| Title: | A covalently constrained congener of the Saccharomyces cerevisiae tridecapeptide mating pheromone is an agonist |
| Author(s): | Xue CB; Eriotou-Bargiota E; Miller D; Becker JM; Naider F; |
| Address: | "Department of Chemistry, College of Staten Island, City University of New York 10301" |
| ISSN/ISBN: | 0021-9258 (Print) 0021-9258 (Linking) |
| Abstract: | "An analog of alpha-factor, the Saccharomyces cerevisiae tridecapeptide mating pheromone (Trp-His-Trp-Leu-Gln-Leu-Lys-Pro-Gly-Gln-Pro-Met-Tyr), in which the side chains of Lys7 and Gln10 were covalently linked, was synthesized using solid phase methodologies. The yield of the purified cyclic analog cyclo7,10[Nle12]alpha-factor was 30%, and its structure was verified by amino acid analysis, peptide sequencing, fast atom bombardment-mass spectrometry, and proton nuclear magnetic resonance spectroscopy. Cyclo7,10[Nle12]alpha-factor caused growth arrest and morphological alterations in S. cerevisiae MATa cells qualitatively identical to those induced by linear pheromone and was one-fourth to one-twentieth as active as the linear alpha-factor depending upon the S. cerevisiae strain tested. Consistent with the relative activities of the linear and cyclic peptides, binding competition studies indicated that cyclo7,10[Nle12]alpha-factor had approximately 20-40-fold less affinity for the alpha-factor receptor. Hydrolysis of the cyclic peptide by the target cells did not lead to opening of the ring and was less rapid than that of linear alpha-factor. The alpha-factor antagonist des-Trp1-[Ala3,Nle12]alpha-factor reversed the activity of the cyclic analog, and cyclo7,10[Nle12]alpha-factor was not active at the restrictive temperature in a temperature-sensitive receptor mutant. These results support the conclusion that the cyclic alpha-factor occupies the same binding site within the receptor as is occupied by the natural pheromone. The cyclic alpha-factor represents a rare example of an agonist among covalently constrained congeners of small linear peptide messengers" |
| Keywords: | "Amino Acid Sequence Indicators and Reagents Mass Spectrometry Mating Factor Molecular Sequence Data Peptides/*chemical synthesis/metabolism/pharmacology Peptides, Cyclic/chemical synthesis/pharmacology Pheromones/*chemical synthesis Protein Binding Protei;" |
| Notes: | "MedlineXue, C B Eriotou-Bargiota, E Miller, D Becker, J M Naider, F eng GM-22086/GM/NIGMS NIH HHS/ GM-22087/GM/NIGMS NIH HHS/ Research Support, U.S. Gov't, P.H.S. 1989/11/15 J Biol Chem. 1989 Nov 15; 264(32):19161-8" |
