title: Identification of endocrine disruptor biodegradation by integration of structure-activity relationship with pathway analysis.
abstract: We present a SAR method that can predict estrogen-like endocrine disrupting chemical (EDC) activity as well as key biodegradation steps for detoxification. This method is based on a recent graph-mining algorithm developed by Kudo et al., which generates a set of descriptors from all potent chemical fragments (including rings). This method is novel in that it achieves chemical diversity in the training data set by sampling another data set of larger diversity. The model achieved an 83% accuracy prediction rate, and identified 1291 EDC candidates from the KEGG database. From this set of candidate compounds, bisphenol A was chosen for assay validation and biodegradation pathway analysis. Results showed that bisphenol A exhibited estrogen-like activity and was degraded in three distinct reactions. The prediction model provided information on the mechanism of the ligand-target binding, such as key functional groups involved. We focused on the enzyme commission number, which is useful for analyses of biodegradation pathways. Results identified oxygenases, ether hydrolases, and carbon-halide lyases as being important in the biodegradation pathway. This combined approach provided new information regarding the biodegradation of EDCs, and can potentially be extended to applications with transcriptomic, proteomic, and metabolomic data to provide a quick screen of biological activity and biodegradation pathway(s).
authors.affiliation: Bioinformatics Center, Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Kadowaki
authors.forename: Craig E
authors.initials: CE
authors.lastname: Wheelock
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Adachi
authors.forename: Taku
authors.initials: T
authors.lastname: Kudo
authors.forename: Shinobu
authors.initials: S
authors.lastname: Okamoto
authors.forename: Nobuya
authors.initials: N
authors.lastname: Tanaka
authors.forename: Koichiro
authors.initials: K
authors.lastname: Tonomura
authors.forename: Gozoh
authors.initials: G
authors.lastname: Tsujimoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mamitsuka
authors.forename: Susumu
authors.initials: S
authors.lastname: Goto
authors.forename: Minoru
authors.initials: M
authors.lastname: Kanehisa
mesh_terms: D001559:Benzhydryl Compounds; D001673:Biodegradation, Environmental; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D052244:Endocrine Disruptors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D004968:Estrogens, Non-Steroidal / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008956:Models, Chemical; D015394:Molecular Structure; D010105:Oxygenases / Q000378:metabolism; D010636:Phenols / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D052244:Endocrine Disruptors; D004968:Estrogens, Non-Steroidal; D010105:Oxygenases; D010636:Phenols; C006780:bisphenol A; D000098826:Bisphenol A Compounds