In contrast with genomics and proteomics, the glycoanalytical toolbox still lacks routine, generic sequencing tools with the ability to characterize all types of carbohydrates. The challenges associated with carbohydrate structure analysis can be categorized as combinatorial and isomeric. The isomeric barrier corresponds specifically to the limitations of Mass Spectrometry (MS) in terms of resolution of isomeric structures: for instance, MS can be used to distinguish between a hexose and a deoxyhexose which has a different mass, but fails to distinguish between two hexoses. The combinatorial barrier corresponds to the exponentially increasing number of potential structures going from a monosaccharide to a disaccharides and so on. It affects several aspects of the analytical work: the production of exhaustive libraries of synthetic standards is virtually impossible, as well as the constitution of libraries of reference data.<br/>From these considerations, it appears that a carbohydrate sequencing method should have two essential properties: the capability to distinguish all types of isomers present in the carbohydrate class; and a “de novo” character, i.e. a sequence identification that does not require that the said sequence had been previously documented to serve as reference.<br/>In recent years, we proposed to apply Physical Chemistry tools developed in the community of gas phase molecular spectroscopy to tackle the challenges of Glycomics. We demonstrated the vibrational ion spectroscopy in the mid-Infrared range, which is implemented by injecting a tunable IR laser inside of the ion trap analyzer of a custom mass spectrometer, is a promising candidate for carbohydrate sequencing. Firstly, we demonstrated that the coupled MS-IR diagnostic can be used to resolve all types of isomers including anomers, epimers, regio- and stereo-isomers, ring size, … Secondly, we established that the monosaccharide content and linkage of an oligosaccharide can be resolved iteratively using a minimal and accessible set of monosaccharides standards. Finally, we showcased the technical integration of the IR module in several MS-based glycomics workflows, including ESI and nanospray sources, ion mobility, liquid chromatography and tandem or multistage MS and screening.<br/>In addition to these proofs of concept, we will discuss the performances of MS-IR-based workflow for the analysis of two types of carbohydrates from natural sources: lichen polysaccharides and human serum glycoproteins.

Integrating molecular spectroscopy tools and concepts to glycomics workflows

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ACS Spring 2023

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