Skip to content

YeastPathways TCA EUK PWY TCA cycle aerobic respiration imported from Saccharomyces Genome Database

Let me now provide a detailed review of the GO-CAM model for the yeast TCA cycle (YeastPathways_TCA-EUK-PWY):

GO-CAM Review: TCA Cycle (YeastPathways_TCA-EUK-PWY)

Model Overview

This GO-CAM model (https://bioregistry.io/go.model:YeastPathways_TCA-EUK-PWY) represents the TCA cycle (tricarboxylic acid cycle, also known as citric acid cycle or Krebs cycle) in Saccharomyces cerevisiae. It was imported from the Saccharomyces Genome Database (SGD) and models the aerobic respiration process (GO:0009060).

Strengths

  1. Comprehensive representation: The model captures all key enzymatic steps of the TCA cycle with appropriate gene products, molecular functions, inputs, and outputs.
  2. Cellular localization: Most activities are correctly annotated to occur in the mitochondrion (GO:0005739), which is the correct subcellular location for the TCA cycle.
  3. Complex representation: Protein complexes (e.g., succinate dehydrogenase, isocitrate dehydrogenase) are correctly represented according to GO-CAM guidelines, with their component subunits listed.
  4. Complete chemical transformations: Each reaction includes appropriate substrate and product molecules with their CHEBI identifiers.

Issues Identified

  1. Inconsistent Causal Relationships:
  2. Only a few causal relationships (RO:0002411 "directly provides input for") are established between reactions, specifically:
    • Aconitate hydratase (ACO1) to aconitate dehydratase (ACO2)
    • Succinate-CoA ligase to succinate dehydrogenase
    • 2-oxoglutarate dehydrogenase to isocitrate dehydrogenase

  3. The majority of reactions lack causal connections, making it difficult to follow the complete cycle flow.

  4. Duplicate Entries:

  5. There are duplicate entries for some reactions:
    • Three separate citrate synthase activities (enabled by CIT1, CIT2, CIT3)
    • Two separate malate dehydrogenase activities (enabled by MDH1, MAE1)
    • Two separate aconitate hydratase activities (enabled by ACO1, ACO2)
    • Two separate pyruvate carboxylase activities (enabled by PYC1, PYC2)

  6. While these may represent isozymes, they are disconnected and not shown as alternative paths in the pathway.

  7. Conflicting Cellular Locations:

  8. Some TCA cycle enzymes are annotated to the cytosol (GO:0005829) rather than mitochondrion:
    • Aconitate hydratase (ACO1, ACO2) - in cytosol
    • Pyruvate carboxylase (PYC1, PYC2) - in cytosol

  9. This is inconsistent with the canonical TCA cycle location (mitochondria).

  10. Inconsistent Complex Representation:

  11. Succinate dehydrogenase complex has two representations with different subunit compositions:
    • One with SGD:S000218027 (proper complex ID) containing SDH1, SDH2, SDH3, SDH4
    • Another with GO:0032991 (generic complex) containing SDH2, SDH3, SDH4, SDH9

  12. This inconsistency creates confusion about the actual complex composition.

  13. Incomplete Activity Flow:

  14. The model does not completely represent the cyclic nature of the TCA cycle.
  15. Many reactions that should be connected are isolated (e.g., citrate synthase to aconitase).

Recommendations

  1. Complete the causal relationships:
  2. Add "directly provides input for" (RO:0002411) relationships between all consecutive reactions to represent the cycle properly.

  3. Ensure the cycle is closed by connecting malate dehydrogenase to citrate synthase.

  4. Consolidate duplicate entries:

  5. If different isozymes perform the same reaction in the same compartment, use causal relationships to indicate they are alternatives.

  6. Alternatively, document in comments why multiple instances of the same reaction are represented.

  7. Correct subcellular localization:

  8. Review and correct the cellular location annotations to ensure all TCA cycle enzymes are properly localized.

  9. If some reactions genuinely occur in the cytosol (e.g., in alternate pathways), this should be clearly documented.

  10. Standardize complex representation:

  11. Resolve the inconsistency in the succinate dehydrogenase complex representation by using a single consistent complex ID with the correct subunits.

  12. Follow the GO-CAM guidelines for complexes (option 1 or 2 from the document).

  13. Add biological context:

  14. Include additional annotations or comments to explain the biological relevance of certain features (e.g., why some enzymes are in the cytosol).

Summary

The GO-CAM model for the yeast TCA cycle provides a valuable representation of this critical metabolic pathway. While it captures most enzymatic steps correctly, it would benefit from improved causal connections between reactions, consistent subcellular localizations, and standardized complex representations. These improvements would make the model more accurate and easier to interpret, especially for researchers unfamiliar with the TCA cycle.

The model is consistent with known biochemistry of the TCA cycle but requires refinement in how the enzymes and reactions are connected to fully represent the cycle's flow and compartmentalization.