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<p>Glycosphingosines (GlycoSphs), a class of simple glycosphingolipids (GSLs), are abundant in the brain and crucial in neurodegenerative diseases. Specific GlycoSphs, including glucosyl-sphingosine (GlcSph) and galactosyl-sphingosine (GalSph), exhibit distinct biological roles due to subtle structural isomeric differences, including anomeric configurations (α, β). These variations influence solubility, membrane interactions, and pathological outcomes, with GlcSph linked to immune modulation and GalSph to neurodegeneration. Standard mass spectrometry (MS) enables rapid analysis of biochemical mixtures but lacks the capability to separate isomers. The integration of ion mobility spectrometry (IMS) with MS overcomes this limitation by providing orthogonal analyte separation based on size and shape. In particular, a high-resolution variant of IMS called cyclic IMS (cIMS) has successfully separated some stereoisomeric mixtures; however, the structural diversity of GSLs remains challenging to fully characterize due to their high degree of structural similarity among multiple stereoisomers. This study investigates the potential of crown ether non-covalent modification to enable the separation of four GlycoSph isomers (GlcSph-α, GlcSph-β, GalSph-α, and GalSph-β). Whereas cIMS analysis of all six binary mixtures without crown ether modification resulted in no observable separation after &gt;50 passes, cIMS analysis of complexes with 15-crown-5, 18-crown-6, and dibenzo-21-crown-7 resulted in varying degrees of separation for GlycoSph stereoisomer mixtures. In particular, 18-crown-6 complexation resulted in three identifiable peaks when separating the mixture of all four isomers and enabled separation of five out of six possible GlycoSph binary mixtures. This approach demonstrates promise for precise monitoring of GlycoSph isomer levels, necessary for biomarker identification and GlycoSph mechanism studies.</p> Graphical abstract <p></p>

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Noncovalent crown ether–assisted separation of stereoisomeric glycosphingosines using cyclic ion mobility spectrometry

  • 期刊论文

  • 发表日期：

    2025年10月24日

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  • Chao Pang,
  • Maria F. Castro-Gonzales,
  • Aunika E. DelHoyo,
  • Kenneth W. Lee

摘要

Glycosphingosines (GlycoSphs), a class of simple glycosphingolipids (GSLs), are abundant in the brain and crucial in neurodegenerative diseases. Specific GlycoSphs, including glucosyl-sphingosine (GlcSph) and galactosyl-sphingosine (GalSph), exhibit distinct biological roles due to subtle structural isomeric differences, including anomeric configurations (α, β). These variations influence solubility, membrane interactions, and pathological outcomes, with GlcSph linked to immune modulation and GalSph to neurodegeneration. Standard mass spectrometry (MS) enables rapid analysis of biochemical mixtures but lacks the capability to separate isomers. The integration of ion mobility spectrometry (IMS) with MS overcomes this limitation by providing orthogonal analyte separation based on size and shape. In particular, a high-resolution variant of IMS called cyclic IMS (cIMS) has successfully separated some stereoisomeric mixtures; however, the structural diversity of GSLs remains challenging to fully characterize due to their high degree of structural similarity among multiple stereoisomers. This study investigates the potential of crown ether non-covalent modification to enable the separation of four GlycoSph isomers (GlcSph-α, GlcSph-β, GalSph-α, and GalSph-β). Whereas cIMS analysis of all six binary mixtures without crown ether modification resulted in no observable separation after >50 passes, cIMS analysis of complexes with 15-crown-5, 18-crown-6, and dibenzo-21-crown-7 resulted in varying degrees of separation for GlycoSph stereoisomer mixtures. In particular, 18-crown-6 complexation resulted in three identifiable peaks when separating the mixture of all four isomers and enabled separation of five out of six possible GlycoSph binary mixtures. This approach demonstrates promise for precise monitoring of GlycoSph isomer levels, necessary for biomarker identification and GlycoSph mechanism studies.

Graphical abstract