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The Subliminal Toolbox: automating steps in the reconstruction of metabolic networks
The Subliminal Toolbox: automating steps in the reconstruction of metabolic networks
The Subliminal Toolbox: automating steps in the reconstruction of metabolic networks
The Subliminal Toolbox: automating steps in the reconstruction of metabolic networks
The Subliminal Toolbox: automating steps in the reconstruction of metabolic networks
The Subliminal Toolbox: automating steps in the reconstruction of metabolic networks
The Subliminal Toolbox: automating steps in the reconstruction of metabolic networks
The Subliminal Toolbox: automating steps in the reconstruction of metabolic networks
The Subliminal Toolbox: automating steps in the reconstruction of metabolic networks
The Subliminal Toolbox: automating steps in the reconstruction of metabolic networks
The Subliminal Toolbox: automating steps in the reconstruction of metabolic networks
The Subliminal Toolbox: automating steps in the reconstruction of metabolic networks
The Subliminal Toolbox: automating steps in the reconstruction of metabolic networks
The Subliminal Toolbox: automating steps in the reconstruction of metabolic networks
The Subliminal Toolbox: automating steps in the reconstruction of metabolic networks
The Subliminal Toolbox: automating steps in the reconstruction of metabolic networks
The Subliminal Toolbox: automating steps in the reconstruction of metabolic networks
The Subliminal Toolbox: automating steps in the reconstruction of metabolic networks
The Subliminal Toolbox: automating steps in the reconstruction of metabolic networks
The Subliminal Toolbox: automating steps in the reconstruction of metabolic networks
The Subliminal Toolbox: automating steps in the reconstruction of metabolic networks
The Subliminal Toolbox: automating steps in the reconstruction of metabolic networks
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The Subliminal Toolbox: automating steps in the reconstruction of metabolic networks

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  • 1. The Subliminal Toolbox: automating steps in the reconstruction of metabolic networks Neil Swainston Manchester Centre for Integrative Systems Biology 1st Conference on Constraint-based Reconstruction and Analysis Reykjavik, Iceland 24 June2011
  • 2. Automation <ul><li>Many of these steps can be automated </li></ul><ul><ul><li>Subliminal Toolbox </li></ul></ul><ul><li>How much of the reconstruction process can be aided by publicly available resources? </li></ul><ul><ul><li>Manual curation still necessary </li></ul></ul><ul><ul><li>BUT reduce what needs to be done </li></ul></ul><ul><li>Relies on semantic model annotations </li></ul><ul><ul><li>e.g. ChEBI , KEGG terms for metabolites </li></ul></ul><ul><ul><li>UniProt terms for enzymes </li></ul></ul>
  • 3. Model annotations <ul><li>Model annotations provide unambiguous, unique identifiers for model components </li></ul><ul><ul><li>Not very interesting </li></ul></ul><ul><li>But – also provide link to chem/bioinformatics resources via web services </li></ul><ul><ul><li>Automatically extract data through web services </li></ul></ul><ul><ul><li>Potentially more interesting / useful </li></ul></ul>
  • 4. Publicly available resources Formula, Charge, Structure GPR relationships Compartment data Sequence, Metadata Web services
  • 5. Subliminal Toolbox
  • 6. Protonate <ul><li>ChEBI provides web service access to structural data </li></ul><ul><ul><li>InChI , SMILES strings </li></ul></ul><ul><li>Cheminformatics software (ChemAxon) can be used to predict charge state at given pH </li></ul><ul><ul><li>Updates FORMULA , CHARGE , metabolite name and annotation </li></ul></ul><ul><ul><li>Consistency – facilitates merging </li></ul></ul>✓ ✗
  • 7. Balance <ul><li>Reaction elemental and charge balancing </li></ul><ul><ul><li>Prevents mass violation and stoichiometric inconsistencies </li></ul></ul><ul><li>Reactions in resources don ’ t always balance </li></ul><ul><ul><li>Incorrect stoichiometry </li></ul></ul><ul><ul><li>Missing protons, water, etc. </li></ul></ul><ul><li>Solution: extract formulae and charges and apply linear programming </li></ul>
  • 8. Balance carbon dioxide + 2-Acetolacetate  Pyruvate Ab = 0 A = b represents a vector of stoichiometries CO 2 + C 5 H 7 O 4 -  C 3 H 3 O 3 - Reactants Products Optional reactants Optional products CO2 C5H7O4 C3H3O3 H+ H20 H+ H20 CO2 C 1 5 -3 0 0 0 0 -1 O 2 4 -3 0 1 0 -1 -2 H 0 7 -3 1 2 -1 -2 0 charge 0 -1 1 1 0 -1 0 0 b min T 1 1 1 0 0 0 0 0
  • 9. Balance <ul><li>Linear programming solver solves Ab = 0 </li></ul>carbon dioxide + 2-Acetolacetate  2 Pyruvate + H + CO 2 + C 5 H 7 O 4 -  2 C 3 H 3 O 3 - + H + Reactants Products Optional reactants Optional products CO2 C5H7O4 C3H3O3 H+ H20 H+ H20 CO2 C 1 5 -3 0 0 0 0 -1 O 2 4 -3 0 1 0 -1 -2 H 0 7 -3 1 2 -1 -2 0 charge 0 -1 1 1 0 -1 0 0 b min T 1 1 1 0 0 0 0 0 b T 1 1 2 0 0 1 0 0
  • 10. Merge <ul><li>Works on simple premises </li></ul><ul><li>Metabolites / enzymes are the same if the share the same annotation and compartment </li></ul><ul><li>Reactions are the same if the have the same stoichiometry </li></ul><ul><ul><li>Hence balancing </li></ul></ul><ul><ul><li>Isoenzymes collated ( “ OR ” relationship in GPR definition) </li></ul></ul>
  • 11. “ Fuzzy ” Merge <ul><li>Sources can be inconsistent in their definition of stereochemical precision </li></ul><ul><li>Considered different: apparently minor but can cause gaps in the network </li></ul>beta-D-glucose D-glucose
  • 12. “ Fuzzy ” Merge <ul><li>ChEBI is an ontology and contains relationships between metabolites </li></ul><ul><ul><li>Edges not just nodes </li></ul></ul>
  • 13. Compartment <ul><li>Determination of intracellular compartment in which enzymes operate </li></ul><ul><li>Two approaches: </li></ul><ul><ul><li>Extract curated information from UniProt annotation </li></ul></ul><ul><ul><li>Extract protein sequence from UniProt and pipe to WoLF PSORT localisation prediction algorithm </li></ul></ul><ul><li>Infer reaction localisation from enzyme localisation </li></ul><ul><ul><li>Hypothetical transport reactions added to be validated / deleted in manual curation phase </li></ul></ul>
  • 14. Transporters and biomass <ul><li>Extracellular and intracellular transporters are required </li></ul><ul><li>TransportDB and Transporter Classification DB are sources of transporter proteins </li></ul><ul><ul><li>BUT not comprehensive enough to automatically assign these to individual reactions </li></ul></ul><ul><li>Biomass reaction should be added manually </li></ul><ul><li>Automation breaks down… </li></ul>
  • 15. Shorthand Converted to SBML, protonated, balanced and merged as before
  • 16. Usage and availability <ul><li>Java programming API </li></ul><ul><li>Simple command line interface </li></ul><ul><ul><li>SBML file in / SBML file out </li></ul></ul><ul><li>Has some dependencies on third-party software </li></ul><ul><ul><li>Free to academic users </li></ul></ul><ul><li>http://www.mcisb.org/subliminal/ </li></ul>
  • 17. Thanks…
  • 18. The Subliminal Toolbox: automating steps in the reconstruction of metabolic networks Neil Swainston Manchester Centre for Integrative Systems Biology 1st Conference on Constraint-based Reconstruction and Analysis Reykjavik, Iceland 24 June 2011
  • 19. UniProt compartmentalisation
  • 20. UniProt compartmentalisation UniProt curated information
  • 21. PSORT compartmentalisation
  • 22. PSORT compartmentalisation WoLF PSORT prediction

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