The Miracle Berry and Miraculin: A Review

Title: The Miracle Berry and Miraculin: A Review

Author Details: Doreen Renee Cudnik, MS, RD, LD

Purpose – The objective of this literature review is to provide an overview of the miracle berry and its unique taste-modifying glycoprotein, miraculin, with particular reference to its history, function, proposed mechanisms of action, limitations, and current and potential uses.

Design/methodology/approach – Database queries utilizing PubMed, the Web of Knowledge, Google Scholar, and Science Direct were conducted with combinations of following keywords:  miraculin, miracle berry, miracle fruit, Synsepalum dulcificum, and taste-modifier.

Findings – The miracle berry’s glycoprotein, miraculin, has a unique ability to sweeten sour tastes. Its applications are intriguing, particularly as an alternative sweetener and antioxidant, its expression in transgenic plants, and for improving the dysgeusia of chemotherapy patients.

Originality/value – To the author’s knowledge there is a deficiency of current literature reviews on the miracle berry and miraculin. Its mechanism of action and applications need to be researched to a further degree.

Keywords:  Miracle berry, Miraculin, Synsepalum dulcificum, Miracle Fruit, Taste-modifier, Glycoprotein, Chemotherapy, Antioxidants, Alternative sweetener, Transgenics

Introduction

Indigenous to the tropical rainforests of West Africa from Ghana to the Congo, the fruit of Synsepalum dulcificum—the miracle berry—transforms the taste of sour food and drink into one of remarkable sweetness (Inglett et al., 1965; Irvine, 1961). This taste-modifying sensation is due to a glycoprotein, fittingly named miraculin, found in the pulp of the miracle berry (Faus, 2000). Chewing a miracle berry coats the tongue with miraculin. The combination of an acidic/sour food or drink of less than a pH of 7 along with miraculin activates the sweet taste receptors for an approximate period of thirty minutes to two hours, lasting up to three hours in some cases (Cagan, 1973; Hellekant and van der Wel, 1989; Ito et al., 2010).

History of the Miracle Berry

The miracle berry was briefly mentioned in the literature by Chevalier des Marchais, a French explorer, who travelled to Guinea in 1725. However, it was English physician and botanist William Freeman Daniell who provided the first thorough description of this tropical berry in 1852 (Daniell, 1852). While stationed as an army surgeon in the Gold Coast (now the country of Ghana), Daniell encountered the “miraculous berry” and the West African natives who consumed it. The berry was well known to the indigenous people as assarbah, tanté, or agbayun and was sold in local markets (Inglett et al., 1965; Inglett and May, 1968). Daniell explained that in order to make some food more palatable, the natives often chewed the berry before eating strong, acidulated specialties such as kankies (sour cornbread) and drinking intensely sour palm wine and pitto (beer) (Bartoshuk et al.,1974; Inglett et al., 1965; Inglett and May, 1968).  More than a century passed before two research teams in Japan and the Netherlands independently isolated and purified the active substance that makes the berry unique: the glycoprotein miraculin (Kurihara and Beidler, 1968; Brouwer et al., 1968; Kurihara and Terasaki, 1982).

Description of the Miracle Berry

Grown on a bush (Synsepalum dulcificum), the miracle berry is approximately the size (0.75 inch) and shape (ellipsoidal) of a Spanish peanut (Bartoshuk et al., 1969; Hellekant et al., 1985). It is comprised of a thin-layered pulp over a large seed (Inglett et al., 1965). When ripe, the berry turns red likely on account of anthocyanins within the berry’s flesh (Du et al., 2014). It requires acidic soil (with a pH between 4.5 and 5.8) and frost-free growing conditions (Hiwasa-Tanasa et al., 2012). When grown from seedlings, it takes three to four years before fruiting occurs; the bush grows slowly and eventually reaches six to fifteen feet in height when fully mature (Adansi, 1970). In 1919 the miracle berry was introduced into the United States by Fairchild (1931), founder of the Fairchild Tropical Gardens in Florida.

Although it is nearly tasteless with a slight cherry-like flavor, the miracle berry alters the following taste of any sour- (essentially characterized as acidic) tasting food or drink into a perception of sweetness (Cagan, 1973; Inglett and Chen, 2011; Litt and Shiv, 2012). It modifies the overall flavor perception, for example, changing sour lemon juice into a sweet drink with a subtly altered lemon flavor. As previously stated, this taste-modifying function is due to the active substance found in the berry—miraculin.

Overview of Miraculin

Miraculin is the active component found within the thin-layered pulp of the miracle berry. Functioning as a taste-modifier, it is a glycoprotein consisting of 191 amino acid residues with two glycosylated polypeptides, Asn-42 and Asn-186, cross-linked by a disulfide bond (Theerasilp et al., 1989; Theerasilp and Kurihara, 1988; Hiwasa-Tanasa et al., 2012; Ito et al., 2007; Matsuyama et al., 2009; Paladino et al., 2008). A macromolecule with a molecular mass of 24,600, miraculin is approximately “400,000 times sweeter than sucrose on a molar basis” (Theerasilp et al., 1989; Temussi, 2006). It consists of up to 13.9% of sugars, specifically glucosamine, mannose, galactose, xylose, and fucose (Theerasilp and Kurihara, 1988; Chen et al., 2009; Takahashi et al., 1990).

Once activated by sour food or drink, miraculin displaces a portion of the acidity with sweetness. The effect is that miraculin modifies the overall flavor gustatory perception dramatically by reducing the sour acuity and augmenting the sweetness acuity, mimicking the effect of adding sugar to the acid (Diamant et al., 1972; Hellekant and van der Wel, 1989). The natural aroma and taste of the sour food or drink remain to some degree (Bartoshuk et al., 1974). It should be noted that the miracle berry does not modify bitter, salty, or other sweet tastes (Capitanio et al., 2011; Kurihara, 1992; Igarashi et al., 2013; Morris, 1976). Additionally, miraculin is deactivated by heat and high or low pH values—below pH 2 and above pH 12 (Brouwer et al., 1968; Cagan, 1973).

Hellekant et al. (1976) reported that the potency of the miraculin-induced sweetness effect is contingent upon the concentration of the miraculin along with the type of acid consumed. For example, Igarashi et al. (2013) found that, in conjunction with miraculin, citric acid is perceived twice as sweet as acetic acid, all other factors being equal. Chen et al. (2010) described that the maximum sweetness intensity produced by miraculin is equivalent to 0.3 M of sucrose.

In regard to its commencement, the taste-modifying effect begins a few seconds after consumption. In some cases, however, several minutes of chewing the berry’s pulp are necessary in order to sufficiently coat the taste buds. As far as the duration of the taste-modifying effect, the sweet sensation typically lasts thirty minutes to two hours until the miraculin is thoroughly diluted and dissociated by salivary amylase (Asakura et al., 2011; Kurihara, 1992).

It should be noted that although the taste receptors require less than 0.1 mg of miraculin to induce a sweetening effect, the duration is dose-dependent (Brouwer et al., 1983). Kurihara and Beidler (1969) demonstrated that the effect of a 2.3 µM solution of miraculin held in the mouth for five minutes lasted longer than 3 hours.

Miraculin’s Mechanism of Action

Miraculin’s specific mechanism of action remains an enigma (Gnanavel and Muthukumar, 2011; Ito et al., 2007). Typically, macromolecules do not influence taste or smell (Cagan, 1973). Anomalies exist, however, and miraculin became the first (and is still recognized as the largest) known macromolecule able to elicit a taste sensation (Kurihara, 1992; Ming, 1994).

Although speculative mechanisms have been proposed in the literature, what is known is that miraculin binds tightly to the lingual epithelium’s plasma membrane microvilli of the sweet-taste receptors (hT1R2-hT1R3) without activating them and is consequently experienced without flavor (Asakura et al., 2011; Cagan, 1973; Misaka, 2013; Montmayeur and Mantsunami, 2002). It does not activate these receptors until subjected to an acidic pH, generally between pH 3.0 and 6.0 (Kurihara, 1992; Wong and Kern, 2011; Paladino et al., 2010).

Kurihara and Beidler (1969) first proposed the theory that an acidic environment induces a dynamic conformational change to the shape of the molecule sufficiently to allow the carbohydrate portion of miraculin to stimulate the “sweet site”. Thus, only when the pH decreases within the mouth—when acidic food or drink is consumed—the miraculin changes its structure and activates the sweet-taste receptors (Misaka, 2013; Picone and Temussia, 2012).

As previously mentioned, the acidity of the food or drink still exists, but it is significantly attenuated by the sweetness perception of the activated miraculin. Food or drink that does not have acidity, therefore, is not affected. One could liken this situation to a key and lock. It is as if a key (the miraculin) does not fit all the way into a lock (the sweetness receptors). However, once the key is exposed to acidity, it transforms its shape and fits perfectly. Once unlocked, a person experiences the perception of sweetness.

Misaka (2013) postulates that miraculin pivots between its function as an agonist and an antagonist dependent upon the pH value of the consumed food or drink. When a person treats the tongue with miraculin, it binds to the sweet-taste receptors and behaves as an agonist in an acidic environment. When the receptors detect a neutral pH, miraculin—as an antagonist—inhibits the activation of the receptors.  For a period of time (typically thirty minutes to two hours), miraculin has the ability to reactivate the sweet-taste receptors whenever an acidic pH is detected.

Another theory propounded by Dzendolet (1969) suggests that miraculin blocks the sour receptor sites allowing a sweet taste to be generated by the anionic group of an acid molecule. Also, miraculin could be influencing the taste of acids primarily by causing the excitation of sites that usually mediate sweetness and not by causing any peripheral suppression of responses to acid (Bartoshuk et al., 1969). Miraculin in the presence of acid adds sweetness, while reducing sourness by mixture suppression (Danilova and Hellekant, 2005; Diamant et al., 1972).

Limitations

For a period of time, sour food or drink is perceived sweetly whether or not a person desires this for all that is ingested. As an example, when eating a mixed meal, a grapefruit would be very pleasant, but pickled vegetables, for instance, may not taste particularly appetizing with a sweet overtone. In fact many sour tastes are desirable (Breslin and Spector, 2009). After application of miraculin, for instance, a sour green apple may no longer taste refreshing; it may taste too—almost artificially—sweet as reported in experiments conducted by Litt and Shiv (2012). Essentially, affecting the overall flavor may not always be enjoyable.

One of the largest obstacles lies in the miracle berry’s availability. It not sold within a mass distribution retail chain (e.g., grocery stores) (Kant, 2005). As stated before, the miracle berry is only grown under specific conditions. It is not widely found in nature and not readily available to consumers at this time.

Another weakness of the miracle berry is that it is delicate to an extent. Miraculin is thermolabile and is inactivated below pH 3 and above pH 12 (Inglett et al., 1965; Kurihara, 1992). The protein backbone of miraculin is evidently important as proteolytic modification leads to loss in activity (Swenberg and Henkin, 1975). While the deactivation of miraculin from intense pH values would not be a normal issue, the deactivation from heating can be more of a common problem: for instance, the miracle berry cannot be used in cooking or in processed foods.  Moreover, the miracle berry is also delicate due its short shelf life, and is spoiled in about two days (Witty, 1998). Despite this deficiency, potential preservation techniques are being researched—utilizing a coating of the polysaccharide chitosan (Liu et al., 2011). Currently, the miracle berry can be stored at -20° F for approximately three months before use without concern (Hellekant et al., 1985).

Regulatory Issues

Miraculin faces regulatory impedance from the U.S. Food and Drug Administration (FDA) and the European Union where it has not been yet legally recognized as a food additive. It however, has been recognized by Japan’s Ministry of Health and Welfare (Izawa et al., 2010).

In the late 1960s, a Massachusetts-based company—the Miralin Corporation—was formed and established large-scale plantations of Synsepalum dulcificum in the West Indies and Brazil, developing new hybrids and propagation techniques (Tripp, 1985). They began tentatively to introduce an extract in tablet form called miracle fruit concentrate (MFC) consisting of a partially purified extract containing hydrolyzed cereal solids and a Miracle Fruit Drop (Dastoli and Harvey, 1974; Inglett, 1976). Special diets and menus were developed incorporating MFC as an aid to reduce caloric intake. Despite fairly extensive toxicological evaluation and considerable investment (at least $5 million), the extract did not meet with approval of the FDA who, in 1974, issued a regulatory letter requesting the company to cease “interstate shipments”. The company was liquidated in 1976, and in May 1977, all products of Synsepalum dulcificum were finally denied food additive status (Gibbs, et al., 1996). Sun et al. (2007) report “BioResources International, Inc. (Somerset, NJ, USA) is currently undertaking the commercial development of miraculin for use as a taste masking agent, low-calorie sweetener and flavor enhancer”.

It should be recognized, however, that “there is a fundamental difference between miraculin and food additives because it is not necessary to add miraculin to the food itself” (Bartoshuk et al., 1974). Unlike the FDA, the U.S. Department of Agriculture (USDA) does not have any restrictions on the miracle berry. Growing, selling, and eating miracle berries in the United States is not illegal (Sun et al., 2007).

Relevance

Science has apparently limitless new avenues of research into, for example, the miracle berry’s botany, horticulture, and miraculin’s biochemistry, physiology, and chemical structure-taste relationships, among others. Nevertheless, the miracle berry and miraculin will ultimately stand or fail on the criteria of practicality and usefulness, however academically interesting it may be (Hiwasa-Tanasa et al., 2012). Fortunately, there appears to be a variety of uses. Although it is generally recognized as more of a novelty food item, the miracle berry may provide certain health benefits.

Humans readily crave and ingest sweet-tasting foods, and miraculin may be a healthier alternative to some of the more traditional sweeteners, such as table sugar—sucrose (Breslin and Spector, 2008). Calorically negligible, 100 µg of miraculin is sufficient to provide a long-lasting sweetening effect, and the active ingredient is present in only very low concentration in the miracle berry (Misaka, 2013). “400,000 times sweeter than sucrose on a molar basis”, miraculin provides many times its own weight in sucrose-equivalent sweetness (Izawa et al., 2010; Theerasilp et al., 1989). Because miraculin can be used in minute amounts, it is not a contributing factor in tooth decay (Faus, 2000). The sweetening effect of miraculin could be useful in general, but particularly for chewing gums, mouthwashes, et cetera (Giroux and Henkin, 1974).

Additionally, miraculin has a very similar sweetening effect when compared with sucrose in controlled experiments (Brouwer et al., 1983; Hellekant and van der Wel, 1985; Yamamoto et al., 2006). Participants stated that they could not detect a taste distinction between the two, and, unlike sucrose, miraculin neither induced a subsequent craving for sucrose nor triggered a demand for insulin (Wong and Kern, 2011; Faus and Sisniega, 2003; Gnanavel and Muthukumar, 2011).  Chen et al. (2006) conducted a prospective study that demonstrated miraculin improved insulin sensitivity in rats approximately 18.1% ± 2.1% vs. 18.5% ± 2.3%. “Statistical differences among groups were determined using two-way repeated-measures ANOVA”. Consequently, people who suffer from obesity and diabetes may find miraculin very useful for limiting sugar intake (Kant, 2005). In addition to its potential as an alternative sugar, the miracle berry may be a healthy fruit in its own right, namely for its antioxidant properties.

A study published in 2011 examined the antioxidant properties of the miracle berry (Inglett and Chen, 2011). In regard to flavonoid and phenolic content, the results suggest that the skin, pulp, and seed of the miracle berry exhibit valuable antioxidant activity. A 2014 study presented similar results, but demonstrated that the highest concentrations of antioxidant-rich phytochemicals are found within the miracle berry’s flesh. Even more intriguing is that the miracle berry contains substantially larger quantities of ascorbic acid and several significant (and relatively rare) phenolics when compared with other commonly-known antioxidant-rich berries, such as, blueberries, blackberries, cranberries, red raspberries, and strawberries (Du et al., 2014). Although the antioxidant properties of the miracle berry are notable, its potential for helping chemotherapy patients is of great significance.

The miracle berry can significantly benefit chemotherapy and radiation patients who often experience taste alterations (dysgeusia) or taste reductions (asgeusia). Spielman (1998) explains “as a consequence of ionizing radiation, there are changes in the salivary flow rate and in the composition, oral bacterial flora, and turnover rate of taste cells”.  Serving as a flavor enhancer, it has the ability to restore the appetite of cancer patients whose chemotherapy treatments leave an unpleasant, noxious metallic taste in the mouth for which no standard remedy exists (Peregrin, 2009). Food aversions caused by uncommon or poor tastes is experienced in over 50 percent of chemotherapy patients (Berteretche et al., 2004); this may lead to unfavorable developments involving nutrient intakes, reaction to treatment, and general well-being (Wilken and Satiroff, 2012; Comeau et al., 2009).

In 2008 Soares et al. completed a trial with oncology patients drawn from the Mount Sinai Medical Center in Miami, Florida. The authors led a randomized crossover pilot study of 23 participants in order to determine if the miracle berry improves dysgeusia (Peregrin, 2009; Soares et al., 2010). The miracle berries were obtained from a botanical garden in Miami and stored under proper temperature conditions. 87% of the participants experienced dysgeusia and 78% experienced no taste at all. After using the miracle berry, 30% experienced improvements in taste.

Another pilot study was conducted by Wilken and Satiroff (2012) with patients from a Nebraska oncology clinic. This crossover study consisted of randomly selected chemotherapy patients (n=8). Taste improvements were recorded for all participants after consumption of the miracle berry. Despite the positive results, larger confirmatory research is warranted due to the low sample sizes. Although the miracle berry may be important in regard to its health benefits, it requires greater accessibility in the future.

Transgenics

Despite miraculin’s intrinsic stability, the miracle berry is limited mainly by its availability and perishability (Gibbs et al., 1996). Thus, alternative means to provide a supply is required. Due to its protein nature, endeavors to produce recombinant miraculin are underway using transgenic plants in Japan (Hirai et al., 2010; Kato et al., 2011; Wooding et al., 2004).

Genetically modified Escherichia coli, Aspergillus oryzae, and tobacco plants, have been unsuccessful in expressing active miraculin. In 2006 Japanese biotechnologists reported that they had succeeded in expressing recombinant miraculin in transgenic lettuce that exhibited activity (Duhita et al., 2011; Ito et al., 2007; Kurihara and Nirasawa, 1997). Since that time, recombinant miraculin has also been successfully expressed in transgenic strawberries and transgenic tomatoes (Sun et al., 2007).

Unlike the miracle berry, these plants are readily harvested in more temperate regions and substantial yields of miraculin can be obtained (Duhita et al., 2011). Transgenic tomatoes are the best of the three because transgenic tomatoes yield higher levels of recombinant miraculin when compared with transgenic strawberries and gene silencing from generation to generation was not an issue as it was with transgenic lettuce (Sugaya et al., 2008; Sun et al. 2006; Yano et al. 2010; Kato et al., 2010).  In fact, transgenic tomatoes can attain higher levels of miraculin per gram of fresh weight than the miracle berry itself (Chen et al., 2009; Kurokawa et al., 2013). Moreover, miraculin expressed in transgenic tomatoes appears to be more stable due to the acidic environment of the tomato (Duhita et al., 2011; Gancedo and Luh, 1986; Theerasilp and Kurihara, 1988).  Further studies will assess “toxicity, allergenicity, digestibility, thermal stability, insertion position in the host genome, and processing status” (Hiwasa-Tanasa et al., 2012).

Conclusion

The miracle berry with its glycoprotein, miraculin, is very unique. It has the potential to improve health and modulate disease as a result of its flavor modifying property, namely, the conversion of sour to sweet. The mechanism of action is still not well understood, and small subject sample size in clinical trials is a shortcoming. Nonetheless, its potential is promising as an alternative sugar, as an antioxidant, and for improving dysgeusia in chemotherapy patients. The miracle berry is limited by availability and perishability, so researchers are producing recombinant miraculin in transgenic plants, notably tomatoes. Further research into the mechanisms of action, its potential uses, and production or availability is required. Interest is growing in the miracle berry and deservedly so, and its future holds great promise.

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