Which ChEBIs are used in Rhea?

Content:

The ChEBI ontology

Rhea uses the chemical ontology ChEBI (Chemical Entities of Biological Interest) to describe reaction participants in a computationally tractable manner. The ChEBI ontology is subdivided into three separate sub-ontologies that are organized in separate namespaces. The individual concepts (aka classes) of the ontology are linked with various types of relationships to form a directed graph where a child class may have several parent classes and some relationships are cyclic in nature.

Figure 1: The ChEBI ontology
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Rhea uses the three ChEBI sub-ontologies to varying degrees:

  • Most ChEBI concepts that are used in Rhea belong to the chemical entity sub-ontology (CHEBI:24431).
  • Rhea uses two concepts of the role sub-ontology (CHEBI:50906):
    • AH2: hydrogen donor (CHEBI:17499)
      A molecular entity that can undergo oxidation by the loss of hydrogen atom(s).
    • A: hydrogen acceptor (CHEBI:13193)
      A molecular entity that can undergo reduction by the gain of hydrogen atom(s).

Figure 2: Examples of ChEBI concepts used in Rhea
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The major microspecies at pH 7.3

Most chemical compounds contain functional groups that are likely to lose or gain protons under specific conditions (pH, temperature, pressure). The ChEBI ontology describes each protonation state of a given compound (neutral, protonated, zwitterionic, tautomeric) with a separate class and links related classes by specific relationships (is conjugate acid of, is conjugate base of, is tautomer of). D-alanine, for instance, has two groups, an amino group and a carboxylic acid group, that each can be (de)protonated. The different protonation states are described by 4 linked ChEBI entities (CHEBI:15570, CHEBI:32435, CHEBI:32436, CHEBI:57416).

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To make reactions non-redundant and balanced for mass and charge, Rhea uses only those ChEBI entities that describe the form that is the major microspecies at pH 7.3, the cytosolic pH of E. coli cells. This follows the policy used by MetaCyc, but other reaction databases may have different policies regarding the protonation state that they use (e.g. KEGG and HMDB use fully hydrogenated uncharged molecules).

The equilibrium between the protonated and deprotonated forms of a compound can be described with the pKa value. We use the Marvin pKa software from ChemAxon to compute the major microspecies at pH 7.3 for all ChEBI entities. The right part of the following figure shows the microspecies distribution of D-alanine at different pH values according to ChemAxon.

Figure 3:
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Figure 4:
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The mapping of all ChEBI compounds to their major microspecies at pH 7.3 is available for download in a tab-separated values file and as part of a chebi.owl file that is enriched with additional has_major_microspecies_at_pH_7_3 relationships.

Figure 5: Rhea adds has_major_microspecies_at_pH_7_3 relationships to link different protonation forms of a compound to the form that is the major microspecies at pH 7.3.

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Searching via ontological relationships

Rhea exploits the relationships of the ChEBI ontology, as well as the additional has_major_microspecies_at_pH_7_3 relationship that it adds, in its website search to support queries by ChEBI concepts that are not directly used to describe reaction participants. You can find more information about this in the document Searching Rhea.