Metabolic labeling of glycerophospholipids via clickable analogs derivatized at the lipid headgroup

Abstract

Metabolic labeling, in which substrate analogs containing diminutive tags can infiltrate biosynthetic pathways and generate labeled products in cells, has led to dramatic advancements in the means by which complex biomolecules can be detected and biological processes can be elucidated. Within this realm, metabolic labeling of lipid products, particularly in a manner that is headgroup-specific, brings about a number of technical challenges including the complexity of lipid metabolic pathways as well as the simplicity of biosynthetic precursors to headgroup functionality. As such, only a handful of strategies for metabolic labeling of lipids have thus far been reported. However, these approaches provide enticing examples of how strategic modifications to substrate structures, particularly by introducing clickable moieties, can enable the hijacking of lipid biosynthesis. Furthermore, early work in this field has led to an explosion in diverse applications by which these techniques have been exploited to answer key biological questions or detect and track various lipid-containing biological entities. In this article, we review these efforts and emphasize recent advancements in the development and application of lipid metabolic labeling strategies.

Metabolomic Profiling of Plasma Reveals Differential Disease Severity Markers in COVID-19 Patients

“…These glycerophospholipids mediate signal transduction and immune activation processes in the cells. Sphingolipids regulate several processes, including growth regulation, cell migration, adhesion, apoptosis, senescence, and inflammatory responses (Matsuki et al, 2019 ; Ancajas et al, 2020 ). Thus, the differential expression of sphingolipids (see Supplementary Table 1 ) may have played a role in host immune and inflammatory responses to the COVID-19 infection/severity.…”

Tracing Lipid Metabolism by Alkyne Lipids and Mass Spectrometry: The State of the Art

“…Azido-biotin in combination with gold probes also allows for a localization of alkyne lipids by electron microscopy, offering the highest spatial resolution ( Jao et al, 2009 ; Iyoshi et al, 2014 ). These applications have recently been reviewed ( Haberkant and Holthuis, 2014 ; Kuerschner and Thiele, 2014 ; Bumpus and Baskin, 2018 ; Laguerre and Schultz, 2018 ; Ancajas et al, 2020 ). While RAMAN and MS imaging have significantly advanced in resolution, optical and electron microscopy still excel in spatial resolution by several orders of magnitude ( Berry et al, 2011 ; Wei et al, 2016 ; Jamieson et al, 2018 ; Bowman et al, 2019 ; Porta Siegel et al, 2019 ; Tuck et al, 2021 ).…”

“…Such swapping of functionalities between the click partners is readily possible, and as a component of the head group, the partially charged azide moiety often is well-tolerated by the biological apparatus. Applications of various azide-tagged head groups in studies on lipid metabolism and other topics have recently been reviewed ( Bumpus and Baskin, 2018 ; Ancajas et al, 2020 ).…”

“…Copper(I)-catalyzed azide-alkyne cycloaddition, CuAAC, can be used to detect alkynes using azides or vice versa ( Rostovtsev et al, 2002 ; Tornoe et al, 2002 ). Applying this technique to lipids, including sterols, has yielded numerous examples, where clickable lipids bearing an alkyne or azido tag were successfully used to monitor protein lipidation, protein–lipid interaction, lipid localization and metabolism, and this work has been extensively reviewed ( Haberkant and Holthuis, 2014 ; Kuerschner and Thiele, 2014 ; Jao et al, 2015 ; Bumpus and Baskin, 2018 ; Laguerre and Schultz, 2018 ; Ancajas et al, 2020 ; Schoop et al, 2021 ).…”

Development of oxaalkyne and alkyne fatty acids as novel tracers to study fatty acid beta-oxidation pathways and intermediates

“…With the advent of bioorthogonal chemistry ( 12 ) including click chemistry ( 13 ) the sensitive and specific detection of compounds containing terminal alkynes has become possible ( 14 , 15 ). Clickable lipid tracers were successfully used to monitor protein lipidation, protein-lipid interaction, lipid localization, and metabolism, and this work has been extensively reviewed ( 16 , 17 , 18 , 19 , 20 ). Importantly, alkyne lipids are amenable to various highly sensitive detection procedures including TLC and MS-based lipidomics ( 11 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ).…”