Sweetness and Sweeteners - American Chemical Society

Chapter 1

Sweetness and Sweeteners: What Is All the Excitement About?

Downloaded by 46.165.251.157 on April 27, 2016 | http://pubs.acs.org Publication Date: March 4, 2008 | doi: 10.1021/bk-2008-0979.ch001

Grant E. DuBois Strategic Research Department, The Coca-Cola Company, One Coca-Cola Plaza, Atlanta, GA 30301

Sweetness is a very important sensation and has been throughout human history. Sugar is the prototypical sweet stimulus and, as evidence of its historical importance, one need only consider the wars fought and people enslaved over it, as has been reviewed by Mintz. More sweeteners, principally sugar, but also syrups derived from starch, as well as at least 10 non-caloric sweeteners, are added to foods and beverages than any other ingredient type. The human attraction to sweetness is innate as has been demonstrated by Steiner in the study of newborns who clearly exhibit strong liking for sweet-tasting stimuli. 2

© 2008 American Chemical Society

Weerasinghe and DuBois; Sweetness and Sweeteners ACS Symposium Series; American Chemical Society: Washington, DC, 2008.

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Sweetness and Sweeteners The Role of the Chemist As a consequence of the importance of sweet taste in affecting human behavior as well as in the human diet, chemists have been active in elucidating the structures of naturally occurring sweeteners as well as in the discovery of synthetic sweeteners since early in the 19 century. And this work continues today as the ever-elusive goal of accurate reproduction of sugar taste in a noncaloric sweetener system has not yet been achieved. A summary of some of the major contributions by chemists in elucidation o f structures of natural sweeteners and in discovery of synthetic sweeteners is presented in Figure 1. Shown here are 10 sweet-tasting organic compounds, where the latter 9 are all used in foods and beverages today. Only the first compound, m-nitro-aniline (1), reported in 1846 by Muspratt and Hoftnann, is not a commercial sweetener. It is included here since it is the first sweet-tasting organic compound of defined structure which I have been able to find in the scientific literature. Each of the latter 9 compounds is used in sweetening foods and beverages today and some information on each of them is as follows: • Saccharin (2): The sweetness o f saccharin was discovered by Fahlbergin the laboratory of Remsen at Johns Hopkins University in 1879 and was commercialized in the U.S. as the first product of the Monsanto Chemical Company. Saccharin continues today to be an important sweetener in many foods and beverages. The discovery and development of saccharin have recently been reviewed by the author. • Glucose (3): Glucose is a carbohydrate present in many fruits and has always been a significant component of the human diet. It is also a key nutrient although most o f the glucose ingested is in the form o f starch. The chemical structure of glucose was reported by Fischer in 1891. Today, the diet o f most people contains substantial glucose present in syrups derived from com starch as well as other starch sources. • Sucrose (4): Sucrose has been known since antiquity as the sweet crystalline component of sugar cane. However, the structure elucidation of sucrose was not completed until 1926 by Haworth and Hirst. Sucrose today is produced on a very large scale with 2005 world production at ca. 145 million M T . Sucrose (aka sugar) is the "consumer's standard" as relates to sweet taste quality. • Cvclamate (5): The discovery o f cyclamate as a sweet-tasting compound was made by Sveda in the laboratory of Professor Audrieth at the University of Illinois. Cyclamate is available for food use in the sodium and calcium salt forms. Cyclamates have been widely used in foods and beverages


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Figure 1. Progress in the discovery of synthetic and natural non-caloric sweeteners.


4 in blends with other non-caloric sweeteners. The blend of cyclamate with saccharin was the enabler of the diet food and beverage industry in the 1960s. Up until that time, saccharin was the only approved non-caloric sweetener and diet foods and beverages with good taste quality were not possible. • Stevioside (6): A total of 8 sweet-tasting glycosides of an entkaurenetype diterpenoid known as steviol have been isolated from the plant stevia rebaudiana (Bertoni), indigenous to Paraguay. In the common variety of the plant, stevioside is the most abundant steviol glycoside and several groups participated in elucidation of its structure. This work was completed in 1950s and 1960s by the groups of Fletcher and Mossettig of the National Institutes of Health. The history of the structure elucidation of stevioside has been reviewed by Phillips. • Aspartame (7): Aspartame is the non-caloric sweetener of greatest commercial significance up until this time. The sweet taste of aspartame was serendipitously discovered in 1965 by Schlatter in the laboratory of Mazur of Searle Pharmaceutical Company. Aspartame is unique among non-caloric sweeteners as its metabolism leads only to natural amino acids and methanol, all of which are provided in much higher amounts on consumption of common foods. And, just as cyclamate enabled the beginning of the diet food and beverage industry in the 1960s, aspartame was the enabler of a rebirth of this industry in the 1980s, following the 1970 F D A removal of cyclamates from the US food supply and restrictions on its usage in other countries. • Acesulfame (8): Acesulfame, a sweetener related in structure to saccharin, was reported in 1973 Clauss and Jensen of Hoechst A G . Acesulfame, as its potassium salt, is commonly blended with other non-caloric sweeteners in foods and beverages. • Sucralose (9): Discovery of the substantial elevation in sweetness potency of sucrose by halogen substitution of sugar hydroxyl groups was reported in 1976 by Hough and Phadnis of the University of London. The most well known member of this structural class is sucralose. • Neotame (10): Neotame, a structural analogue of aspartame with substantially increased potency, was reported in 2000 by Nofre and Tinti of the Université Claude Bernard. It is most commonly used today in blends with carbohydrate sweeteners.


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Since the beginning of organic chemistry, chemists have discovered hundreds of synthetic and natural sweeteners with the result that today, at least 50 structural classes of sweet-tasting organic compounds are known. And since early in the 20 century, chemists have appreciated that the chemical compounds that exhibit sweet taste activity are of very diverse structure. In an effort to make sense of this diversity, chemists began to make models for the common pharmacophore that was assumed present in sweet-tasting compounds. Several of the models developed over the 20 century are illustrated in Figure 2. The earliest pharmacophore model was reported by Cohn, in 1914. He argued th

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5 that all sweet-tasting compounds possess a common glucophore. Shortly thereafter, Oertly and Myers (Stanford University), in effort to explain the substantially increased potencies of some sweeteners argued that, in addition to a glucophore, such compounds must also contain an auxogluc}* Much later, in 1967, Shallenberger and Acree (Cornell University) reported their well-known A-H/B model. They hypothesized that all sweeteners contain Η-bond donor and Η-bond acceptor groups separated by not 4.0Â. The Shallenberger/Acree model was subsequently enhanced, first, in 1972, by Kier (Northeastern University), then, in 1991, by Rohse and Belitz (Institut fiir Lebensmittelchemie der T U Mtlnchen) and, also in 1991, by Nofre and Tinti (Université Claude Bernard), to better explain the elevated sweetness potencies of many sweeteners. The Cohn, Oertly/Myers, Shallenberger/Acree, Kier, Rohse/Belitz and Nofre/Tinti models are illustrated in Figure 2. Many other chemists have been active in sweetener model development including groups led by van der Heijden (Unilever), Walters (The NutraSweet Company), Goodman (University of California, San Diego), Temussi (University of Naples) and Bassoli (University of Milan). An assumption implicit in nearly all of the models referenced above, is that sweetness is initiated following the binding of a sweetener to a single site (i.e., orthosteric site) on a single receptor. However, recent receptor/sweetener mapping studies by L i and associates (Senomyx) and by the collaborative team of the Margolskee, Max and Osman groups (Mt Sinai School of Medicine) , demonstrate that the human sweetener receptor contains at least 3 orthosteric sites and thus the A - H / B model as well as all of the common pharmacophore models, are substantial oversimplifications. And therefore at least 3, and probably more, pharmacophore models are required to characterize the relationship between chemical structure and sweet taste. The first model consistent with this logic was the Walters/Culberson Model developed for the aspartame orthosteric site. In the development of this model, only sweeteners for which there was evidence of a common binding locus were included in model development. Later, in 1995, D'Angelo and Iacobucci (The Coca-Cola Company) employed Comparative Molecular Field Analysis to enhance the Walters/Culberson Model to provide quantitative predictive power. In summary, over nearly two centuries, chemists have discovered many, many sweet-tasting organic compounds. And, over the last century, they have developed increasingly useful models that may be applied to the design of new sweeteners which better replicate the sweet taste quality of sugar than ever before. 15

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Sweetness and Sweeteners: The Role of the Biologist The science of sweet taste, and the molecules that initiate it, is no longer the exclusive domain of the chemist. Over the last two decades, biologists have




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Figure 2. Progress in the development of sweetener pharmacophore models.

1989: (Nofre & Tinti)

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8 played an ever-increasing role in understanding sweetness and how the molecules responsible for sweetness initiate their effects. And their efforts have led to some fantastic advances in understanding the pathways whereby sweeteners excite sweet-sensitive taste bud cells. Some of the most significant scientific breakthroughs are summarized in Figure 3. And in the following discussion, comment is made on these breakthroughs, nearly all of which have occurred within the last decade and with the most significant occurring just within the last 5 years. Until the late 1980s, the biochemistry of sweet taste was largely unknown. Then, evidence began to accumulate that sweetness must be G Protein-Coupled Receptor (GPCR) mediated. The discovery of gustducin, a G protein, in the Margolskee laboratory, was generally accepted as strong support for G P C R involvement in sweet taste. And throughout the 1990s, sweet taste was thought to result from activation of several GPCRs since the findings of biochemical, electrophysiological and psychophysical experiments could most easily be explained by a plurality of receptors, a topic reviewed by Faurion in 1987 and by the author in 1997. Then a breakthrough occurred dramatically improving our understanding of sweet taste. In 2001, a collaborative team from the laboratories of Zuker (University of California, San Diego) and Ryba (National Institutes of Health) reported the discovery of the rat sweetener receptor. In a functional assay, they showed that responses to many of the substances that rats generalize to sucrose taste appear to be mediated by a receptor which required the co-expression of two 7-transmembrane domain (TMD) proteins. They named these proteins T1R2 and T1R3 and speculated that they combine to form a heterodimer which is the sweetener receptor. This receptor is now commonly referred to as T1R2/T1R3. Both T1R2 and T1R3 are members of the small family of Class C GPCRs. The most studied members of the Class C GPCRs are the 8 metabotrophic glutamate (mGluR), 1 γaminobutyric acid type Β ( G A B A R ) and 1 extracellular calcium (ECR) receptors, which have been recently reviewed by Pin. The mGluRs and the ECR are believed to be homodimers and the G A B A R , a heterodimer. The rat sweetener receptor discovery was quickly followed by the report in 2002 by L i and coworkers at Senomyx of parallel findings for the human system. As in the rodent, the results were most consistent with human sweet taste initiation by the single heterodimeric receptor T1R2/T1R3. Heterologous cells (i.e., H E K 293 cells), in which both human T1R2 and human T1R3 were expressed, responded to all structural types of sweeteners tested in a manner consistent with expectation from sensory experiments. Thus, at the present time, there is a general consensus that the heterodimer T1R2/T1R3 is the sweetener receptor. Thus, all initial evidence on rat and human sweet taste was consistent with sweet taste emanating from activation of a single receptor. In 2003, however, evidence was reported by the Zuker and Ryba laboratories for a second sweetener receptor in the mouse. Their results suggested that a TlR3-only 29

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9 receptor, perhaps a homodimer, is functional in the mouse as a carbohydrateonly sweetener receptor. However, no evidence has yet been reported for such a receptor in humans or other animals. At about the same time as the pioneering work by the Zuker and Ryba laboratories, several other laboratories also identified the T1R3 component of the sweetener receptor including teams led by Alexander Bachmanov (Monell Chemical Senses Center), Marianna Max and Robert Margolskee (Mt. Sinai School of Medicine), Linda Buck (Harvard Medical School), and James Battey (National Institutes of Health). Class C GPCRs are unique in that they possess very large N-terminal Venus flytrap-like domains (VFDs). For the case of the metabotrophic glutamate receptor m G l u R l , in 2000, Kunishima and coworkers reported that its V F D closes on binding glutamate, hence the analogy to a Venus flytrap. This precedent and the fact that the sweetener receptor and the umami receptor, shown in parallel work by L i and coworkers to be the G P C R heterodimer T1R1/T1R3, contain the common subunit T1R3, lead to the expectation that sweeteners likely bind in the V F D of T1R2. Subsequent work by L i and coworkers probed the fundamental question of sweetener binding locus with the finding that, while some sweeteners do bind in the V F D of T1R2 (e.g., aspartame and neotame), at least one sweetener (i.e., cyclamate) does not, but rather binds within the 7-TMD of T1R3. The binding of cyclamate to the T M D of T1R3 was corroborated by site-directed-mutagenesis studies in the Margolskee laboratory which provided significant detail on the interactions of cyclamate with T1R3. Other work in the Margolskee laboratory on brazzein, a natural protein sweetener, showed that its locus of binding is in the cysteine-rich domain (CRD) of T1R3, a subunit of the protein which connects the V F D and T M D domains. The human sweetener receptor is the first Class C G P C R demonstrated to have multiple agonist binding loci (orthosteric sites). A topic of considerable controversy in the field of taste research has been that of taste quality coding. Taste bud cells (TBCs) are known to be innvervated by nerve fibers of three gustatory nerves, the chorda tympani, the glossopharyngeal and the suprapetrosal nerves. Each of these nerves is a bundle of many individual fibers and some have argued that taste quality is coded by a cross-fiber pattern of activity and others have argued that individual fibers are taste modality specific. Evidence for taste-modality-specific coding was first provided by electrophysiological studies in chimpanzees by Hellekant and Ninomiya. They carried out single fiber recordings and reported that some fibers responded only to sweeteners, while others responded only to bitterants leading them to conclude that taste quality is coded at the level of the T B C . In other words, they argued that individual TBCs are specific sensors for sweet, bitter, umami, sour or salty. Further convincing evidence for tastemodality-specific coding comes from recent work from the Zuker and Ryba laboratories. Early in 2003, working with P L C knockout mice, they engineered mice in which they selectively rescued P L C function in bitterreceptor expressing cells and found that these mice responded normally to 35

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Sweet-Taste Transduction:

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Effector Enzyme (PLCp ) and Ion Channel (TRPm5)


2001: Zuker & Ryba (Rat) 2002: Li (Human)

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Sweetener Receptor Mapping:

Sweet-Taste Transduction: G-Protein (Gustducin)

Multiple Loci of Sweetener Binding onTlR2/TlR3

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2004: Li (Aspartame and Cyclamate) 2004: Margolskee (Cyclamate and Brazzein) 2005: Munger (Sucrose) Sweet Taste Coding: Labeled Line to CNS 1991/1994: Hellekant & Ninomiya 2003: Zuker & Ryba Figure 3. Progress in elucidation of the biochemistry and pharmacology of sweet taste.


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bitterants but still exhibited no responses to sweet or umami stimuli. Later, working with T1R knockout mice that gave no responses to sweet or umami stimuli, they engineered mice in which human T1R2 function was added to sweet-sensitive TBCs and found that these mice responded to aspartame, a compound sweet to humans but inactive in mice. They also selectively introduced an opioid receptor into sweet-sensing TBCs and observed that these mice now responded with attraction to opioid agonists. In summary, the evidence is now convincing that taste quality is coded at the level of the T B C with a labeled line communication pathway to the CNS. The recent identification of the sweetener receptor and elucidation of the mechanism of sweet taste coding was preceded by the discovery, in the Margolskee laboratory, of gustducin, a specific G protein that mediates sweet taste, as has already been discussed. Other key elements of the sweet taste transduction cascade were also identified in the Margolskee laboratory as well as by the Zuker/Ryba team. Both groups found that phospholipase Cp2 ( P L C ) , the inositol trisphosphate (IP ) receptor (IP3R) and the transient receptor potential channel m5 (TRPm5) are key elements in sweet taste transduction. Thus, at this time, evidence exists for initiation of the human sweet taste response by activation of the single receptor T1R2/T1R3, the G protein gustducin, the affecter enzyme ( P L C ) , the 2 messenger receptor IP R and the ion channel TRPm5 in sweet-sensing TBCs. Recognition of the relatively high concentrations of non-caloric sweeteners commonly employed in foods and beverages and the fact that such lipophilic molecules are generally absorbed into cells, led to speculation by the author that some sweeteners may initiate their activity at intracellular elements of the transduction cascade. Support for this idea was provided by Nairn and associates (Hebrew University) who reported that some non-caloric sweeteners have the capability to directly activate G proteins. And further support was provided in recent work by the Nairn group in studies showing that some sweeteners (i.e., saccharin and D tryptophan) are rapidly taken up into T B C s . However, in view of the finding that every sweetener tested, activated T1R2/T1R3-receptor-expressing HEK-293 cells, while otherwise identical control cells, lacking the T1R2/T1R3 receptor, are unaffected, it remains to be demonstrated that any sweeteners do actually act at downstream elements in the sweet-sensing T B C activation cascade. Nonetheless, since Nairn and coworkers have demonstrated that small molecules are readily taken up into TBCs, it is logical to expect that some may.


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In summary, transduction of sweet taste is generally accepted as proceeding via activation of the heterodimeric sweetener receptor T1R2/T1R3 with subsequent activation of the G protein gustducin. In this generally accepted transduction pathway, the gustducin G G subunit is thought to activate P L C , thus enabling it to act on membrane phosphatidylinositol bisphosphate to produce IP , which acts at its receptor IP R on intracellular C a storage sites thus promoting C a release into the cytoplasm. And finally, C a is thought to gate the TRPm5 ion channel enabling the inward flow of N a , depolarizing the p

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12 sweet-sensing T B C and initiating the signaling to the CNS. Evidence from the Zuker/Ryba laboratories argues that this gustducin G G pathway is the only sweet taste transduction pathway since mice in which the TRPm5 gene was partially deleted were observed to lack all behavioral and nerve responses to sweeteners. Earlier work, however, reported in 2000 by Varkevisser and Kinnamon, and later by Margolskee, argues for involvement of gustducin G in sweet taste transduction. And very recent work from the Margolskee laboratory in which TRPmS gene expression in the mouse was fully blocked, continues to argue for a sweet taste transduction pathway not mediated by TRPm5. In this work, the TRPm5 knockout mice continue to exhibit weak responses to sweeteners. And, in the electrophysiological component of this work, glossopharyngeal nerve responses were observed while the chorda tympani nerve responses were not, thus suggesting that transduction pathway may vary between TBCs innervated by the two different nerve systems. Thus, at this time, while there remains a general consensus that the primary pathway for sweet taste transduction is the gustducin GpG /PLCp /IP3R/TRPm5 pathway, it appears that at least one additional pathway must exist for activation of sweetsensing TBCs. P

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What is All the Excitement About? In brief, the excitement is about the fantastic progress that has been made by biologists in understanding sweet taste and how sweet-sensitive taste bud cells initiate their communication to the CNS. It is now generally accepted that the sweet tastes of all sweeteners are mediated, or at least predominantly mediated, by a single receptor in a single subset of taste bud cells. And we know that this sweetener receptor has multiple sweetener binding sites, all of which cause the receptor to undergo activation and signaling. This receptor can now be expressed in heterologous cell systems and thus is accessible in unlimited quantities for studies that, until now, were unimaginable. Included among such studies are the following: 1) High-throughput-screening of synthetic and natural product libraries for the discovery of novel synthetic and natural non-caloric sweeteners. 2) High-throughput-screening of synthetic and natural product libraries for the discovery of novel synthetic and natural sweetness enhancers and sweetness inhibitors. 3) Mechanistic studies targeted at understanding the reasons for differences Concentration/Response functions of carbohydrate and high-potency sweeteners. 4) Mechanistic studies targeted at understanding the reasons for differences in Temporal Profiles of carbohydrate and high-potency sweeteners.


13 5) Mechanistic studies targeted at understanding the reasons for differences Adaptation behaviors of carbohydrate and high-potency sweeteners. In this symposium "Sweetness and Sweeteners", the attempt has been made to comprehensively cover the scientific advances in the field since they were covered in 1989 in a special symposium of the Agricultural & Food Chemistry Division of the American Chemical Society. In this special symposium, the papers presented have been organized into the following 7 sessions: 1) Structural Studies of the Sweetener Receptor. 2) Modeling of the Sweetener Receptor. 3) Sweet Taste Transduction. 4) Quantifying the Responses of Sweet-Sensitive Taste Bud Cells. 5) Modulation of Sweet-Sensitive Taste Bud Cell Signaling. 6) Advances in the Discovery and Commercial Development o f Synthetic Non-Caloric Sweeteners. 7) Advances in the Discovery and Commercial Development of Natural Non-Caloric Sweeteners.


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Mintz, S. W. Sweetness and Power: The Place of Sugar in Modern History; Penquin Books, New York, N Y , 1985. 2. Steiner, J. E., Olfaction and Taste XI, Proceedings of the 11 International Symposium on Olfaction and Taste and of the 27 Japanese Symposium on Taste and Smell; Kurihara, K . ; Suzuki, N . ; Ogawa, H . J., Eds., SpringerVerlag: Tokyo, 1994, pp 284-287. 3. Muspratt, J. T.; Hofmann, A . W. Ann. Chem. 1846, 57, 201-224. 4. DuBois, G. E. Sweeteners and Sugar Alternatives in Food Technology, Part II: Non-Nutritive / Low-Calorie Sweeteners: Principles and Practice; Mitchell, H . , Ed., Blackwell Publishing Ltd.: Oxford, U K , 2006, pp 103129. 5. Fischer, E. Ber. Dtsch. Chem. Ges. 1891, 24, 2683-2687. 6. Haworth, W. N.; Hirst, E. L . J. Chem. Soc. 1926, 1858-1868. 7. Audrieth, L . F.; Sveda, M. J. Org. Chem. 1944, 9, 89-101. 8. Phillips, K . C . Developments in Sweeteners-3; Grenby, T. H . , Ed., Elsevier Applied Science, 1987, pp 1-43. 9. Mazur, R. H.; Schlatter, J. M.; Goldkamp, A . H . J. Am. Chem. Soc. 1969, 91, 2684-2691. 10. Clauss, K . ; Jensen, H . Angewandte Chemie, International Edition in English, 1973, 12, 869-876. 11. Hough, L.; Phadnis, S. P. Nature, 1976, 263, 800. 12. Nofre, C.; Tinti, J.-M. Food Chemistry, 2000, 69(3), 245-257. th

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