title: Metabolome-scale prediction of intermediate compounds in multistep metabolic pathways with a recursive supervised approach.
abstract: BACKGROUND
  Metabolic pathway analysis is crucial not only in metabolic engineering but also in rational drug design. However, the biosynthetic/biodegradation pathways are known only for a small portion of metabolites, and a vast amount of pathways remain uncharacterized. Therefore, an important challenge in metabolomics is the de novo reconstruction of potential reaction networks on a metabolome-scale.
  
  
  RESULTS
  In this article, we develop a novel method to predict the multistep reaction sequences for de novo reconstruction of metabolic pathways in the reaction-filling framework. We propose a supervised approach to learn what we refer to as 'multistep reaction sequence likeness', i.e. whether a compound-compound pair is possibly converted to each other by a sequence of enzymatic reactions. In the algorithm, we propose a recursive procedure of using step-specific classifiers to predict the intermediate compounds in the multistep reaction sequences, based on chemical substructure fingerprints/descriptors of compounds. We further demonstrate the usefulness of our proposed method on the prediction of enzymatic reaction networks from a metabolome-scale compound set and discuss characteristic features of the extracted chemical substructure transformation patterns in multistep reaction sequences. Our comprehensively predicted reaction networks help to fill the metabolic gap and to infer new reaction sequences in metabolic pathways.
  
  
  METHODS
  Materials are available for free at http://web.kuicr.kyoto-u.ac.jp/supp/kot/ismb2014/
authors.affiliation: Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 2-12-1 Ookayama, Meguro-ku, Tokyo, 152-8550, Japan, PRESTO, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan, Division of System Cohort, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan, Institute for Advanced Study, Kyushu University, 6-10-1 Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan, Graduate School of Biological Sciences, Nara Institute of Science and Technology (NAIST), 8916-5 Takayama, Ikoma, Nara 630-0192, Japan and Bioinformatics Center, Institute for Chemical Research, Kyoto University, Gokasho, Uji, Kyoto 611-0011, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Kotera
authors.affiliation: Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 2-12-1 Ookayama, Meguro-ku, Tokyo, 152-8550, Japan, PRESTO, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan, Division of System Cohort, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan, Institute for Advanced Study, Kyushu University, 6-10-1 Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan, Graduate School of Biological Sciences, Nara Institute of Science and Technology (NAIST), 8916-5 Takayama, Ikoma, Nara 630-0192, Japan and Bioinformatics Center, Institute for Chemical Research, Kyoto University, Gokasho, Uji, Kyoto 611-0011, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Tabei
authors.affiliation: Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 2-12-1 Ookayama, Meguro-ku, Tokyo, 152-8550, Japan, PRESTO, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan, Division of System Cohort, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan, Institute for Advanced Study, Kyushu University, 6-10-1 Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan, Graduate School of Biological Sciences, Nara Institute of Science and Technology (NAIST), 8916-5 Takayama, Ikoma, Nara 630-0192, Japan and Bioinformatics Center, Institute for Chemical Research, Kyoto University, Gokasho, Uji, Kyoto 611-0011, JapanGraduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 2-12-1 Ookayama, Meguro-ku, Tokyo, 152-8550, Japan, PRESTO, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan, Division of System Cohort, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan, Institute for Advanced Study, Kyushu University, 6-10-1 Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan, Graduate School of Biological Sciences, Nara Institute of Science and Technology (NAIST), 8916-5 Takayama, Ikoma, Nara 630-0192, Japan and Bioinformatics Center, Institute for Chemical Research, Kyoto University, Gokasho, Uji, Kyoto 611-0011, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Yamanishi
authors.affiliation: Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 2-12-1 Ookayama, Meguro-ku, Tokyo, 152-8550, Japan, PRESTO, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan, Division of System Cohort, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan, Institute for Advanced Study, Kyushu University, 6-10-1 Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan, Graduate School of Biological Sciences, Nara Institute of Science and Technology (NAIST), 8916-5 Takayama, Ikoma, Nara 630-0192, Japan and Bioinformatics Center, Institute for Chemical Research, Kyoto University, Gokasho, Uji, Kyoto 611-0011, Japan.
authors.forename: Ai
authors.initials: A
authors.lastname: Muto
authors.affiliation: Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 2-12-1 Ookayama, Meguro-ku, Tokyo, 152-8550, Japan, PRESTO, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan, Division of System Cohort, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan, Institute for Advanced Study, Kyushu University, 6-10-1 Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan, Graduate School of Biological Sciences, Nara Institute of Science and Technology (NAIST), 8916-5 Takayama, Ikoma, Nara 630-0192, Japan and Bioinformatics Center, Institute for Chemical Research, Kyoto University, Gokasho, Uji, Kyoto 611-0011, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Moriya
authors.affiliation: Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 2-12-1 Ookayama, Meguro-ku, Tokyo, 152-8550, Japan, PRESTO, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan, Division of System Cohort, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan, Institute for Advanced Study, Kyushu University, 6-10-1 Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan, Graduate School of Biological Sciences, Nara Institute of Science and Technology (NAIST), 8916-5 Takayama, Ikoma, Nara 630-0192, Japan and Bioinformatics Center, Institute for Chemical Research, Kyoto University, Gokasho, Uji, Kyoto 611-0011, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Tokimatsu
authors.affiliation: Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 2-12-1 Ookayama, Meguro-ku, Tokyo, 152-8550, Japan, PRESTO, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan, Division of System Cohort, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan, Institute for Advanced Study, Kyushu University, 6-10-1 Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan, Graduate School of Biological Sciences, Nara Institute of Science and Technology (NAIST), 8916-5 Takayama, Ikoma, Nara 630-0192, Japan and Bioinformatics Center, Institute for Chemical Research, Kyoto University, Gokasho, Uji, Kyoto 611-0011, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Goto
mesh_terms: D000465:Algorithms; D053858:Metabolic Networks and Pathways; D055442:Metabolome; D055432:Metabolomics / Q000379:methods*; D060388:Support Vector Machine