A superactive peptidomimetic analog of a farnesylated dodecapeptide yeast pheromone.
The S. cerevisiae a-factor, YIIKGVFWDPAC(s-farnesyl)-OCH3, is one of two peptide mating pheromones which mediate cell-cell communication in S. cerevisiae. We previously reported that replacing Gly5 with D-Ala led to a 4-6 fold increase in activity while the L-Ala5 homolog was 4 to 16-fold less active than the wildtype. To clarify the structural implications of these findings, we conformationally restricted the center of the pheromone by inserting gamma-lactam constraints in place of either the Lys4Gly5 or the Gly5Val6 dipeptide unit. Incorporation of (R)-3-amino-2-oxo-1-pyrrolidineacetic acid in place of Lys4Gly5 led to a super-active agonist which exhibited a 32-fold higher bioactivity than that of the a-factor. In contrast, an analog with (S)-3-amino-2-oxo-1-pyrrolidineacetic acid in place of Gly5Val6 is about 30 to 60-fold less active than the a-factor. These data strongly suggest that the a-factor adopts a reverse turn as its bioactive conformation.
Zhang
Y L
YL
Department of Chemistry, College of Staten Island, City University of New York, New York 10314, USA.
Dawe
A L
AL
Jiang
Y
Y
Becker
J M
JM
Naider
F
F
D000595:Amino Acid Sequence; D007202:Indicators and Reagents; D007769:Lactams; D000072235:Mating Factor; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000494:pharmacology*; D010455:Peptides / Q000138:chemical synthesis* / Q000494:pharmacology*; D010675:Pheromones / Q000138:chemical synthesis / Q000494:pharmacology; D017368:Protein Prenylation; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics / Q000254:growth & development*; D013329:Structure-Activity Relationship
D007202:Indicators and Reagents; D007769:Lactams; D009842:Oligopeptides; D010455:Peptides; D010675:Pheromones; D000072235:Mating Factor