Identifying epimetabolites and its elucidations by computational mass spectrometry

• Project/Area Number: 18K19155
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 37:Biomolecular chemistry and related fields
• Research Institution: Tokyo University of Agriculture and Technology (2021); Institute of Physical and Chemical Research (2018-2020)
• Principal Investigator: Tsugawa Hiroshi 東京農工大学, 工学(系)研究科(研究院), 准教授 (30647235)
• Project Period (FY): 2018-06-29 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2020: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000)
• Keywords: システムバイオロジー / メタボロミクス / リピドミクス / 質量分析 / インフォマティクス / エピメタボライト / ノンターゲット解析 / 質量分析インフォマティクス / メタボローム / データサイエンス / 構造推定 / LC-MS/MS / 組成式推定 / 代謝物クラス推定 / メタボローム解析 / 化合物同定

Outline of Final Research Achievements

In this study, we developed novel untargeted metabolome analysis platform that can identify previously unknown metabolites. Characterizing epimetabolites, which are not defined by known metabolic pathways but arise from enzymatic changes or nonspecific reactions, is the main aim of this study. The machine learning of tandem mass spectra (MS/MS) performed in this study enabled us to predict the metabolite class from unknown MS/MS spectrum information. In addition, the development of lipid theoretical MS/MS spectral library has laid the foundation for the annotation of a total of 117 lipid classes, successfully capturing more than 8,000 lipid molecules (lipid diversity) from biological samples.

Academic Significance and Societal Importance of the Research Achievements

本研究で構築した新たなMS/MS解釈論であるfragment set enrichment analysis (FSEA)は、過去に報告例が無いことはもちろん、既知構造とリファレンススペクトルの情報を必要としない全く新しい網羅的な化合物構造推定手法である。当該研究で構築される手法は疾患代謝研究だけでなく、腸内細菌叢を含めた微生物研究、および植物化学研究においても化合物構造決定の効率が飛躍的に向上し、全世界の代謝研究に貢献できると期待される。また、10万種を超えるとされる生命の脂質多様性を明らかにすることは、脂質異常症の背後に潜む動作原理を分子レベルで明らかにするための基礎的なデータを提供する。

Research Products

• [Int'l Joint Research] UC Davis/University of Florida/UCSD(米国)
• [Int'l Joint Research] Wageningen University & Research(オランダ)
• [Int'l Joint Research] Czech Academy of Sciences(チェコ)
• [Int'l Joint Research] Karolinska Institutet(スウェーデン)
• [Int'l Joint Research] Wageningen University & Research/Laboratory of Genetics(オランダ)
• [Journal Article] Metabolomics and complementary techniques to investigate the plant phytochemical cosmos (2021)
  • Author(s): Tsugawa Hiroshi、Rai Amit、Saito Kazuki、Nakabayashi Ryo
  • Journal Title: Natural Product Reports Volume: 38 Issue: 10 Pages: 1729-1759
  • DOI: 10.1039/d1np00014d
  • Peer Reviewed / Open Access
• [Journal Article] Global profiling of gut microbiota-associated lipid metabolites in antibiotic-treated mice by LC-MS/MS-based analyses (2021)
  • Author(s): Okahashi Nobuyuki、Ueda Masahiro、Yasuda Shu、Tsugawa Hiroshi、Arita Makoto
  • Journal Title: STAR Protocols Volume: 2 Issue: 2 Pages: 100492-100492
  • DOI: 10.1016/j.xpro.2021.100492
  • Peer Reviewed / Open Access
• [Journal Article] Food Lipidomics for 155 Agricultural Plant Products (2021)
  • Author(s): Matsuzawa Yuki、Higashi Yasuhiro、Takano Kouji、Takahashi Mikiko、Yamada Yutaka、Okazaki Yozo、Nakabayashi Ryo、Saito Kazuki、Tsugawa Hiroshi
  • Journal Title: Journal of Agricultural and Food Chemistry Volume: 69 Issue: 32 Pages: 8981-8990
  • DOI: 10.1021/acs.jafc.0c07356
  • Peer Reviewed
• [Journal Article] Stage-specific de novo synthesis of very long chain dihydroceramides confers dormancy to Entamoeba parasites (2021)
  • Author(s): Fumika Mi-ichi Kazutaka Ikeda Hiroshi Tsugawa Sharmina Deloer Hiroki Yoshida Makoto Arita
  • Journal Title: mSphere Volume: 6 Issue: 2 Pages: 00174-21
  • DOI: 10.1128/msphere.00174-21
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] OS-PCA: Orthogonal Smoothed Principal Component Analysis Applied to Metabolome Data (2021)
  • Author(s): Yamamoto Hiroyuki、Nakayama Yasumune、Tsugawa Hiroshi
  • Journal Title: Metabolites Volume: 11 Issue: 3 Pages: 149-149
  • DOI: 10.3390/metabo11030149
  • Peer Reviewed / Open Access
• [Journal Article] Chromosome-level genome assembly of Ophiorrhiza pumila reveals the evolution of camptothecin biosynthesis (2021)
  • Author(s): Rai Amit、Hirakawa Hideki、Nakabayashi Ryo、Kikuchi Shinji、Hayashi Koki、Rai Megha、Tsugawa Hiroshi、Nakaya Taiki、Mori Tetsuya、Nagasaki Hideki、Fukushi Runa、Kusuya Yoko、Takahashi Hiroki、Uchiyama Hiroshi、Toyoda Atsushi、Hikosaka Shoko、Goto Eiji、Saito Kazuki、Yamazaki Mami
  • Journal Title: Nature Communications Volume: 12 Issue: 1 Pages: 405-405
  • DOI: 10.1038/s41467-020-20508-2
  • Peer Reviewed / Open Access
• [Journal Article] Elucidation of Gut Microbiota-Associated Lipids Using LC-MS/MS and 16S rRNA Sequence Analyses (2020)
  • Author(s): Yasuda Shu、Okahashi Nobuyuki、Tsugawa Hiroshi、Ogata Yusuke、Ikeda Kazutaka、Suda Wataru、Arai Hiroyuki、Hattori Masahira、Arita Makoto
  • Journal Title: iScience Volume: 23 Issue: 12 Pages: 101841-101841
  • DOI: 10.1016/j.isci.2020.101841
  • Peer Reviewed / Open Access
• [Journal Article] A lipidome atlas in MS-DIAL 4 (2020)
  • Author(s): Tsugawa Hiroshi、Ikeda Kazutaka、Takahashi Mikiko、Satoh Aya、Mori Yoshifumi、Uchino Haruki、Okahashi Nobuyuki、Yamada Yutaka、Tada Ipputa、Bonini Paolo、Higashi Yasuhiro、Okazaki Yozo、Zhou Zhiwei、Zhu Zheng-Jiang、Koelmel Jeremy、Cajka Tomas、Fiehn Oliver、Saito Kazuki、Arita Masanori、Arita Makoto
  • Journal Title: Nature Biotechnology Volume: 38 Issue: 10 Pages: 1159-1163
  • DOI: 10.1038/s41587-020-0531-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Feature-based molecular networking in the GNPS analysis environment (2020)
  • Author(s): Nothias Louis-Felix、Petras Daniel、Schmid Robin、Duhrkop Kai、Rainer Johannes、Sarvepalli Abinesh、Protsyuk Ivan、Ernst Madeleine、Tsugawa Hiroshi et al.
  • Journal Title: Nature Methods Volume: 17 Issue: 9 Pages: 905-908
  • DOI: 10.1038/s41592-020-0933-6
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Metabolomics with 15N Labeling for Characterizing Missing Monoterpene Indole Alkaloids in Plants (2020)
  • Author(s): Nakabayashi Ryo、Mori Tetsuya、Takeda Noriko、Toyooka Kiminori、Sudo Hiroshi、Tsugawa Hiroshi、Saito Kazuki
  • Journal Title: Analytical Chemistry Volume: 92 Issue: 8 Pages: 5670-5675
  • DOI: 10.1021/acs.analchem.9b03860
  • Peer Reviewed / Open Access
• [Journal Article] Creating a Reliable Mass Spectral-Retention Time Library for All Ion Fragmentation-Based Metabolomics (2019)
  • Author(s): Tada Ipputa、Tsugawa Hiroshi、Meister Isabel、Zhang Pei、Shu Rie、Katsumi Riho、Wheelock Craig E.、Arita Masanori、Chaleckis Romanas
  • Journal Title: Metabolites Volume: 9 Issue: 11 Pages: 251-251
  • DOI: 10.3390/metabo9110251
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Characterization of Lipid Profiles after Dietary Intake of Polyunsaturated Fatty Acids Using Integrated Untargeted and Targeted Lipidomics (2019)
  • Author(s): Naoe Satoko、Tsugawa Hiroshi、Takahashi Mikiko、Ikeda Kazutaka、Arita Makoto
  • Journal Title: Metabolites Volume: 9 Issue: 10 Pages: 241-241
  • DOI: 10.3390/metabo9100241
  • Peer Reviewed / Open Access
• [Journal Article] Mass Spectrometry Data Repository Enhances Novel Metabolite Discoveries with Advances in Computational Metabolomics (2019)
  • Author(s): Tsugawa Hiroshi、Satoh Aya、Uchino Haruki、Cajka Tomas、Arita Makoto、Arita Masanori
  • Journal Title: Metabolites Volume: 9 Issue: 6 Pages: 119-119
  • DOI: 10.3390/metabo9060119
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A cheminformatics approach to characterize metabolomes in stable-isotope-labeled organisms (2019)
  • Author(s): Tsugawa Hiroshi、Nakabayashi Ryo、Mori Tetsuya、Yamada Yutaka、Takahashi Mikiko、Rai Amit、Sugiyama Ryosuke、Yamamoto Hiroyuki、Nakaya Taiki、Yamazaki Mami、Kooke Rik、Bac-Molenaar Johanna A.、Oztolan-Erol Nihal、Keurentjes Joost J. B.、Arita Masanori、Saito Kazuki
  • Journal Title: Nature Methods Volume: 16 Issue: 4 Pages: 295-298
  • DOI: 10.1038/s41592-019-0358-2
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Advances in computational metabolomics and databases deepen the understanding of metabolisms (2018)
  • Author(s): Hiroshi Tsugawa
  • Journal Title: Current Opinion in Biotechnology Volume: 54 Pages: 10-17
  • DOI: 10.1016/j.copbio.2018.01.008
  • Peer Reviewed / Int'l Joint Research
• [Presentation] PlaSMA: decoding plant specialized metabolome by the suite of mass spectrometry cheminformatics (2018)
  • Author(s): Hiroshi Tsugawa, Ryo Nakabayashi, Amit Rai, Tetsuya Mori, Yutaka Yamada, Hiroyuki Yamamoto, Makoto Arita, Masanori Arita, Kazuki Saito
  • Organizer: Metabolomics conference
  • Int'l Joint Research
• [Remarks] RIKEN PRIMe Computational Mass Spectrometry
  • URL: http://prime.psc.riken.jp/compms/index.html
• [Remarks] Computational mass spectrometry
  • URL: http://prime.psc.riken.jp/compms/index.html
• [Remarks] Computational metabolomics
  • URL: http://prime.psc.riken.jp/Metabolomics_Software/