Photoswitchable Isoprenoid Lipids Enable Optical Control of Peptide Lipidation

Area of Science:

• Biochemistry
• Chemical Biology
• Molecular Biology

Background:

• Photoswitchable lipids offer optical control over lipid properties and functions.
• Isoprenoid lipids are crucial in biological processes but lack photoswitchable analogs.
• Protein prenylation is a key post-translational modification involving isoprenoid lipids.

Purpose of the Study:

• To develop photoswitchable isoprenoid lipid analogs.
• To investigate their utility in controlling the isoprenylation pathway of CaaX proteins in Saccharomyces cerevisiae.
• To assess the impact of photoswitching on prenylation, proteolysis, and methylation.

Main Methods:

• Synthesis of photoswitchable isoprenoid lipid analogs, including AzoFPP-1.
• In vitro assays to evaluate enzyme activity (farnesyltransferase, Ste24, Rce1, Ste14).
• Analysis of substrate (a-factor) processing and bioactivity in yeast cells.

Main Results:

• AzoFPP-1 effectively enabled optical control of substrate prenylation by farnesyltransferase.
• Subsequent processing steps (proteolysis and methylation) were less sensitive to photoswitching.
• The study demonstrated the first successful creation of a photoswitchable isoprenoid lipid.

Conclusions:

• Photoswitchable isoprenoid lipids can be synthesized and utilized for optical control of prenylation.
• This approach provides a novel tool for investigating and manipulating lipid-dependent biological pathways.
• The findings open avenues for optogenetic control of protein prenylation and related cellular processes.