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665912ed00000015 tricarboxylic acid cycle GO 0006099

Based on my review of the GO-CAM model "tricarboxylic acid cycle (GO:0006099)" with ID gomodel:665912ed00000015, I'll provide a comprehensive analysis focusing on the model's biological content, connectivity, and adherence to GO-CAM best practices.

Overview

This model represents the tricarboxylic acid (TCA) cycle, also known as the citric acid cycle or Krebs cycle, in Schizosaccharomyces pombe (fission yeast, taxon NCBITaxon:4896). The model includes all the major enzymes of the TCA cycle and their molecular functions, with appropriate causal connections between activities.

Strengths of the Model

  1. Complete Pathway Representation: The model captures all essential enzymes of the TCA cycle:
  2. Citrate synthase (cit1)
  3. Aconitase (aco1, aco2)
  4. Isocitrate dehydrogenase (idh1, idh2)
  5. α-Ketoglutarate dehydrogenase complex (kgd1, kgd2, kgd4, dld1)
  6. Succinyl-CoA ligase (sca1, lsc2)
  7. Succinate dehydrogenase complex (sdh1, sdh2, sdh3, tim18)
  8. Fumarate hydratase (fum1)

  9. Malate dehydrogenase (mdh1)

  10. Proper Subcellular Localization: Appropriate mitochondrial locations are specified (GO:0005739, GO:0005759, GO:0005743).

  11. Causal Connectivity: Activities are connected using RO:0002413 (provides input for), creating a coherent representation of the cycle's reaction sequence.

  12. Appropriate Molecular Functions: Each enzyme is annotated with the correct molecular function term.

  13. Adaptor Protein Annotation: KGD4 is correctly represented as having a protein-macromolecule adaptor activity (GO:0030674), following the "How to annotate complexes in GO-CAM" guidance.

Areas for Improvement

  1. Missing Molecular Inputs/Outputs: While some activities have inputs and outputs (e.g., dihydrolipoamide for dld1, succinyl-CoA for sca1 and lsc2), many activities are missing their explicit chemical inputs/outputs, which would make the model more complete.

  2. Duplicate Causal Associations: Several activities have duplicate causal associations with the same predicate and target. For example:

  3. kgd4 has duplicate associations to kgd1 and kgd2

  4. Multiple activities have both evidenced and non-evidenced causal associations to the same targets

  5. Incomplete Evidence: Some activities have connections without evidence annotations.

  6. Redundant Connections: There are multiple causal paths from some activities to others. For example, aco2 has three identical causal connections to idh1 and idh2.

  7. Comment Clarity: The comment about "directons, particularly fumerate hydratase /dehydratase" contains a typo ("directons" should be "directions") and is unclear.

Specific Technical Issues

  1. KGD4 Complex Annotations: The comment about KGD4 indicates it functions as an adaptor protein in the α-ketoglutarate dehydrogenase complex, which is correctly represented. However, the causal associations from kgd4 to both kgd1 and kgd2 use RO:0012009 instead of a more specific term that would clarify its role in stabilizing the complex.

  2. Respiratory Chain Complex II: The electron transfer from SDH to ubiquinone (GO:0006121) is included, but could be better integrated with the main TCA cycle.

  3. ACO2 Annotation: The comment "aco2 is TCA in S. cerevisiae when glucose is limiting" is present in the model, but this statement is about S. cerevisiae while the model represents S. pombe. This may be confusing.

Recommendations

  1. Add Missing Chemical Inputs/Outputs: For each enzymatic reaction, include all relevant chemical inputs and outputs to fully represent the transformations in the TCA cycle.

  2. Remove Duplicate Associations: Clean up duplicate causal associations that have the same predicate and target.

  3. Add Evidence for All Assertions: Ensure all causal connections have appropriate evidence annotations.

  4. Clarify Comments: Revise the comment about fumarate hydratase to make it clearer, and ensure all comments are relevant to S. pombe.

  5. Standardize Representation of Complex Subunits: For the α-ketoglutarate dehydrogenase and succinate dehydrogenase complexes, ensure consistent representation of how subunits interact.

Conclusion

Overall, this GO-CAM model provides a good representation of the TCA cycle in S. pombe with all essential enzymes and connections. The model follows GO-CAM best practices for complex annotation, particularly with the representation of kgd4 as an adaptor protein. With the suggested improvements, the model would be more precise and informative for users, while maintaining its parsimony and readability.

The model is biologically accurate and consistent with standard textbook knowledge of the TCA cycle, with appropriate evidence support from both literature and orthology-based assignments.