Metabolomics analysis: Finding out metabolic building blocks

Abstract

In this paper we propose a new methodology for the analysis of metabolic networks. We use the notion of strongly connected components of a graph, called in this context metabolic building blocks. Every strongly connected component is contracted to a single node in such a way that the resulting graph is a directed acyclic graph, called a metabolic DAG, with a considerably reduced number of nodes. The property of being a directed acyclic graph brings out a background graph topology that reveals the connectivity of the metabolic network, as well as bridges, isolated nodes and cut nodes. Altogether, it becomes a key information for the discovery of functional metabolic relations. Our methodology has been applied to the glycolysis and the purine metabolic pathways for all organisms in the KEGG database, although it is general enough to work on any database. As expected, using the metabolic DAGs formalism, a considerable reduction on the size of the metabolic networks has been obtained, specially in the case of the purine pathway due to its relative larger size. As a proof of concept, from the information captured by a metabolic DAG and its corresponding metabolic building blocks, we obtain the core of the glycolysis pathway and the core of the purine metabolism pathway and detect some essential metabolic building blocks that reveal the key reactions in both pathways. Finally, the application of our methodology to the glycolysis pathway and the purine metabolism pathway reproduce the tree of life for the whole set of the organisms represented in the KEGG database which supports the utility of this research.

Fig 1. The m-DAG of the purine metabolism pathway in Homo sapiens.

The nodes in this graph are the MBBs in the reaction graph of the purine metabolism pathway in Homo sapiens. Yellow nodes denote MBBs with only one reaction, while grey nodes denote MBBs with more than one reaction.

Fig 2. The reaction graph corresponding to the metabolic pathway of the glycolysis in Homo sapiens.

It shows the reaction graph corresponding to the metabolic pathway depicted on the left side of Fig 4. The nodes in this graph are the reactions of the pathway, depicted in blue nodes are the reverse of a reversible reaction and in yellow the reaction itself.

Fig 3. Relation between the reaction graph of the glycolysis in Homo sapiens and its corresponding m-DAG.

It shows the relation between the reaction graph corresponding to the glycolysis pathway in Homo sapiens and its corresponding m-DAG. The m-DAG has seven nodes which are the corresponding MBBs in the reaction graph. Notice that three of them are yellow nodes, that is, a MBB with only one reaction, and four of them are grey nodes which are MBBs with more than one reaction. In Table 1 we list the reactions in every MBB.

Fig 4. Relation between the Homo sapiens glycolysis pathway and its corresponding m-DAG.

On the right is depicted the m-DAG corresponding to the Homo sapiens glycolysis pathway. For every MBB we show their corresponding reactions over the glycolysis pathway depicted on the left, as it is shown in the KEGG database.

Fig 5. The glycolysis reference m-DAG.

This figure shows the glycolysis reference m-DAG associated to the glycolysis reference pathway in the KEGG database. We again show the relation between the MBBs and their corresponding reactions over the reference glycolysis pathway depicted on the left.

Fig 6. Relation between the reference m-DAG and the m-DAGs of six organisms from each kingdom.

This figure shows the m-DAGs of six organisms, one in each kingdom and their relation with the reference m-DAG (in the center). The two MBBs in the reference m-DAG with more than one reaction are depicted in green and blue. With the corresponding color (green or blue) in the background, we show the inclusion of the MBBs of every organism into the MBBs in the reference m-DAG.

Fig 7. The glycolysis kingdom reference m-DAGs.

This figure shows the kingdom reference m-DAGs obtained for the six kingdoms as well as their relation with the reference m-DAG in the center of the figure.

Fig 8. The purine metabolism reference m-DAG.

This figure shows the purine metabolism reference m-DAG associated to the purine metabolism reference pathway in the KEGG database.

Fig 9. Glycolysis evolution.

This figure shows the dendrogram obtained with the hierarchical clustering of the glycolysis pathway. Red, green, brown, grey, dark blue and light blue labels are m-DAGs in Animalia, Plantae, Fungi, Protista, Bacteria and Archaea, respectively. In S15 Fig we provide the vectorial format of this image for a better visualization.

Fig 10. Purine metabolism evolution.

This figure shows the dendrogram obtained with the hierarchical clustering of the purine metabolism pathway. Red, green, brown, grey, dark blue and light blue labels are m-DAG in Animalia, Plantae, Fungi, Protista, Bacteria and Archaea, respectively. In S16 Fig we provide the vectorial format of this image for a better visualization.