Photoswitchable Isoprenoid Lipids Enable Optical Control of Peptide Lipidation

Johannes Morstein, Taysir Bader, Ariana L. Cardillo, Julian Schackmann, Sudhat Ashok, James L. Hougland, Christine A. Hrycyna, Dirk H. Trauner, Mark D. Distefano

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


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- A nd cis-form using two different wavelengths of light. While glycero- A nd 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.

Original languageEnglish (US)
Pages (from-to)2945-2953
Number of pages9
JournalACS Chemical Biology
Issue number10
StatePublished - Oct 21 2022

Bibliographical note

Funding Information:
J.M. thanks the NCI for a K00 award (K00CA253758). J.L.H. thanks the NIH for funding (R01GM132606). D.T. thanks the National Institutes of Health for financial support (R01NS108151). M.D.D. and C.A.H. thank the National Science Foundation for funding (NSF/CHE 1905204). The authors thank Ian M. Ahearn and Mark R. Philips for their helpful comments and experimental support in the early stages of this study.

Publisher Copyright:
© 2022 American Chemical Society. All rights reserved.


  • Saccharomyces cerevisiae/metabolism
  • Terpenes/metabolism
  • Farnesyltranstransferase/metabolism
  • Peptides/chemistry
  • Protein Prenylation
  • Pheromones
  • Lipids
  • Sphingolipids/metabolism
  • Membrane Proteins/metabolism
  • Metalloendopeptidases/metabolism
  • Saccharomyces cerevisiae Proteins/metabolism

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.


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