Prediction of enzymatic pathways by integrative pathway mapping
| Autor: | John A. Gerlt, Sara Calhoun, Brian San Francisco, Matthew P. Jacobson, Nawar Al-Obaidi, Suwen Zhao, Dmitry A. Rodionov, Magdalena Korczynska, John H. Morris, David Scott, Henry Lin, Daniel J. Wichelecki, Matthew J. O’Meara, Steven C. Almo, Andrej Sali, Matthew W. Vetting, Brian K. Shoichet, Daniel Russel, Andrei L. Osterman |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
QH301-705.5 Computer science Science Structural Biology and Molecular Biophysics Systems biology Computational biology General Biochemistry Genetics and Molecular Biology 03 medical and health sciences l-gulonate catabolic pathway Metabolomics None Biology (General) Virtual screening 030102 biochemistry & molecular biology General Immunology and Microbiology Systems Biology General Neuroscience pathway prediction Computational Biology General Medicine Ligand (biochemistry) Haemophilus influenzae structure based pathway discovery Enzymes Metabolic pathway 030104 developmental biology Structural biology Cheminformatics Medicine enzyme function annotation integrative pathway mapping Metabolic Networks and Pathways Function (biology) Research Article Computational and Systems Biology |
| Zdroj: | eLife eLife, Vol 7 (2018) |
| ISSN: | 2050-084X |
| DOI: | 10.7554/elife.31097 |
| Popis: | The functions of most proteins are yet to be determined. The function of an enzyme is often defined by its interacting partners, including its substrate and product, and its role in larger metabolic networks. Here, we describe a computational method that predicts the functions of orphan enzymes by organizing them into a linear metabolic pathway. Given candidate enzyme and metabolite pathway members, this aim is achieved by finding those pathways that satisfy structural and network restraints implied by varied input information, including that from virtual screening, chemoinformatics, genomic context analysis, and ligand -binding experiments. We demonstrate this integrative pathway mapping method by predicting the L-gulonate catabolic pathway in Haemophilus influenzae Rd KW20. The prediction was subsequently validated experimentally by enzymology, crystallography, and metabolomics. Integrative pathway mapping by satisfaction of structural and network restraints is extensible to molecular networks in general and thus formally bridges the gap between structural biology and systems biology. |
| Databáze: | OpenAIRE |
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