Metabolite Identification Using Infrared Ion Spectroscopy─Novel Biomarkers for Pyridoxine-Dependent Epilepsy.

Autor: van Outersterp RE; Institute for Molecules and Materials, FELIX Laboratory, Radboud University, Toernooiveld 7, 6525 ED Nijmegen, The Netherlands., Engelke UFH; Department of Laboratory Medicine, Translational Metabolic Laboratory, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The Netherlands., Merx J; Institute for Molecules and Materials, Synthetic Organic Chemistry, Radboud University, Heyendaalseweg 135, 6525 AJ, Nijmegen, The Netherlands., Berden G; Institute for Molecules and Materials, FELIX Laboratory, Radboud University, Toernooiveld 7, 6525 ED Nijmegen, The Netherlands., Paul M; Department of Chemistry, University of Cologne, Greinstrasse 4, 50939 Cologne, Germany., Thomulka T; Department of Chemistry, University of Cologne, Greinstrasse 4, 50939 Cologne, Germany., Berkessel A; Department of Chemistry, University of Cologne, Greinstrasse 4, 50939 Cologne, Germany., Huigen MCDG; Department of Laboratory Medicine, Translational Metabolic Laboratory, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The Netherlands., Kluijtmans LAJ; Department of Laboratory Medicine, Translational Metabolic Laboratory, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The Netherlands., Mecinović J; University of Southern Denmark, Department of Physics, Chemistry and Pharmacy, Campusvej 55, 5230 Odense, Denmark., Rutjes FPJT; Institute for Molecules and Materials, Synthetic Organic Chemistry, Radboud University, Heyendaalseweg 135, 6525 AJ, Nijmegen, The Netherlands., van Karnebeek CDM; Department of Pediatrics-Metabolic Diseases, Radboud Center for Mitochondrial Medicine, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The Netherlands., Wevers RA; Department of Laboratory Medicine, Translational Metabolic Laboratory, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The Netherlands., Boltje TJ; Institute for Molecules and Materials, Synthetic Organic Chemistry, Radboud University, Heyendaalseweg 135, 6525 AJ, Nijmegen, The Netherlands., Coene KLM; Department of Laboratory Medicine, Translational Metabolic Laboratory, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The Netherlands., Martens J; Institute for Molecules and Materials, FELIX Laboratory, Radboud University, Toernooiveld 7, 6525 ED Nijmegen, The Netherlands., Oomens J; Institute for Molecules and Materials, FELIX Laboratory, Radboud University, Toernooiveld 7, 6525 ED Nijmegen, The Netherlands.; van't Hoff Institute for Molecular Sciences, University of Amsterdam, Science Park 908, 1098XH Amsterdam, The Netherlands.
Jazyk: angličtina
Zdroj: Analytical chemistry [Anal Chem] 2021 Nov 23; Vol. 93 (46), pp. 15340-15348. Date of Electronic Publication: 2021 Nov 10.
DOI: 10.1021/acs.analchem.1c02896
Abstrakt: 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 α-aminoadipic semialdehyde (α-AASA), piperideine-6-carboxylate (P6C), and pipecolic acid in body fluids. While α-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.
Databáze: MEDLINE
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