The Subliminal Toolbox: automating steps in the reconstruction of metabolic networks
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The Subliminal Toolbox is a software that automates several steps in the reconstruction of metabolic networks from publicly available resources. It can protonate metabolites, balance reactions, merge models, and determine metabolite and enzyme compartmentalization. While it reduces the manual effort needed, some steps like transporter assignment and adding a biomass reaction still require human curation. The tool is available for free to academic users.
The Subliminal Toolbox: automating steps in the reconstruction of metabolic networks
- 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 Many of these steps can be automated Subliminal Toolbox How much of the reconstruction process can be aided by publicly available resources? Manual curation still necessary BUT reduce what needs to be done Relies on semantic model annotations e.g. ChEBI , KEGG terms for metabolites UniProt terms for enzymes
- 3. Model annotations Model annotations provide unambiguous, unique identifiers for model components Not very interesting But – also provide link to chem/bioinformatics resources via web services Automatically extract data through web services Potentially more interesting / useful
- 4. Publicly available resources Formula, Charge, Structure GPR relationships Compartment data Sequence, Metadata Web services
- 6. Protonate ChEBI provides web service access to structural data InChI , SMILES strings Cheminformatics software (ChemAxon) can be used to predict charge state at given pH Updates FORMULA , CHARGE , metabolite name and annotation Consistency – facilitates merging ✓ ✗
- 7. Balance Reaction elemental and charge balancing Prevents mass violation and stoichiometric inconsistencies Reactions in resources don ’ t always balance Incorrect stoichiometry Missing protons, water, etc. Solution: extract formulae and charges and apply linear programming
- 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 Linear programming solver solves Ab = 0 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 Works on simple premises Metabolites / enzymes are the same if the share the same annotation and compartment Reactions are the same if the have the same stoichiometry Hence balancing Isoenzymes collated ( “ OR ” relationship in GPR definition)
- 11. “ Fuzzy ” Merge Sources can be inconsistent in their definition of stereochemical precision Considered different: apparently minor but can cause gaps in the network beta-D-glucose D-glucose
- 12. “ Fuzzy ” Merge ChEBI is an ontology and contains relationships between metabolites Edges not just nodes
- 13. Compartment Determination of intracellular compartment in which enzymes operate Two approaches: Extract curated information from UniProt annotation Extract protein sequence from UniProt and pipe to WoLF PSORT localisation prediction algorithm Infer reaction localisation from enzyme localisation Hypothetical transport reactions added to be validated / deleted in manual curation phase
- 14. Transporters and biomass Extracellular and intracellular transporters are required TransportDB and Transporter Classification DB are sources of transporter proteins BUT not comprehensive enough to automatically assign these to individual reactions Biomass reaction should be added manually Automation breaks down…
- 15. Shorthand Converted to SBML, protonated, balanced and merged as before
- 16. Usage and availability Java programming API Simple command line interface SBML file in / SBML file out Has some dependencies on third-party software Free to academic users http://www.mcisb.org/subliminal/
- 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
- 20. UniProt compartmentalisation UniProt curated information
- 22. PSORT compartmentalisation WoLF PSORT prediction