Photoswitchable Isoprenoid Lipids Enable Optical Control of Peptide Lipidation
- Johannes MorsteinJohannes MorsteinDepartment of Cellular and Molecular Pharmacology and Howard Hughes Medical Institute, University of California, San Francisco, California 94158, United StatesDepartment of Chemistry, New York University, New York, New York 10003, United StatesMore by Johannes Morstein
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- Taysir BaderTaysir BaderDepartment of Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, United StatesMore by Taysir Bader
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- Ariana L. CardilloAriana L. CardilloDepartment of Chemistry, Purdue University, West Lafayette, Indiana 47907, United StatesMore by Ariana L. Cardillo
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- Julian SchackmannJulian SchackmannDepartment of Chemistry, New York University, New York, New York 10003, United StatesMore by Julian Schackmann
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- Sudhat AshokSudhat AshokDepartment of Chemistry, Syracuse University, Syracuse, New York 13244, United StatesMore by Sudhat Ashok
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- James L. HouglandJames L. HouglandDepartment of Chemistry, Syracuse University, Syracuse, New York 13244, United StatesDepartment of Biology, Syracuse University, Syracuse, New York 13244, United StatesBioInspired Syracuse: Institute for Material and Living Systems, Syracuse University, Syracuse, New York 13244, United StatesMore by James L. Hougland
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- Christine A. Hrycyna*Christine A. Hrycyna*[email protected]Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, United StatesMore by Christine A. Hrycyna
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- Dirk H. Trauner*Dirk H. Trauner*[email protected]Department of Chemistry, New York University, New York, New York 10003, United StatesDepartment of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United StatesMore by Dirk H. Trauner
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- Mark D. Distefano*Mark D. Distefano*[email protected]Department of Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, United StatesMore by Mark D. Distefano
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.
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