X-ray structures of new dipeptide taste ligands

Abstract

The molecular basis of sweet taste was investigated by carrying out the crystal state conformational analysis by X-ray diffraction of the following dipeptide taste ligands: N-3,3-dimethylbutyl-aspartylphenylalanine methyl ester, I (N-DMB-Asp-Phe-OMe), its sodium salt (N-DMB-Asp-Phe-ONa), II, aspartyl-D-2-aminobutyric acid-(S)-alpha-ethylbenzylamide, III (Asp-D-Abu-(S)-alpha-ethylbenzylamide), aspartyl-N'-((2,2,5,5-tetramethylcyclopentanyl)-carbonyl)-(R)- 1,1-diamino-ethane, IV (Asp-(R)-gAla-TMCP), and aspartyl-D-valine-(R)-alpha-methoxymethylbenzyl amide, V (Asp-D-Val-(R)-alpha-methoxymethylbenzylamide). With the exception of the sodium salt II, all compounds are sweet-tasting, showing in some cases considerable potency enhancement with respect to sucrose. The results of this study confirm the earlier model that an 'L-shape' molecular array is essential for eliciting sweet taste for dipeptide-like ligands. In addition, it was established that (i) substitution of the N-terminal group does not inhibit sweet taste, if its zwitterionic character is maintained; (ii) a hydrophobic group located between the stem and the base of the L-shape could be responsible for sweetness potency enhancement, as found in I, III and IV; in fact, the extraordinary potency of the N-alkylated analogue I would support a model with an additional hydrophobic binding domain above the base of the 'L'; (iii) removal of the methyl ester at the C-terminus of compound I with the salt formation gives rise to the tasteless compound II; (iv) for the first time all possible side-chain conformers (g-, g+ and t) for the N-substituted aspartyl residue were observed; and (v) a retro-inverso modification, incorporated at position 2 of the dipeptide chain, confers greater flexibility to the molecule, as demonstrated by the contemporary presence of six conformationally distinct independent molecules in the unit cell and yet sweet taste properties are maintained, as found in IV.

Active Conformations of Neotame and Other High-Potency Sweeteners

“…Goodman and co-workers have published extensively on their proposed “L-shape” conformation of aspartame, neotame, and related analogues. − Their proposal is based on NMR, X-ray crystallography, and conformational energy calculations of dipeptides and retro-inverso peptides. All three side-chain rotamers of both the aspartate and phenylalanine side chains have been observed crystallographically.…”

Structures of artificial sweeteners – cyclamic acid and sodium cyclamate with other cyclamates

“…Some research was also devoted to their solution chemistry Birch, 2002;Birch et al, 2004;Klofutar et al, 1999;Klofutar et al, 2006a,b;Rudan-Tasič et al, 2006). While there are abundant data on the crystal structures of other artificial sweeteners [saccharin (Okaya, 1969;Wardell et al, 2005), aspartame (Hatada et al, 1985), acesulfame-K (Paulus, 1975), sucralose (Kanters et al, 1988), alitame (Feinstein et al, 1991;Goodman et al, 1997), neotame (Wink et al, 1999)], the literature lacks X-ray structural data on cyclamates (Benson & Spillane, 1980;Lee, 1987;Immel, 1995;Yazicilar et al, 2002). To the best of our knowledge there is only one report on the structural investigation of a monoclinic !…”

Structure, Dynamics, and Stability of β-Cyclodextrin Inclusion Complexes of Aspartame and Neotame

“…Aspartame and, more recently, neotame have drawn attention from researchers interested in elucidating the structure−function relationship of high-intensity sweeteners ( − ). The three-dimensional structure of neotame, determined by single-crystal X-ray analysis, demonstrates that the compound exists in an L-shaped conformation, which fits the proposed model for sweetness of aspartyl-based dipeptide compounds.…”