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[Display omitted] • Protein sweeteners are healthier than synthetic ones. • Synthetic dipeptide sweeteners alter gut micro biota. • Sweeteners prevent dental caries. • Sweeteners decrease calories intake. • Aspartame metabolites lead to several drawbacks. Artificial sweeteners have become increasingly popular worldwide owing to their lower calorie content in addition to the claims of health benefits such as weight control, blood glucose level regulation in diabetics, and protection against dental caries. Nevertheless, there is still controversy regarding their safety, especially when administered over the long term, taking into account that most of the safety studies are based on animal models and only a few human studies. This review focuses on low-calorie protein/peptide sweeteners. These include artificial sweeteners, i.e. aspartame, advantame, neotame, and alitame which are synthetic, versus those of natural origin such as thaumatin, monellin, brazzein, pentadin, mabinlin, curculin, and egg white lysozyme. We conducted a systematic literature survey to ensure the accuracy of the data regarding the chemical properties, synthesis, and industrial applications. The health benefits and safety of these sweeteners in humans are presented for the first time in context to their metabolic profiles and gut interaction. [ABSTRACT FROM AUTHOR]

Abstract: Miraculin differs from other sweet-tasting proteins because it is a taste-modifier having the unusual property of modifying sourness into sweetness. Its dimer is covalently linked by an inter-chain disulphide bond, and shows its taste-modifying activity at acidic pH, with maximum at pH 3.0, while it is flat at neutral pH. Previous studies suggested the importance of two histidine residues for the taste-modifying activity of miraculin. In this work, we have conducted molecular dynamics simulations on wild type miraculin and on three mutated dimers (H29A, H59A and H29A/H59A) both at neutral and acidic pH to investigate the structural and functional role of these two His residues. Our results suggested that at acidic pH the presence of two charged His at the interface induced a structural rearrangement of the two monomers, thus leading to their relative opening and the following adaptation of their conformation to the receptor surface. On the other hand the simulations on three mutants showed that the mutated dimers had a closed form, and highlighted the important role of H29 in stabilizing/destabilizing the dimer arrangement and also a cooperative effect of the two histidines. [Copyright &y& Elsevier]

A few proteins, discovered mainly in tropical fruits, have a distinct sweet taste. These proteins have played an important role towards a molecular understanding of the mechanisms of taste. Owing to the huge difference in size, between most sweeteners and sweet proteins, it was believed that they must interact with a different receptor from that of small molecular weight sweeteners. Recent modelling studies have shown that the single sweet taste receptor has multiple active sites and that the mechanism of interaction of sweet proteins is intrinsically different from that of small sweeteners. Small molecular weight sweeteners occupy small receptor cavities inside two subdomains of the receptor, whereas sweet proteins can interact with the sweet receptor according to a mechanism called the ‘wedge model’ in which they bind to a large external cavity. This review describes these mechanisms and outlines a history of sweet proteins. [ABSTRACT FROM AUTHOR]

The mechanism of interaction of sweet proteins with the T1R2-T1R3 sweet taste receptor has not yet been elucidated. Low molecular mass sweeteners and sweet proteins interact with the same receptor, the human T1R2-T1R3 receptor. The presence on the surface of the proteins of ‘sweet fingers’, i.e. protruding features with chemical groups similar to those of low molecular mass sweeteners that can probe the active site of the receptor, would be consistent with a single mechanism for the two classes of compounds. We have synthesized three cyclic peptides corresponding to the best potential ‘sweet fingers’ of brazzein, monellin and thaumatin, the sweet proteins whose structures are well characterized. NMR data show that all three peptides have a clear tendency, in aqueous solution, to assume hairpin conformations consistent with the conformation of the same sequences in the parent proteins. The peptide corresponding to the only possible loop of brazzein, c[CFYDEKRNLQC(37–47)], exists in solution in a well ordered hairpin conformation very similar to that of the same sequence in the parent protein. However, none of the peptides has a sweet taste. This finding strongly suggests that sweet proteins recognize a binding site different from the one that binds small molecular mass sweeteners. The data of the present work support an alternative mechanism of interaction, the ‘wedge model’, recently proposed for sweet proteins [Temussi, P. A. (2002) FEBS Lett. 526, 1–3.]. [ABSTRACT FROM AUTHOR]

The mechanism by which sweet proteins elicit a response on the T1R2-T1R3 sweet taste receptor is still mostly unknown but has been so far related to the presence of “sweet fingers” on the protein surface able to interact with the same mechanism as that of low molecular mass sweeteners. In the search for the identification of sweet fingers, we have solved the solution structure of G16A MNEI, a structural mutant that shows a reduction of one order of magnitude in sweetness with respect to its parent protein, MNEI, a single-chain monellin. Comparison of the structures of wild-type monellin and its G16A mutant shows that the mutation does not affect the structure of potential glucophores but produces a distortion of the surface owing to the partial relative displacement of elements of secondary structure. These results show conclusively that sweet proteins do not possess a sweet finger and strongly support the hypothesis that the mechanism of interaction of sweet-tasting proteins with the recently identified T1R2-T1R3 GPC receptor is different from that of low molecular mass sweeteners. [Copyright &y& Elsevier]