Monatin, Its Stereoisomers and Derivatives : Modeling of the Sweet Taste Chemoreception Mechanism

The sweet natural compound monatin has two stereogenic centers, and the 2S,4S absolute configuration has been attributed previously to the natural isomer. Among the four stereoisomers of monatin, three of them, particularly the 2R,4R isomer, taste intensely sweet. The conformation of the four compounds has been studied by means of molecular modeling techniques. Both the diastereoisomeric forms show strong intramolecular hydrogen bonds which involve different functional groups and give rise to two different minimum energy conformations. The tertiary alcohol group in monatin seems to be indirectly involved in the generation of taste, acting as an important constraint in generating the active conformation. The most important glucophores have been identified as the terminal NH3+ and COO- groups and the indole ring by comparison with known topological models of sweet compounds and through the synthesis of appropriate derivatives in which some of these groups are lacking or modified. The relative affinity of each stereoisomer for its putative sweet taste receptor has been estimated semiquantitatively with the pseudoreceptor modeling technique. The predicted activity calculated with this technique is in good agreement with the experimental data and explains why the 2R,4R isomer (and not the natural 2S,4S isomer) is the swetest of the series.