Ionizable isotopic labeling reagents for relative quantification of metabolites by LC-MS

ANYL 192

Brian L. Frey, bfrey@chem.wisc.edu1, Michael R Shortreed2, Shane M. Lamos1, Margaret F. Philips1, Peter J Belshaw1, and Lloyd M. Smith2. (1) Department of Chemistry, University of Wisconsin - Madison, 1101 University Avenue, Madison, WI 53706, (2) Department of Chemistry, University of Wisconsin-Madison, 1101 University Avenue, Madison, WI 53706
Comprehensive analyses of small molecule metabolites can provide important insight into biological systems. The desired outcomes of such metabolomics studies are the detection, identification, and precise quantification of a large number of metabolites with diverse chemical structures and broad concentration ranges. A precise quantitative comparison of many analytes between two or more samples is readily accomplished by employing a chemically identical but isotopically distinct labeling reagent for each sample. After the labeling reactions, the samples are mixed and then analyzed by LC-MS. This approach has been widely used in proteomics (e.g. isotope-coded affinity tags), but it has seen minimal use in metabolomics, partly due to the lack of a common functional group present in all metabolites to act as the target for the labeling chemistry. We envision a small set of labeling reagents that target the most prevalent functional groups in the metabolome. Here, we report some examples of such labeling reagents, two for amine-containing metabolites and one for carboxylic acids. The reagents require minimal cleanup after the labeling reaction, have limited impact on LC retention time, and enhance sensitivity in positive-mode electrospray ionization mass spectrometry. We describe the synthesis and use of heavy and light isotopic forms of these reagents for relative quantification in metabolomics experiments involving Arabidopsis thaliana.