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Unbalanced Reactions

This tool balances reactions in FBA models and checks for unbalanced or undetermined reactions. It lists problematic reactions and provides remedies for balancing.

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Unbalanced Reactions

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  1. Unbalanced Reactions by Markus Krummenacker June 2011

  2. FBA needs balanced reactions • If an FBA model contains unbalanced reactions, it can cause infinite sources of material • Thus, reactions have to balance all the atoms on the left with the atoms on the right • Including H+ . Our convention is pH7.3 • Reaction balance checker filters away reactions that are unbalanced or undetermined

  3. .log file lists unbalanced reactions • Lists unbalanced reactions for the current PGDB (but not for MetaCyc) • 4 sections of problematic reactions: • In pathways • Standalone small-molecule reactions • In signalling-pathways (which contain non-metabolic protein metabolites). (Should be empty these days, because of an earlier filtering step.) • All other problematic reactions. Usually, macromolecule metabolites. Usually, not involved in core metabolism.

  4. Common sources of problems (1) • SRI has ongoing curation efforts to fix erroneous reactions. By now, most straight forward errors in compound structures or reaction equations have been fixed. • Sometimes, in old PGDBs, reactions are wrong, which no longer exist in MetaCyc, and so they can’t be updated automatically. • Some reactions describe fairly unknown biochemistry. Lack of knowledge is indicated by the CANNOT-BALANCE? flag (in Reaction Editor).

  5. Common sources of problems (2) • H+ unbalanced, with metabolite classes. • Protonation by Marvin can not handle structures with R groups. Thus generic reactions have not been automatically proton-balanced. • Have to be manually balanced by using Marvin to edit structure (by educated guess) • Class metabolites without structures. • Macromolecule metabolites, like redox proteins • Tricky class metabolites for extremely generic classes. Example: NUCLEOSIDE-DIPHOSPHATASE-RXN

  6. Remedies • Add/Edit metabolite structures with Marvin • Edit reaction with Reaction Editor • Balance checker in editor, shows residual • Special cases of the balance checker: • Structure with R groups: R, R1, R2, R3, R4, R5 • MOLECULAR-WEIGHT slot set (by Frame Editor) to less than 0.01 (e.g. E- , light) • Frame pairs, where one is a modifed form of the other. Structure of modified form has to use unmodified frame as an “atom”. Only 1 such reference supported currently. Example: NAD(P)+ / NAD(P)H

  7. Consistency Checker • Under Manual Tasks, “Generate reaction balance report” • Independent of FBA. But a good idea in any case. • Right-click on listed reaction, to show or fix

  8. - Non sequitur -

  9. Compartments of Transporters • For FBA modelling core metabolism, a few transport reactions are essential: ATP synthase, some ETRs like cytochrome oxidase, NADH:ubiquinone oxidoreductase • Pathologic inference for a PGDB may not yet infer the correct compartments. RXN-LOCATIONS slot will be cleared, and so defaults are “in” and “out” • Reaction Editor can be used to manually fix compartment assignments

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