| Title: | Photoswitchable Isoprenoid Lipids Enable Optical Control of Peptide Lipidation |
| Author(s): | Morstein J; Bader T; Cardillo AL; Schackmann J; Ashok S; Hougland JL; Hrycyna CA; Trauner DH; Distefano MD; |
| Address: | "Department of Cellular and Molecular Pharmacology and Howard Hughes Medical Institute, University of California, San Francisco, California 94158, United States. Department of Chemistry, New York University, New York, New York 10003, United States. Department of Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, United States. Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, United States. Department of Chemistry, Syracuse University, Syracuse, New York 13244, United States. Department of Biology, Syracuse University, Syracuse, New York 13244, United States. BioInspired Syracuse: Institute for Material and Living Systems, Syracuse University, Syracuse, New York 13244, United States. Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States" |
| DOI: | 10.1021/acschembio.2c00645 |
| ISSN/ISBN: | 1554-8937 (Electronic) 1554-8929 (Print) 1554-8929 (Linking) |
| Abstract: | "Photoswitchable lipids have emerged as attractive tools for the optical control of lipid bioactivity, metabolism, and biophysical properties. Their design is typically based on the incorporation of an azobenzene photoswitch into the hydrophobic lipid tail, which can be switched between its trans- and cis-form using two different wavelengths of light. While glycero- and sphingolipids have been successfully designed to be photoswitchable, isoprenoid lipids have not yet been investigated. Herein, we describe the development of photoswitchable analogs of an isoprenoid lipid and systematically assess their potential for the optical control of various steps in the isoprenylation processing pathway of CaaX proteins in Saccharomyces cerevisiae. One photoswitchable analog of farnesyl diphosphate (AzoFPP-1) allowed effective optical control of substrate prenylation by farnesyltransferase. The subsequent steps of isoprenylation processing (proteolysis by either Ste24 or Rce1 and carboxyl methylation by Ste14) were less affected by photoisomerization of the group introduced into the lipid moiety of the substrate a-factor, a mating pheromone from yeast. We assessed both proteolysis and methylation of the a-factor analogs in vitro and the bioactivity of a fully processed a-factor analog containing the photoswitch, exogenously added to cognate yeast cells. Combined, these data describe the first successful conversion of an isoprenoid lipid into a photolipid and suggest the utility of this approach for the optical control of protein prenylation" |
| Keywords: | *Saccharomyces cerevisiae/metabolism Terpenes/metabolism Farnesyltranstransferase/metabolism Peptides/chemistry Protein Prenylation Pheromones Lipids Sphingolipids/metabolism Membrane Proteins/metabolism Metalloendopeptidases/metabolism *Saccharomyces cer; |
| Notes: | "MedlineMorstein, Johannes Bader, Taysir Cardillo, Ariana L Schackmann, Julian Ashok, Sudhat Hougland, James L Hrycyna, Christine A Trauner, Dirk H Distefano, Mark D eng R01 GM132606/GM/NIGMS NIH HHS/ K00 CA253758/CA/NCI NIH HHS/ R01 NS108151/NS/NINDS NIH HHS/ Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S. 2022/10/05 ACS Chem Biol. 2022 Oct 21; 17(10):2945-2953. doi: 10.1021/acschembio.2c00645. Epub 2022 Oct 4" |
