Electron-activated dissociation for structural resolution of lipid isomers: Principles, performance, and the path to...

Area of Science:

• Analytical Chemistry
• Biochemistry
• Molecular Biology

Background:

• Lipids contain vital structural information beyond basic composition, including isomer-specific details.
• Conventional lipidomics methods struggle to resolve fine structural features like double-bond location and stereospecific numbering.
• These isomeric features are critical for cell membrane organization, signaling, and disease pathogenesis.

Purpose of the Study:

• To systematically review electron-activated dissociation (EAD) fragmentation principles for various lipid classes.
• To survey current literature on EAD's applications in structural lipidomics.
• To evaluate challenges and advancements for integrating EAD into routine lipidomics.

Main Methods:

• Detailed review of EAD fragmentation mechanisms, including low-energy electron impact excitation of ions from organics (EIEIO).
• Systematic survey of published studies utilizing EAD for lipid structural elucidation.
• Analysis of bottlenecks and recent technological advancements (instrument sensitivity, DIA, bioinformatics).

Main Results:

• EAD enables precise resolution of stereospecific numbering, double-bond position/geometry, branching, and hydroxylation in complex lipids.
• EAD provides direct, diagnostic fragment ions for comprehensive isomer identification.
• Recent advancements are addressing challenges in sensitivity, data acquisition, and automated analysis.

Conclusions:

• EAD offers powerful capabilities for isomer-resolved lipidomics, essential for understanding lipid roles in biology and disease.
• Overcoming adoption bottlenecks requires continued advancements in instrumentation and bioinformatics.
• Full integration of EAD into high-throughput lipidomics workflows is achievable and necessary.