Consensus and conflict cards for metabolic pathway databases

Abstract

Background: The metabolic network of H. sapiens and many other organisms is described in multiple pathway databases. The level of agreement between these descriptions, however, has proven to be low. We can use these different descriptions to our advantage by identifying conflicting information and combining their knowledge into a single, more accurate, and more complete description. This task is, however, far from trivial.

Results: We introduce the concept of Consensus and Conflict Cards (C₂Cards) to provide concise overviews of what the databases do or do not agree on. Each card is centered at a single gene, EC number or reaction. These three complementary perspectives make it possible to distinguish disagreements on the underlying biology of a metabolic process from differences that can be explained by different decisions on how and in what detail to represent knowledge. As a proof-of-concept, we implemented C₂Cards(Human), as a web application http://www.molgenis.org/c2cards, covering five human pathway databases.

Conclusions: C₂Cards can contribute to ongoing reconciliation efforts by simplifying the identification of consensus and conflicts between pathway databases and lowering the threshold for experts to contribute. Several case studies illustrate the potential of the C₂Cards in identifying disagreements on the underlying biology of a metabolic process. The overviews may also point out controversial biological knowledge that should be subject of further research. Finally, the examples provided emphasize the importance of manual curation and the need for a broad community involvement.

Figure 1

Examples of two C₂Cards. C₂Card centered at the CTPS gene (top) and the C₂Card retrieved by clicking on the reaction of Reactome in the C₂Card centered at the CTPS gene (bottom). Each C₂Card consists of a table in which each row contains the following basic elements: a reaction and the EC number(s), gene(s) and pathway linked to it in one of the pathway databases. One can switch perspective by clicking on any of the elements in the table. For additional information provided by the pathway databases, e.g., pathway visualizations and literature references, a direct link is provided to the original entry of the reaction in the pathway database. The second core ingredient of a C₂Card is that each card explicitly shows the similarity of the reactions displayed on it. The percentage of overlap between reactions is indicated and relevant cells are colored according to the degree of overlap. Information on the IDs assigned to the metabolites and genes by a pathway database is shown by clicking on the i icon. For EC numbers the reaction and name linked to it by NC-IUBMB are shown.

Figure 2

Excerpt of the C₂Card centered at the reaction ‘ATP + UMP <==> ADP + UDP’. Different EC numbers linked to the same reaction and gene, which illustrates the difference in enzyme activity assigned to the product of the CMPK1 gene. Matching EC numbers have the same color.

Figure 3

Excerpt of the C₂Card centered at the EC number ‘4.2.1.3’ (aconitate hydratase). Conversion of citrate into isocitrate (part of the TCA cycle) in one (green) or two steps (blue). The EC number and gene on which all five databases agree are underlined.

Figure 4

Excerpt of the C₂Card centered at the EC number ‘6.2.1.4’ (succinate-CoA ligase (GDP-forming)). The reaction in grey is found in all databases, the reaction in red only in EHMN and KEGG. ‘|==|’ indicates no direction provided by the database. Genes are represented by HGNC symbols, retrieved via Entrez Gene IDs. Genes, the products of which form a complex, are placed between parentheses and connected by the Boolean operator ‘and' (see Materials and methods). If gene products are isozymes ‘or’ is used.