Increased confidence of metabolite identification in high-resolution mass spectra using prior biological and chemical knowledge-based approaches

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http://eprints.org/relation/isVolatileVersionOf http://etheses.bham.ac.uk/id/document/3727 http://eprints.org/relation/ispreviewThumbnailVersionOf http://etheses.bham.ac.uk/id/document/3727 http://eprints.org/relation/isVersionOf http://etheses.bham.ac.uk/id/document/3727 archive 4031 disk0/00/00/16/22 2011-06-15 16:09:41 2019-01-23 09:54:32 2011-07-19 16:39:14 thesis show 0 Weber Ralf Johannes Maria Viant Mark University of Birmingham Increased confidence of metabolite identification in high-resolution mass spectra using prior biological and chemical knowledge-based approaches unpub QH301 10col_life Mass spectrometry-based metabolomics aims to study endogenous, low molecular weight metabolites and can be used to examine a variety of biological systems. To substantially increase the accuracy of metabolite identification and increase coverage of the metabolome detected by high-resolution (HR) mass spectrometry I developed, optimised and/or employed several analytical and bioinformatics methods. Biological samples contain thousands of metabolites that are related through specific substrate-product transformations. This prior biological knowledge together with a mass error surface, which represents the mass accuracy of peak differences within mass spectra, were employed to significantly reduce the false positive rate of metabolite identification. To maximise the sensitivity of the Thermo LTQ FT Ultra mass spectrometer, the existing direct-infusion SIM-stitching acquisition parameters (Southam et al., 2007) were reoptimised, yielding a ca. 3-fold increase in sensitivity. Finally, relative isotopic abundance measurements (RIA) using HR direct-infusion MS were characterised on the two most popular Fourier transform MS instruments (FT-ICR and Oribitrap) using the reoptimised SIM-stitching acquisition parameters. Several novel observations regarding RIA measurements were reported. Utilising these RIA characterisations within a putative metabolite identification pipeline increased the number of single true empirical formula assignments compared to using accurate mass alone. To conclude, analytical and bioinformatics methods developed in this thesis have successfully facilitated the putative identification of hundreds of metabolites in several metabolomics studies. 2011-07 2011-03 graduation eng author unchecked This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder. The Darwin Trust of Edinburgh public 213 University of Birmingham School of Biosciences d_ph other 2011-07 graduation