Metabolite identification using infrared ion spectroscopy

The metabolome refers to the collection of all small molecules present in an organism. It contains a plethora of information on the biomolecular processes underlying health and disease. Over the last decades, advances in analytical technologies have made it possible to detect many thousands of different metabolites in a single analysis, enabling untargeted, and potentially comprehensive, profiling of the metabolome. In particular, mass spectrometry (MS) is one of the key analytical technologies, mainly owing to its unmatched sensitivity and selectivity. However, the major limitation of MS is the limited degree of structural information obtained for detected compounds, making full identification of these compounds often challenging. Infrared ion spectroscopy (IRIS) allows one to record infrared spectra of mass-selected ions inside a mass spectrometer, providing structural information on the ions that can aid identification. This thesis describes several developments of IRIS that have contributed to its emergence as an analytical technique as well as several of its applications in metabolomics. Part A of this thesis describes technological developments required for the application of IRIS in biochemical sample analysis. Here, the focus is the coupling of IRIS with liquid chromatography to establish a generally applicable metabolite identification workflow. Part B explores applications of IRIS in the study of drug metabolism, a crucial step in drug discovery and development. We show that IRIS can identify drug metabolites resulting from common biotransformations and we evaluate turn-key table-top laser systems that pave the way towards the use of IRIS in pharmaceutical research laboratories. Part C describes the application of IRIS in the study of inborn errors of metabolism, a large and diverse group of inherited genetic disorders. We use IRIS to find novel biomarkers for these diseases, which can be used to obtain a biochemical understanding of the disease and to develop diagnostic strategies

Structural characterization of nucleotide 5-triphosphates by infrared ion spectroscopy and theoretical studies

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IRMPD Spectroscopy of Homo- and Heterochiral Asparagine Proton-Bound Dimers in the Gas Phase

[Image: see text] We investigate gas-phase structures of homo- and heterochiral asparagine proton-bound dimers with infrared multiphoton dissociation (IRMPD) spectroscopy and quantum-chemical calculations. Their IRMPD spectra are recorded at room temperature in the range of 500–1875 and 3000–3600 cm(–1). Both varieties of asparagine dimers are found to be charge-solvated based on their IRMPD spectra. The location of the principal intramolecular H-bond is discussed in light of harmonic frequency analyses using the B3LYP functional with GD3BJ empirical dispersion. Contrary to theoretical analyses, the two spectra are very similar