Visible-Light Paternò–Büchi Reaction for Lipidomic Profiling at Detailed Structure Levels

The Paternò–Büchi (PB) derivatization
of carbon–carbon
double bond (CC) has been increasingly employed with tandem
mass spectrometry to analyze unsaturated lipids. It enables the discovery
of altered or uncanonical lipid desaturation metabolism, which would
be otherwise undetected by conventional methods. Although highly useful,
the reported PB reactions only provide moderate yield (∼30%).
Herein, we aim to determine the key factors that affect the PB reactions
and develop a system with improved capabilities for lipidomic analysis.
An Ir­(III) photocatalyst is chosen as the triplet energy donor for
the PB reagent under 405 nm light irradiation, while phenylglyoxalate
and its charge-tagging version, pyridylglyoxalate, are developed as
the most efficient PB reagents. The above visible-light PB reaction
system provides higher PB conversions than all previously reported
PB reactions. Around 90% conversion can be achieved at high concentrations
(>0.5 mM) for different classes of lipids but drops as the lipid
concentration
decreases. The visible-light PB reaction has then been integrated
with shotgun and liquid chromatography-based workflows. The limits
of detection for locating CC in standard lipids of glycerophospholipids
(GPLs) and triacylglycerides (TGs) are in the sub-nM to nM range.
More than 600 distinct GPLs and TGs have been profiled at the CC
location level or the sn-position level from the
total lipid extract of bovine liver, demonstrating that the developed
method is capable of large-scale lipidomic analysis.