into the active complexed form. hamster. Depolarization then triggers neurotransmitter release. it would also exist as a mixture of these 3 forms. Neoculin elicits a sweet response in humans and also has taste-modifying activity in that it converts sour taste to sweet taste. form and 2 free forms termed Free form I and Free form II. and thaumatin fit into a large cavity of the sweet receptor with wedge-shaped surfaces of their structure. Free form II can exist in a conformation nearly identical to that of the active complex. mutations in this region could undermine the structural integrity of the sweet receptor. and thus perceived sweetness of the molecule. a saccharide sweetener activates G s via the GPCR. the nonsaccharide sweetener activates phospholipase (PLCβ2) generating IP 3 and diacylglycerol (DAG). If the T1R2–T1R3 receptor behaves like the mGlu receptor. R86 JOURNAL OF FOOD SCIENCE—Vol. Seven MNEI mutants were designed. Nr. suggested that 2 different sweet taste transduction mechanisms may exist for saccharide and nonsaccharide sweeteners. the same cysteine-rich region identified in this study has a predominant structural role in other class C receptors (Esposito and others 2006). Docking calculations show that all 3 sweet proteins brazzein. upon binding a small molecular weight ligand. mutations at the Phe-540 position reduced responses to brazzein (and monellin). that the validity of these conclusions has been called into question. The 2nd model describes a transduction pathway for nonsaccharide sweeteners. residues 536-545 in the cysteine-rich region were required for a response to brazzein. This is the 1st tertiary structure identified for a protein of this nature. whereas a greater concentration of cAMP occurs in response to sucrose (Bernhardt and others 1996). In addition. . a positive neoculin response occurred in human T1R2–human T1R3 (hT1R2-hT1R3) cells. Although transduction pathways are generally similar for all senses. Upon binding to the GPCR. If monellin indeed interacts with the wedge site of the sweet receptor. Margolskee (2002) proposed 2 models for sweet taste transduction. . (A) Binding of aspartame transforms inactive. however. whereas a negative response occurred in human T1R2–mouse T1R3 (hT1R2-mT1R3) cells. the crystal structure of the sweet heterodimeric protein neoculin. 6. sweet protein. Prior to the discovery of the sweet taste receptor. Ca2+ release causes cell depolarization and neurotransmitter release. then interacts with the T1R2–T1R3 receptor. which induce Ca2+ release from internal stores. found in the fruit of Curculigo latifolia. Long-lasting signal transmission is due to stabilization for form II by protein complexation. it offers insight into the importance of the electrostatic potential of sweet protein–receptor interactions. then acts directly. causing the lack of sweet protein response as reported by Jiang and others (2004).Possible mechanisms of sweet molecule– sweet receptor interactions (adapted from Tancredi and others 2004). the protein shifts into the open conformation. Sensory studies. Using human/mouse chimeras of the T1R3 subunit. the receptor in Free form I would stabilize to the active-conformation. although brazzein and other sweet proteins may interact with the T1R2 complex of the sweet receptor.5-triphosphate [IP 3 ]) in signal transduction pathways of TRCs in response to sweet ligands because these chemicals increase in rats. Walters and Hellekant (2006) also propose a greater likelihood that these mutations affect the conformational change required to activate downstream 2nd messengers as opposed to the actual binding of brazzein. Using human/mouse chimeras of T1R3 paired with human T1R2 (hT1R2). expressed.4. This Wedge Model is currently the most widely accepted theoretical mechanism by which proteins can activate the sweet receptor (Figure 5). Increases in IP 3 in response to nonsaccharide ligands. Therefore. Docking calculations showed that the proposed interaction surface of MNEI with the wedge site of the sweet receptor was positively charged. Kinnamon and Margolskee 1996). Electrostatic potential is important in the sweet protein–sweet receptor interaction in the Wedge Model (Esposito and others 2006). via activation of a protein kinase. was solved (Shimizu-Ibuka and others 2006). interactions with the T1R3 complex are crucial to elicit a sweet response. A far greater increase in IP 3 concentration occurs in response to the high potency sweeteners saccharin and SC-45647 than to sucrose. Koizumi and others (2007) demonstrated that the NTD of human T1R3 (hT1R3) is required for the reception of neoculin. changes in MNEI uncharged residues into either acidic or basic states would affect the surface that interacts with the sweet protein. a more direct confirmation of the validity of the Wedge Model for sweet protein–sweet receptor interaction than studies using human/mouse chimeras. or indirectly. and frog taste cells in response to a variety of sweet stimuli (Brand and Feign 1996. A Free Form I Aspartame Complexed B Free Form I Protein Free Form II Figure 5 --. and there is some debate as to the exact mechanism by which it occurs. Tancredi and others 2004).R: Concise Reviews in Food Science Sweet taste review . Jiang and others (2004) proposed an alternate binding site for sweet proteins located in the cysteine-rich region of the T1R3 receptor. Neoculin exists in pH-dependent open and closed conformations. confirm this hypothesis. and characterized with specific electrostatic changes in several neutrally charged residues. Perhaps a 2nd mechanism for sweet receptor stabilization exists via a Free form I shift to Free form II due to external binding of a macromolecule (for example. As in the 1st proposed transduction pathway. It should be noted.
suggesting possible interference with signal termination. The known sweet water-taste stimuli. however. G-protein receptor signaling is reduced as a result of phosphorylation mediated by 2 types of protein kinases: 2nd messenger-dependent protein kinases (PKA) and GPCR kinases (GRK). The mammalian transient receptor potential channel 5 (TRPM5). Changes in Ca2+ concentration in TRCs occur in response to several classes of sweeteners (Bernhardt and others 1996). Leptin. do not respond similarly to leptin. supporting the theory that this receptor regulates sweet (and/or bitter) transduction. The sweet tastants cyclamate. a cationic ion channel believed to regulate Ca2+ entry into cells. .” Water-tastes are elicited by water after the tastant chemical has been removed from the mouth. Possible allosteric modulation of the sweet receptor The possibility that the class C GPCRs function allosterically has been proposed (Pin and others 2005. a strong response occurred. Phosphorylation inhibition could delay signal termination. sodium saccharin. and acesulfame-K. Vol. 73.Schematic representation of transduction mechanisms leading to taste cell depolarization (adapted from Margolskee 2002). Interaction with protein kinases in the taste receptor might be the mechanism behind characteristic sweet and bitter aftertastes in a variety of compounds. When cells were exposed to 50 mM concentrations of the sweet compounds. a hormone released by adipose tissue. A recent hypothesis that nonsaccharide sweeteners interfere with downstream elements of the transduction pathway (ZubareSamuelov and others 2005) is supported by characteristic sweet aftertaste of many of compounds (Schiffman and others 2007). and in 2 orientations: resting “R” and active “A”. have been used to model the interaction. The NTD exists in both open and closed conformations. and neohesperidin dihydrochalcone (NHD). 6. which are deficient in the leptin receptor ObRb gene. Membrane permeability of several 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). a minimal response was observed. In mice. upon rinsing. Several downstream taste signaling molecules are coexpressed with TRPM5. when exposed to 3 mM Adenyl A enyl Cyclase GPCR ? ? ? Phospholipase GPCR ? ? ? ? cAMP DAG IP 3 Protein Kinase A Na + K+ Ca 2 Ca 2 Ca 2 Ca 2 Ca 2 Ca 2 Ca 2 K+ K+ Na + K+ Ca 2 Ion Channels Figure 6 --. this effect occurs for several gustatory sensations. .Sweet taste review . hT1R1-hT1R3 cell cultures have been used to replicate the action of rinsing with water in vitro. These observations highlight the importance of Ca2+ and ion channel regulation for transduction of sweet taste and for bitter and umami tastes as well. inhibits food intake and increases energy expenditure. and several bitter compounds. is present in TRCs (Perez and others 2002. Ca2+ and ion channels are crucial to the sweet taste transduction pathway. Different domains of the receptor exist in different conformations and may alter its activity. Sugimoto and others (2002) argued that leptin’s interaction with Ob-Rb is essential to K+ ion channel activation that inhibits sweet taste through hyperpolarization of the taste cell. Galindo-Cuspinera and others (2006) pointed to an allosteric model of the T1R1/T1R3 complex to explain the phenomenon of sweet “water-taste. leptin decreases sensitivity to sweet compounds by enhancing K+ influx into the cell limiting sweet-induced depolarization. 2008—JOURNAL OF FOOD SCIENCE R87 R: Concise Reviews in Food Science . However. Oscillations between these conformations and orientations provide potential allosteric modulation of the taste receptor in response to ligand binding. inhibited GRK-phosphorylated rhodopsin and PKA-phosphorylated casein. In the taste cells of healthy mice. To identify the mechanism for this sensation in human sweet TRCs. Genetically diabetic db/db mice. This may explain unique sweetener taste properties such as sweetener synergy and cross-adaptation (Pin and others 2005). Nr. 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). 2003). Research by Sugimoto and others (2002) further supports the importance of ion channel activity in sweet taste transduction. saccharin. Galindo-Cuspinera and others 2006).
which must be considered when evaluating the sweet taste receptor. CRD: Cysteine-rich domain of the T1R2–T1R3 receptor complex. the T1R2 subunit (Inoue and others 2004). maltose. falling into such a wide range of chemical classes. understanding advanced as to how such a variety of sweet ligands. Dulcin: p-ethoxyphenylurea. Although most transduction pathways in humans show very similar mechanisms. this begs the JOURNAL OF FOOD SCIENCE—Vol. L-proline. They concluded that sweet water-taste could be used as predictor of sweet-taste blockers such as saccharin and acesulfame-K at high concentrations.R: Concise Reviews in Food Science Sweet taste review . Cyclic adenosine monophosphate (cAMP): A 2nd messenger in signal transduction that is a derivative of ATP and is manufactured by the enzyme adenyl cyclase. the opposite effect was observed in that a strong initial response occurred followed by no after-rinsing effect. question—What impact will this knowledge have on the future of sweet taste? Will new. Early theories were inferentially based on the structure of the sweeteners. the receptor again assumes the active conformation and the sweet taste returns. GA-1: Guanidinoacetic acid 1. With the discovery of the T1R2/T1R3 receptor complex. Many strains of inbred. The crystal structure of the NTD has been solved and is often used as a homology model for the sweet receptor. 6. HEK293: A strain of Human Embroytic Kidney Cells often used for in vitro testing. hybrid high sweetener-preferring and low sweetenerpreferring and 129. which is approximately 200 times sweeter than sugar (von Rymon Lipinski and Hanger 2001). Effect of allelic variation of the T1R3 receptor Citing discrepancies between previously observed sweetener interactions in mice and rat species. at high concentrations. Lactisole: An aralkyl carboxylic acid that inhibits sweet and umami taste perception by humans but not by rats (Jiang and others 2005b). Adenyl cyclase (AC): An enzyme involved in the manufacture of cAMP . concentrations. D-phenylalanine. ATD: Amino terminal domain of the T1R2–T1R3 receptor complex. and L-proline. is a high potency sweetener approximately 200 times sweeter than sugar (Kinghorn and Compadre 2001). an attempt to design a more accurate system for measuring the sweetener response of the T1R3 subunit was undertaken by Bachmanov (2005). 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. L-glutamine). Cross adaptation: The phenomenon of adaptation to a sweetener resulting in the subsequent decreased sweet response to another sweetener (Schiffman and others 2008). Diacylglycerol (DAG): A 2nd messenger in the signal transduction pathway produced by the enzyme phopholipase. not on the receptor itself. 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). glycine. glucose. Glossary of Terms Acesulfame-K: Acesulfame potassium is the potassium salt of a dihydrooxathiazinone dioxide. making this a particularly exciting time for research in this field. Inositol 1. and SC45647. additional binding to the low-affinity site allostericallly shifts the receptor into an inactive conformation. Ligand: A molecule that binds to a receptor. namely. inhibiting sweet taste. It appears that it is only a matter of time until a complete picture of the sweet taste pathway in humans from chemoreception through transduction is realized. Further research in this field should provide food scientists with the tools necessary to meet this challenge. Although much has been gained in recent years. Aspartame: A dipeptide sweetener composed of L-aspartic acid and the methyl ester of L-phenylalanine. L-alanine. which is approximately 200 times sweeter than sugar (Butchko and others 2001). . mGluR1: A G-protein coupled glutamate receptor. acesulfame. leading the author to conclude that allelic variation of the T1R3 gene affected response to some. erythritol. the amino acids D-phenylalanine. However. sucralose. Varying responses to a variety of sweet compounds were observed among the different strains of mice. 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. 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.4. also referred to as NTD. An effect occurred in response to the sugars sucrose. Monellin: The sweet protein found in the African plant species Dioscorephyllum cumminsii ranging from 1500 to 2000 times sweeter than sugar. but not all sweeteners. indicating that many of these sweeteners interact with another taste receptor. At low concentrations. 73. as with any new research. and the artificial sweeteners saccharin. a urea derivative. therefore. discovery of the sweet taste receptor and application of homology models allow for a far greater understanding of sweet taste than was available only a few years ago. there are some mechanisms unique to the sweet receptor. T Conclusions he accepted theory of the mechanism by which the human sweet taste receptor functions has undergone many changes in recent times. these sweeteners bind preferentially to the high-affinity site. G1-2: Guanidinoacetic acid 2. Allelic differences within species can result in observable phenotypic differences in taste. Mice lacking or expressing allelic variation in the T1R3 receptor genes responded to several sweeteners (sucrose. 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 allosterically modified? How important is allelic variation? While work remains to be done. Heterodimer: A dimer composed of 2 different subunits. Brazzein: One of 2 sweet proteins found in the African plant species Pentadiplandra brazzeana ranging from 500 to 2000 times sweeter than sugar. Nr. As the compounds are washed from the low-affinity binding site. GPCR: G-protein coupled receptor. are able to bind to the same receptor. but not to the sweet amino acids glycine and L-alanine. a high potency sweetener estimated to be > 200000 sweeter than sugar when compared to 2% sucrose (Nagarajan and others 1996).B6-Sac congenic mice were used because of the genetic variations in their T1R3 alleles. a sugar alcohol. 2008 R88 . SC-45647. and fructose. . 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. Dtryptophan.5-triphosphate (IP 3 ): A 2nd messenger in signal transduction made by the enzyme phopholipase C. D-tryptophan. saccharin.
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