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The Subliminal Toolbox: automating steps in the reconstruction of metabolic networks  Neil Swainston Manchester Centre for...
Automation <ul><li>Many of these steps can be  automated </li></ul><ul><ul><li>Subliminal Toolbox </li></ul></ul><ul><li>H...
Model annotations <ul><li>Model annotations provide unambiguous,  unique identifiers  for model components </li></ul><ul><...
Publicly available resources Formula, Charge, Structure GPR relationships Compartment data Sequence, Metadata Web services
Subliminal Toolbox
Protonate <ul><li>ChEBI provides  web service access  to  structural data </li></ul><ul><ul><li>InChI ,  SMILES  strings <...
Balance <ul><li>Reaction  elemental  and  charge balancing </li></ul><ul><ul><li>Prevents  mass violation  and stoichiomet...
Balance carbon dioxide + 2-Acetolacetate    Pyruvate Ab = 0 A = b represents a vector of stoichiometries CO 2  + C 5 H 7 ...
Balance <ul><li>Linear programming solver solves Ab = 0 </li></ul>carbon dioxide + 2-Acetolacetate     2   Pyruvate +  H ...
Merge <ul><li>Works on simple premises </li></ul><ul><li>Metabolites / enzymes are the same if the share the same  annotat...
“ Fuzzy ”  Merge <ul><li>Sources can be inconsistent in their definition of  stereochemical precision </li></ul><ul><li>Co...
“ Fuzzy ”  Merge <ul><li>ChEBI is an  ontology  and contains  relationships  between metabolites </li></ul><ul><ul><li>Edg...
Compartment <ul><li>Determination of  intracellular compartment  in which enzymes operate </li></ul><ul><li>Two approaches...
Transporters and biomass <ul><li>Extracellular  and  intracellular  transporters are required </li></ul><ul><li>TransportD...
Shorthand Converted to  SBML, protonated, balanced  and  merged  as before
Usage and availability <ul><li>Java  programming  API </li></ul><ul><li>Simple  command line  interface </li></ul><ul><ul>...
Thanks…
The Subliminal Toolbox: automating steps in the reconstruction of metabolic networks  Neil Swainston Manchester Centre for...
UniProt compartmentalisation
UniProt compartmentalisation UniProt curated information
PSORT compartmentalisation
PSORT compartmentalisation WoLF PSORT prediction
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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

  1. 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. 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. 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. 4. Publicly available resources Formula, Charge, Structure GPR relationships Compartment data Sequence, Metadata Web services
  5. 5. Subliminal Toolbox
  6. 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. 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. 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. 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. 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. 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. 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. 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. 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. 15. Shorthand Converted to SBML, protonated, balanced and merged as before
  16. 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. 17. Thanks…
  18. 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. 19. UniProt compartmentalisation
  20. 20. UniProt compartmentalisation UniProt curated information
  21. 21. PSORT compartmentalisation
  22. 22. PSORT compartmentalisation WoLF PSORT prediction

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