Universität zu Köln

van Outersterp, Rianne E., Engelke, Udo F. H., Merx, Jona, Berden, Giel, Paul, Mathias, Thomulka, Thomas, Berkessel, Albrecht, Huigen, Marleen C. D. G., Kluijtmans, Leo A. J., Mecinovic, Jasmin ORCID: 0000-0002-5559-3822, Rutjes, Floris P. J. T., van Karnebeek, Clara D. M., Wevers, Ron A., Boltje, Thomas J., Coene, Karlien L. M., Martens, Jonathan and Oomens, Jos ORCID: 0000-0002-2717-1278 (2021). Metabolite Identification Using Infrared Ion Spectroscopy-Novel Biomarkers for Pyridoxine-Dependent Epilepsy. Anal. Chem., 93 (46). S. 15340 - 15349. WASHINGTON: AMER CHEMICAL SOC. ISSN 1520-6882

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Abstract

Untargeted liquid chromatography-mass spectrometry (LC-MS)-based metabolomics strategies are being increasingly applied in metabolite screening for a wide variety of medical conditions. The long-standing grand challenge in the utilization of this approach is metabolite identification-confidently determining the chemical structures of m/z-detected unknowns. Here, we use a novel workflow based on the detection of molecular features of interest by high-throughput untargeted LC-MS analysis of patient body fluids combined with targeted molecular identification of those features using infrared ion spectroscopy (IRIS), effectively providing diagnostic IR fingerprints for mass-isolated targets. A significant advantage of this approach is that in silico-predicted IR spectra of candidate chemical structures can be used to suggest the molecular structure of unknown features, thus mitigating the need for the synthesis of a broad range of physical reference standards. Pyridoxine-dependent epilepsy (PDE-ALDH7A1) is an inborn error of lysine metabolism, resulting from a mutation in the ALDH7A1 gene that leads to an accumulation of toxic levels of alpha-aminoadipic semialdehyde (alpha-AASA), piperideine-6-carboxylate (P6C), and pipecolic acid in body fluids. While alpha-AASA and P6C are known biomarkers for PDE in urine, their instability makes them poor candidates for diagnostic analysis from blood, which would be required for application in newborn screening protocols. Here, we use combined untargeted metabolomics-IRIS to identify several new biomarkers for PDE-ALDH7A1 that can be used for diagnostic analysis in urine, plasma, and cerebrospinal fluids and that are compatible with analysis in dried blood spots for newborn screening. The identification of these novel metabolites has directly provided novel insights into the pathophysiology of PDE-ALDH7A1.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code van Outersterp, Rianne E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Engelke, Udo F. H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Merx, Jona UNSPECIFIED UNSPECIFIED UNSPECIFIED Berden, Giel UNSPECIFIED UNSPECIFIED UNSPECIFIED Paul, Mathias UNSPECIFIED UNSPECIFIED UNSPECIFIED Thomulka, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Berkessel, Albrecht UNSPECIFIED UNSPECIFIED UNSPECIFIED Huigen, Marleen C. D. G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kluijtmans, Leo A. J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Mecinovic, Jasmin UNSPECIFIED orcid.org/0000-0002-5559-3822 UNSPECIFIED Rutjes, Floris P. J. T. UNSPECIFIED UNSPECIFIED UNSPECIFIED van Karnebeek, Clara D. M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Wevers, Ron A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Boltje, Thomas J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Coene, Karlien L. M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Martens, Jonathan UNSPECIFIED UNSPECIFIED UNSPECIFIED Oomens, Jos UNSPECIFIED orcid.org/0000-0002-2717-1278 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-585283
DOI:	10.1021/acs.analchem.1c02896
Journal or Publication Title:	Anal. Chem.
Volume:	93
Number:	46
Page Range:	S. 15340 - 15349
Date:	2021
Publisher:	AMER CHEMICAL SOC
Place of Publication:	WASHINGTON
ISSN:	1520-6882
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language MASS-SPECTROMETRY; HMDB; ANTIQUITIN; DATABASE Multiple languages Chemistry, Analytical Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/58528