title: Power of isotopic fine structure for unambiguous determination of metabolite elemental compositions: in silico evaluation and metabolomic application.
abstract: In mass spectrometry (MS)-based metabolomics studies, reference-free identification of metabolites is still a challenging issue. Previously, we demonstrated that the elemental composition (EC) of metabolites could be unambiguously determined using isotopic fine structure, observed by ultrahigh resolution MS, which provided the relative isotopic abundance (RIA) of (13)C, (15)N, (18)O, and (34)S. Herein, we evaluated the efficacy of the RIA for determining ECs based on the MS peaks of 20,258 known metabolites. The metabolites were simulated with a ≤25% error in the isotopic peak area to investigate how the error size effect affected the rate of unambiguous determination of the ECs. The simulation indicated that, in combination with reported constraint rules, the RIA led to unambiguous determination of the ECs for more than 90% of the tested metabolites. It was noteworthy that, in positive ion mode, the process could distinguish alkali metal-adduct ions ([M+Na](+) and [M+K](+)). However, a significant degradation of the EC determination performance was observed when the method was applied to real metabolomic data (mouse liver extracts analyzed by infusion ESI), because of the influence of noise and bias on the RIA. To achieve ideal performance, as indicated in the simulation, we developed an additional method to compensate for bias on the measured ion intensities. The method improved the performance of the calculation, permitting determination of ECs for 72% of the observed peaks. The proposed method is considered a useful starting point for high-throughput identification of metabolites in metabolomic research.
authors: Graduate School of Bioresource and Bioenvironmental Sciences, Kyushu University, 6-10-1 Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan.
authors: Tatsuhiko
authors: T
authors: Nagao
authors: Graduate School of Bioresource and Bioenvironmental Sciences, Kyushu University, 6-10-1 Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan.
authors: Daichi
authors: D
authors: Yukihira
authors: Innovation Center for Medical Redox Navigation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors: Yoshinori
authors: Y
authors: Fujimura
authors: Bruker Daltonics K.K., 3-9 Moriya-cho, Kanagawa-ku, Yokohama 221-0022, Japan.
authors: Kazunori
authors: K
authors: Saito
authors: Research Institute of Instrumentation Frontier, National Institute of Advanced Industrial Science and Technology, 2-42 Aomi, Koutou-ku, Tokyo 135-0064, Japan.
authors: Katsutoshi
authors: K
authors: Takahashi
authors: Innovation Center for Medical Redox Navigation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. Electronic address: daipon@agr.kyushu-u.ac.jp.
authors: Daisuke
authors: D
authors: Miura
authors: Innovation Center for Medical Redox Navigation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan; Faculty of Arts and Science, Kyushu University, 6-10-1 Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan. Electronic address: hirowari@agr.kyushu-u.ac.jp.
authors: Hiroyuki
authors: H
authors: Wariishi
mesh_terms: D000818:Animals; D002247:Carbon Isotopes / Q000032:analysis; D003198:Computer Simulation; D005583:Fourier Analysis; D008297:Male; D013058:Mass Spectrometry / Q000379:methods*; D055442:Metabolome; D055432:Metabolomics / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D009587:Nitrogen Isotopes / Q000032:analysis; D010103:Oxygen Isotopes / Q000032:analysis; D013460:Sulfur Isotopes / Q000032:analysis
chemical_list: D002247:Carbon Isotopes; D009587:Nitrogen Isotopes; D010103:Oxygen Isotopes; D013460:Sulfur Isotopes
keywords: Elemental composition; Fourier transform ion cyclotron resonance mass spectrometry; Metabolite; Metabolomics; Simulation