Novel modifications to the farnesyl moiety of the a-factor lipopeptide pheromone from Saccharomyces cerevisiae : a role for isoprene modifications in ligand presentation
The a-factor of Saccharomyces cerevisiae is a dodecapeptide pheromone [YIIKGVFWDPAC(farnesyl)-OCH3] in which posttranslational modification with a farnesyl isoprenoid and carboxymethyl group is required for full biological activity. Utilizing novel synthetic techniques and a well-characterized array of biological assays, we prepared original modifications to the farnesyl moiety of the pheromone in order to assess the importance of this part of the lipopeptide for biological activity. Specifically, the 3-methyl group was replaced to create analogs containing the ethyl, vinyl, tert-butyl, and phenyl moieties at the 3-position of the farnesyl chain. Subsequent biological analyses demonstrated that all of these modifications render an active pheromone, with the vinyl and ethyl analogs exhibiting higher activity than the native a-factor. However, the level of activity varied with the modification; the bulkier and more hydrophobic groups (tert-butyl and phenyl) exhibited lower biological activity than the smaller moieties (ethyl and vinyl). Furthermore, two analogs with phenyl substitutions that differ only in the presumed isomerization of the allylic double bond show up to an 8-fold difference in bioactivity. It has previously been surmised that the role of isoprenoid additions is solely to target the attached polypeptides to membranes by increasing their hydrophobicity. However, these studies demonstrate that even modest structural changes to the isoprenoid can significantly affect biological activity. These results are clearly inconsistent with a simple hydrophobic role for the isoprenoid and instead illustrate that it plays an active role in mediating optimal a-factor/receptor interaction.
| Medienart: |
Artikel |
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| Erscheinungsjahr: |
1997 |
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| Erschienen: |
1997 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:36 |
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| Enthalten in: |
Biochemistry - 36(1997), 40 vom: 07. Okt., Seite 12036-44 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Dawe, A L [VerfasserIn] |
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| Anmerkungen: |
Date Completed 23.10.1997 Date Revised 15.11.2012 published: Print Citation Status MEDLINE |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM09267299X |
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| 041 | |a eng | ||
| 100 | 1 | |a Dawe, A L |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Novel modifications to the farnesyl moiety of the a-factor lipopeptide pheromone from Saccharomyces cerevisiae |b a role for isoprene modifications in ligand presentation |
| 264 | 1 | |c 1997 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ohne Hilfsmittel zu benutzen |b n |2 rdamedia | ||
| 338 | |a Band |b nc |2 rdacarrier | ||
| 500 | |a Date Completed 23.10.1997 | ||
| 500 | |a Date Revised 15.11.2012 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a The a-factor of Saccharomyces cerevisiae is a dodecapeptide pheromone [YIIKGVFWDPAC(farnesyl)-OCH3] in which posttranslational modification with a farnesyl isoprenoid and carboxymethyl group is required for full biological activity. Utilizing novel synthetic techniques and a well-characterized array of biological assays, we prepared original modifications to the farnesyl moiety of the pheromone in order to assess the importance of this part of the lipopeptide for biological activity. Specifically, the 3-methyl group was replaced to create analogs containing the ethyl, vinyl, tert-butyl, and phenyl moieties at the 3-position of the farnesyl chain. Subsequent biological analyses demonstrated that all of these modifications render an active pheromone, with the vinyl and ethyl analogs exhibiting higher activity than the native a-factor. However, the level of activity varied with the modification; the bulkier and more hydrophobic groups (tert-butyl and phenyl) exhibited lower biological activity than the smaller moieties (ethyl and vinyl). Furthermore, two analogs with phenyl substitutions that differ only in the presumed isomerization of the allylic double bond show up to an 8-fold difference in bioactivity. It has previously been surmised that the role of isoprenoid additions is solely to target the attached polypeptides to membranes by increasing their hydrophobicity. However, these studies demonstrate that even modest structural changes to the isoprenoid can significantly affect biological activity. These results are clearly inconsistent with a simple hydrophobic role for the isoprenoid and instead illustrate that it plays an active role in mediating optimal a-factor/receptor interaction | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, U.S. Gov't, P.H.S. | |
| 650 | 7 | |a Butadienes |2 NLM | |
| 650 | 7 | |a Fungal Proteins |2 NLM | |
| 650 | 7 | |a Hemiterpenes |2 NLM | |
| 650 | 7 | |a Ligands |2 NLM | |
| 650 | 7 | |a Lipoproteins |2 NLM | |
| 650 | 7 | |a MFA2 protein, S cerevisiae |2 NLM | |
| 650 | 7 | |a Pentanes |2 NLM | |
| 650 | 7 | |a Pheromones |2 NLM | |
| 650 | 7 | |a Saccharomyces cerevisiae Proteins |2 NLM | |
| 650 | 7 | |a isoprene |2 NLM | |
| 650 | 7 | |a 0A62964IBU |2 NLM | |
| 700 | 1 | |a Becker, J M |e verfasserin |4 aut | |
| 700 | 1 | |a Jiang, Y |e verfasserin |4 aut | |
| 700 | 1 | |a Naider, F |e verfasserin |4 aut | |
| 700 | 1 | |a Eummer, J T |e verfasserin |4 aut | |
| 700 | 1 | |a Mu, Y Q |e verfasserin |4 aut | |
| 700 | 1 | |a Gibbs, R A |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Biochemistry |d 1962 |g 36(1997), 40 vom: 07. Okt., Seite 12036-44 |w (DE-627)NLM000000469 |x 1520-4995 |7 nnns |
| 773 | 1 | 8 | |g volume:36 |g year:1997 |g number:40 |g day:07 |g month:10 |g pages:12036-44 |
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