Distinguishing Oligosaccharide Isomers Using Far-Infrared Ion Spectroscopy: Identification of Biomarkers for Inborn Errors of Metabolism

Rianne E van Outersterp, Pieter C Kooijman, Jona Merx, Udo F H Engelke, Nematollah Omidikia, Mei-Lan H Tonneijck, Kas J Houthuijs, Giel Berden, Tessa M A Peters, Dirk J Lefeber, Michel A A P Willemsen, Jasmin Mecinović, Jeroen J Jansen, Karlien L M Coene, Ron A Wevers, Thomas J Boltje, Jos Oomens, Jonathan Martens

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Distinguishing isomeric saccharides poses a major challenge for analytical workflows based on (liquid chromatography) mass spectrometry (LC-MS). In recent years, many studies have proposed infrared ion spectroscopy as a possible solution as the orthogonal, spectroscopic characterization of mass-selected ions can often distinguish isomeric species that remain unresolved using conventional MS. However, the high conformational flexibility and extensive hydrogen bonding in saccharides cause their room-temperature fingerprint infrared spectra to have broad features that often lack diagnostic value. Here, we show that room-temperature infrared spectra of ion-complexed saccharides recorded in the previously unexplored far-infrared wavelength range (300-1000 cm-1) provide well-resolved and highly diagnostic features. We show that this enables distinction of isomeric saccharides that differ either by their composition of monosaccharide units and/or the orientation of their glycosidic linkages. We demonstrate the utility of this approach from single monosaccharides up to isomeric tetrasaccharides differing only by the configuration of a single glycosidic linkage. Furthermore, through hyphenation with hydrophilic interaction liquid chromatography, we identify oligosaccharide biomarkers in patient body fluid samples, demonstrating a generalized and highly sensitive MS-based method for the identification of saccharides found in complex sample matrices.

Original languageEnglish
JournalAnalytical Chemistry
Issue number26
Pages (from-to)9787-9796
Publication statusPublished - Jul 2023


  • Biomarkers
  • Humans
  • Ions
  • Isomerism
  • Metabolism, Inborn Errors
  • Monosaccharides
  • Oligosaccharides/chemistry
  • Spectrophotometry, Infrared


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