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Biosynthetic potentials of metabolites and their hierarchical organization.

Matthäus F, Salazar C, Ebenhöh O - PLoS Comput. Biol. (2008)

Bottom Line: We observe that most of the resulting consensus scopes overlap or are fully contained in others, revealing a hierarchical ordering of metabolites according to their biosynthetic potential.A central result is that chemically very similar substances with different biological functions may differ significantly in their biosynthetic potentials.Our studies provide an important step towards understanding fundamental design principles of metabolic networks determined by the structural and functional complexity of metabolites.

View Article: PubMed Central - PubMed

Affiliation: Interdisciplinary Center for Scientific Computing, University of Heidelberg, Heidelberg, Germany.

ABSTRACT
A major challenge in systems biology is to understand how complex and highly connected metabolic networks are organized. The structure of these networks is investigated here by identifying sets of metabolites that have a similar biosynthetic potential. We measure the biosynthetic potential of a particular compound by determining all metabolites than can be produced from it and, following a terminology introduced previously, call this set the scope of the compound. To identify groups of compounds with similar scopes, we apply a hierarchical clustering method. We find that compounds within the same cluster often display similar chemical structures and appear in the same metabolic pathway. For each cluster we define a consensus scope by determining a set of metabolites that is most similar to all scopes within the cluster. This allows for a generalization from scopes of single compounds to scopes of a chemical family. We observe that most of the resulting consensus scopes overlap or are fully contained in others, revealing a hierarchical ordering of metabolites according to their biosynthetic potential. Our investigations show that this hierarchy is not only determined by the chemical complexity of the metabolites, but also strongly by their biological function. As a general tendency, metabolites which are necessary for essential cellular processes exhibit a larger biosynthetic potential than those involved in secondary metabolism. A central result is that chemically very similar substances with different biological functions may differ significantly in their biosynthetic potentials. Our studies provide an important step towards understanding fundamental design principles of metabolic networks determined by the structural and functional complexity of metabolites.

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Assignment of combined biosynthetic potentials to selected clusters.The fraction of combined biosynthetic potentials, which are assigned to one of five selected clusters (XIII, APS; III, ATP; I, L-Glutamate; VI, dTTP; IX, Acetyl-CoA), is plotted versus the seed size.
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pcbi-1000049-g004: Assignment of combined biosynthetic potentials to selected clusters.The fraction of combined biosynthetic potentials, which are assigned to one of five selected clusters (XIII, APS; III, ATP; I, L-Glutamate; VI, dTTP; IX, Acetyl-CoA), is plotted versus the seed size.

Mentions: To analyze which particular consensus scopes can be reached from a combination of metabolites, we plot in Figure 4 the fraction of scopes that are assigned to a particular consensus scope in dependence of the seed size. Shown are the values for the five clusters with the largest consensus scopes (XIII−APS, III−ATP, I−L-Glutamate, VI−dTTP, IX−Acetyl-CoA), all other clusters are assigned with negligible frequency. The frequency of assignment to the largest consensus scope increases strongly with increasing seed size. This is expected because the addition of new metabolites to the seed may only increase the biosynthetic potential, so that a randomly chosen large set of metabolites is more likely to display the full potential of metabolites from cluster XIII than a small set. However, the numbers provide further insight into the structural design of metabolism. For 20 randomly selected compounds, the chance that one of them belongs to the four compounds forming cluster XIII is still below 2%. On the other hand, more than half of the scopes for this seed size get assigned to the corresponding consensus scope. This indicates that the particular, chemically very rich, compounds from cluster XIII are not necessary to obtain the full biosynthetic potential characterized by the scope of APS. Instead, the same potential is contained in many combinations of smaller substances. This result generalizes the observation made in [14] that the scope of APS may also be reached if, for instance, CO2, NH3, phosphate, sulfate, water and oxygen are used as seed. The frequency of assignment to the second largest consensus scope also increases with increasing seed size, however, it does not change considerably for seed sizes larger than 10. For the assignment to the consensus scope of cluster I, and in fact for the other clusters as well, the frequency also increases for small seed sizes but tends to decrease when the seed sizes become large. The reason is that for larger sets of seed compounds it becomes increasingly difficult to find such combinations which do not exhibit a large biosynthetic potential. Therefore, for larger seed sizes, the frequency of assignment is shifted towards the larger consensus scopes.


Biosynthetic potentials of metabolites and their hierarchical organization.

Matthäus F, Salazar C, Ebenhöh O - PLoS Comput. Biol. (2008)

Assignment of combined biosynthetic potentials to selected clusters.The fraction of combined biosynthetic potentials, which are assigned to one of five selected clusters (XIII, APS; III, ATP; I, L-Glutamate; VI, dTTP; IX, Acetyl-CoA), is plotted versus the seed size.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2289774&req=5

pcbi-1000049-g004: Assignment of combined biosynthetic potentials to selected clusters.The fraction of combined biosynthetic potentials, which are assigned to one of five selected clusters (XIII, APS; III, ATP; I, L-Glutamate; VI, dTTP; IX, Acetyl-CoA), is plotted versus the seed size.
Mentions: To analyze which particular consensus scopes can be reached from a combination of metabolites, we plot in Figure 4 the fraction of scopes that are assigned to a particular consensus scope in dependence of the seed size. Shown are the values for the five clusters with the largest consensus scopes (XIII−APS, III−ATP, I−L-Glutamate, VI−dTTP, IX−Acetyl-CoA), all other clusters are assigned with negligible frequency. The frequency of assignment to the largest consensus scope increases strongly with increasing seed size. This is expected because the addition of new metabolites to the seed may only increase the biosynthetic potential, so that a randomly chosen large set of metabolites is more likely to display the full potential of metabolites from cluster XIII than a small set. However, the numbers provide further insight into the structural design of metabolism. For 20 randomly selected compounds, the chance that one of them belongs to the four compounds forming cluster XIII is still below 2%. On the other hand, more than half of the scopes for this seed size get assigned to the corresponding consensus scope. This indicates that the particular, chemically very rich, compounds from cluster XIII are not necessary to obtain the full biosynthetic potential characterized by the scope of APS. Instead, the same potential is contained in many combinations of smaller substances. This result generalizes the observation made in [14] that the scope of APS may also be reached if, for instance, CO2, NH3, phosphate, sulfate, water and oxygen are used as seed. The frequency of assignment to the second largest consensus scope also increases with increasing seed size, however, it does not change considerably for seed sizes larger than 10. For the assignment to the consensus scope of cluster I, and in fact for the other clusters as well, the frequency also increases for small seed sizes but tends to decrease when the seed sizes become large. The reason is that for larger sets of seed compounds it becomes increasingly difficult to find such combinations which do not exhibit a large biosynthetic potential. Therefore, for larger seed sizes, the frequency of assignment is shifted towards the larger consensus scopes.

Bottom Line: We observe that most of the resulting consensus scopes overlap or are fully contained in others, revealing a hierarchical ordering of metabolites according to their biosynthetic potential.A central result is that chemically very similar substances with different biological functions may differ significantly in their biosynthetic potentials.Our studies provide an important step towards understanding fundamental design principles of metabolic networks determined by the structural and functional complexity of metabolites.

View Article: PubMed Central - PubMed

Affiliation: Interdisciplinary Center for Scientific Computing, University of Heidelberg, Heidelberg, Germany.

ABSTRACT
A major challenge in systems biology is to understand how complex and highly connected metabolic networks are organized. The structure of these networks is investigated here by identifying sets of metabolites that have a similar biosynthetic potential. We measure the biosynthetic potential of a particular compound by determining all metabolites than can be produced from it and, following a terminology introduced previously, call this set the scope of the compound. To identify groups of compounds with similar scopes, we apply a hierarchical clustering method. We find that compounds within the same cluster often display similar chemical structures and appear in the same metabolic pathway. For each cluster we define a consensus scope by determining a set of metabolites that is most similar to all scopes within the cluster. This allows for a generalization from scopes of single compounds to scopes of a chemical family. We observe that most of the resulting consensus scopes overlap or are fully contained in others, revealing a hierarchical ordering of metabolites according to their biosynthetic potential. Our investigations show that this hierarchy is not only determined by the chemical complexity of the metabolites, but also strongly by their biological function. As a general tendency, metabolites which are necessary for essential cellular processes exhibit a larger biosynthetic potential than those involved in secondary metabolism. A central result is that chemically very similar substances with different biological functions may differ significantly in their biosynthetic potentials. Our studies provide an important step towards understanding fundamental design principles of metabolic networks determined by the structural and functional complexity of metabolites.

Show MeSH