MetaRoute
News
Last database update: 21/10/2007

Information

About MetaRoute

MetaRoute is a computational method to search for relevant routes between a source and a product in metabolic networks. Its speed allows the method to be used in a webinterface for interactive navigation through genome scale networks and local network visualization. The underlying approach is based on graph-theory and the basic algorithm uses atom mapping rules and path weighting schemes to search for relevant paths in a directed graph representing the metabolic network. Precalculated atom mapping rules are incorporated into both the graph representation and the path finding algorithm (Eppsteins k-shortest path algorithm) to ensure fast calculation and to enforce biochemical constraints. To this end, the weighted path search is constrained to only trace feasible paths transferring atoms from the user-specified source to the product metabolite.

Besides the typical search between a given source and product metabolite, it is also possible to search for routes just consuming a source metabolite (or producing a product) without specified product (or source). By adding arbitrary constraints (forbidden or required compounds and reactions), the user can refine the search. Up to 500 routes can be searched and visualized within seconds in one run. Cross-species comparison is possible by the search in the combined network of an arbitrary number of organisms. The underlying data stems from the Biological Network Database (BNDB) and is based on data from KEGG.


Input instructions

Search settings

Before starting a search several search settings have to be defined by the user. However, only the first three (source metabolite, product metabolite, network) are necessary. The remaining settings are pre-defined using default values which can be changed by experienced users.

source metabolite: You can enter the name of the metabolite which will be used as source (e.g. glucose). However, it is also possible to leave the field empty and to search for metabolic routes with unspecified source just producing a given product metabolite.

product metabolite: You can enter the name of the metabolite which will be used as product (e.g. pyruvate). However, it is also possible to leave the field empty and to search for metabolic routes with unspecified product just consuming a given source metabolite.

network: It is possible to search for relevant routes in the metabolic network of one organism of interest or in the combined network of multiple organisms which is interesting for species comparison. Furthermore, the user can search in the `super network' containing all KEGG reactions as well as in an external or user-defined network.

max. number of routes: The seach algorithm stops after the detection of a predefined number of routes (50 by default). Up to a maximum of 500 routes can be searched in one run. Increasing the number of routes per run will also increase the number of reactions in the resulting local network.

rank routes: The metabolic routes found can be ranked using different weighting schemes. The combined weight (by default) integrates the compound and reaction weight. It is also possible to rank the routes just by their length (number of reactions). However, this is not recommanded.

atom trace type: You can select one of four atom types (carbon by default) which will be used for tracing the transfere of structural moiety between the source and product metabolites.

ignore C1 compounds: Compounds containing only one carbon atom like Formate, HCO3-, etc often are fast available via conversions from the ubiquitous CO2. If carbon is the selected atom trace type, those compounds are ignored as intermediates by default.

ignore compounds without structural information: All compounds without any given structural information (e.g. Acceptor(C00028) or Branched chain fatty acid(C05996)) are ignored as a main intermediate by default.

consider compound hierarchy relations: Hierarchy relations between generic (e.g. D-Glucose(C00031)) and more specific compounds (alpha-D-Glucose(C00267) and beta-D-Glucose(C00221)) are detected from the given structural information and considered in the search process.

ignore reactions with unbalanced equation: All reactions with the comment -unclear reaction- or -incomplete reaction- are removed from the selected metabolic network by default. Furthermore, reactions with an unbalanced number of the selected atom trace type and not annotated with the mentioned comments are additionally removed.

Define constraints

After the first run the user can refine the search by the addition of arbitrary constraints (forbidden or required compounds and reactions). All reactions are set to be reversible by default. Here, the user can define reactions to be irreversible.

Species comparison

If multiple organisms are selected, the user can assign them to two groups which are differently highlighted for species comparisons.

Export data

Search results can be exported in various formats, e.g. Systems Biology Markup Language (SBML) or METATOOL format for further processing or analysis.

Output description

Result summary: This output section summarizes the user-defined search settings and gives several information including the selected network size, the number of metabolic routes found and the number of distinct reactions within the routes. Furthermore, an option is offered to visualize at once all routes found in a local network using a separate window. The local network view shows only the main metabolites which were traced in the path finding algorithm. Image maps offer direct links to the KEGG database, but the user also immediately gets more information in a small popup box simply by moving the mouse over the compounds and reactions. Reactions for which no atom mapping rule could be calculated because of missing structural information or complicated mechanism (more than two broken bonds per compound) are drawn using red color. The arcs, representing metabolic conversions present in top rankes routes, are drawn in bold. All routes witch have a weight maximal 15 percent higher than the minimum weight are classified as top ranked.

Routes found in detail: Each route found can be visualized in a separate window with differently highlighted main and side metabolites for each reaction. Again, direct links to KEGG and small popup boxes are offered. Futhermore, for each route the resulting weight (reflecting its relevance), the number of reactions and the number of atoms (of the selected atom trace type) which were transferred from the source to the product metabolite, is shown. If the atom count is drawn using red color then the metabolic route contains at least one reaction with missing atom mapping rule.


References

Blum,T., Kohlbacher,T. (2008) MetaRoute: fast search for relevant metabolic routes for interactive network navigation and visualization, Bioinformatics

Blum,T., Kohlbacher,T. (2008) Using atom mapping rules for an improved detection of relevant routes in weighted metabolic networks, J. Comput. Biol., 15(6)