Optical Control of Sphingolipid Biosynthesis Using Photoswitchable Sphingosines

Overview

Journal bioRxiv

Date 2024 Nov 1

PMID 39484495

Authors

Matthijs Kol

Alexander J E Novak

Johannes Morstein

Christian Schroer

Tolulope Sokoya

Svenja Mensing

Sergei M Korneev

Dirk Trauner

Joost C M Holthuis

Affiliations

Soon will be listed here.

Abstract

Sphingolipid metabolism comprises a complex interconnected web of enzymes, metabolites and modes of regulation that influence a wide range of cellular and physiological processes. Deciphering the biological relevance of this network is challenging as numerous intermediates of sphingolipid metabolism are short-lived molecules with often opposing biological activities. Here, we introduce clickable, azobenzene-containing sphingosines, termed s, as light-sensitive substrates for sphingolipid biosynthesis. Photo-isomerization of the azobenzene moiety enables reversible switching between a straight - and curved -form of the lipid's hydrocarbon tail. Combining enzyme assays with metabolic labeling studies, we demonstrate that -to- isomerization of s profoundly stimulates their metabolic conversion by ceramide synthases and downstream sphingomyelin synthases. These light-induced changes in sphingolipid production rates are acute, reversible, and can be implemented with great efficiency in living cells. Our findings establish s as versatile tools with unprecedented opportunities to manipulate sphingolipid biosynthesis and function with the spatiotemporal precision of light.

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