Model for the sweet taste of stereoisomeric retro-inverso and dipeptide amides

Goodman, Murray; Coddington, Jan M.; Mierke, Dale F.; Fuller, Wayne A.

doi:10.1021/ja00249a040

Cited by 61 publications

(33 citation statements)

References 2 publications

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“…It is possible that optimal interaction of the pheromone with the receptor requires a long branched hydrocarbon on the cysteine sulfur and a smaller organic group on the cysteine carboxyl. Such a requirement would be similar to those models used to explain the interaction of aspartamelike sweeteners with their receptor (20). The possibility must also be considered that the requirement of hydrophobic modification of a-factor for biological activity reflects not only the specificity of the a-factor receptor of MATa cells, but also the ability of hydrophobically modified peptides to enter the plasma membranes of these cells.…”

Section: Discussionmentioning

confidence: 96%

Significance of C-terminal cysteine modifications to the biological activity of the Saccharomyces cerevisiae a-factor mating pheromone.

et al. 1991

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We have undertaken total synthesis of the Saccharomyces cerevisiae a-factor (NH2-YIIKGVFWDPAC[Sfarnesyl]-COOCH3) and several Cys-12 analogs to determine the significance of S-farnesylation and carboxyterminal methyl esterification to the biological activity of this lipopeptide mating pheromone. Replacement of either the farnesyl group or the carboxy-terminal methyl ester by a hydrogen atom resulted in marked reduction but not total loss of bioactivity as measured by a variety of assays. Moreover, both the farnesyl and methyl ester groups could be replaced by other substituents to produce biologically active analogs. The bioactivity of a-factor decreased as the number of prenyl units on the cysteine sulfur decreased from three to one, and an a-factor analog having the S-farnesyl group replaced by an S-hexadecanyl group was more active than an S-methyl a-factor analog. Thus, with two types of modifications, a-factor activity increased as the Salkyl group became bulkier and more hydrophobic. MATa cells having deletions of the a-factor structural genes (mfal mfa2 mutants) were capable of mating with either sst2 or wild-type MATa cells in the presence of exogenous a-factor, indicating that it is not absolutely essential for MATa cells to actively produce a-factor in order to mate. Various a-factor analogs were found to partially restore mating to these strains as well, and their relative activities in the mating restoration assay were similar to their activities in the other assays used in this study. Mating was not restored by addition of exogenous a-factor to a cross of a wild-type MATa strain and a MATaste6 mutant, indicating a role of the STE6 gene product in mating in addition to its secretion of a-factor.

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Section: Discussionmentioning

confidence: 96%

Significance of C-terminal cysteine modifications to the biological activity of the Saccharomyces cerevisiae a-factor mating pheromone.

et al. 1991

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“…Application of partial RI modification to the dipeptide sweeteners led to the (S,R) and (S,S) N-(L-Asp)-NЈ- [2,2,5,5-tetramethylcyclopentanyl)carbonyl]-diaminomethanes some of the sweetest pseudopeptides, 8 which were very instrumental in the development of the "L-shaped" molecular model for sweet peptidic tastants (Figure 4). 15,16 The versatile partially modified retro--inverso (PMRI) and end-group modified RI transformations were introduced initially 17 into leutinizing hormonereleasing hormone (LH-RH)-derived agonists and antagonists, 18 thyrotropin-releasing hormone (TRH), enkephalins, 19 substance P, 20 and somatostatin. 3,21 The most exciting results in these early days came from our studies on PMRI analogs of [D-Ala 2 ]-enkephalin amides.…”

Section: Early Daysmentioning

confidence: 99%

“…15,16 The reversed peptide bond is colored in red and the consequent gAla residue is highlighted in blue.…”

Section: Figurementioning

confidence: 99%

The partial retro–inverso modification: A road traveled together

Chorev

2005

Biopolymers

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“…These circumstances have stimulated the development of general models of the receptor active site [2][3][4][5][6][7][8][9][10][11][12].…”

Section: Introductionmentioning

confidence: 99%

Structural determination of the active site of a sweet protein A ¹H NMR investigation of pMNEI

Tancredi¹,

Iijima²,

Saviano³

et al. 1992

FEBS Letters

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pMNEI, a single chain sweet protein ~'¢lat~ to monellin, has been studied by means of ~H NMR at 500 MHz. A partial sequential assignment performed by means of the MCD method allowed the determination of the secondary structure of a large portion of theft-sheet of pMNEI that contains a likely 'sweet finger': the loop connecting the fl-strands from residue 59 to residue 78, corresponding to segment 16--35 of the A chain of monellin. The detailed three-dimensional structure of the loop (Tyr~.Ala6LSer~.A~p~), determined from several interresida¢ and intraresidue NOEs and subsequent energy minimization, shows that the side chains of Tyr ~ and Asp ~9 tit our model of the sweet receptor in a manner very similar to that of the side chains of Ph¢ and Asp of aspartmne.

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Model for the sweet taste of stereoisomeric retro-inverso and dipeptide amides

Cited by 61 publications

References 2 publications

Significance of C-terminal cysteine modifications to the biological activity of the Saccharomyces cerevisiae a-factor mating pheromone.

Significance of C-terminal cysteine modifications to the biological activity of the Saccharomyces cerevisiae a-factor mating pheromone.

The partial retro–inverso modification: A road traveled together

Structural determination of the active site of a sweet protein A ¹H NMR investigation of pMNEI

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Model for the sweet taste of stereoisomeric retro-inverso and dipeptide amides

Cited by 61 publications

References 2 publications

Significance of C-terminal cysteine modifications to the biological activity of the Saccharomyces cerevisiae a-factor mating pheromone.

Significance of C-terminal cysteine modifications to the biological activity of the Saccharomyces cerevisiae a-factor mating pheromone.

The partial retro–inverso modification: A road traveled together

Structural determination of the active site of a sweet protein A 1H NMR investigation of pMNEI

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Structural determination of the active site of a sweet protein A ¹H NMR investigation of pMNEI