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Based on my review of the GO-CAM model gomodel:63894f2500002043 and the supporting evidence, I'll now provide a comprehensive evaluation of this model.

GO-CAM Model Review: gomodel:63894f2500002043

Basic Model Information

  • Model ID: gomodel:63894f2500002043
  • Title: Positive regulation of glycolytic process 1 (Mouse)
  • Taxon: NCBITaxon:10090 (Mouse)
  • Status: Production

Model Overview

This GO-CAM model represents the positive regulation of the glycolytic process in mouse, specifically focusing on the regulation of glycolysis through fructose-2,6-bisphosphate (F2,6BP). The model includes four key activities represented by four distinct proteins:

  1. Pfkfb1 (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 1) - MGI:MGI:107816
  2. Pfkl (ATP-dependent 6-phosphofructokinase, liver type) - MGI:MGI:97547
  3. Gpi1 (Glucose-6-phosphate isomerase) - MGI:MGI:95797
  4. Ppp2ca (Protein phosphatase 2A catalytic subunit alpha) - MGI:MGI:1321159

The model illustrates how these proteins interact to positively regulate glycolysis through a sequence of activities that involves producing and responding to fructose-2,6-bisphosphate, a key regulator of glycolytic flux.

Detailed Review

1. Biological Accuracy

The model accurately represents the canonical understanding of fructose-2,6-bisphosphate-mediated regulation of glycolysis:

  • Pfkfb1 catalyzes the synthesis of fructose-2,6-bisphosphate from fructose-6-phosphate, which is supported by evidence from PMID:12230553.
  • Pfkl is positively regulated by fructose-2,6-bisphosphate, enhancing glycolytic flux, as evidenced in PMID:8172601 and PMID:35530161.
  • Gpi1 provides input for the Pfkfb1 activity, consistent with its role in converting glucose-6-phosphate to fructose-6-phosphate (PMID:2344351).
  • Ppp2ca (Protein phosphatase 2A) positively regulates Pfkfb1 activity, consistent with its known role in dephosphorylating and thus activating Pfkfb1, as supported by PMID:7592845.

The molecular interactions and causal relationships depicted in the model align with the known biochemistry of glycolysis regulation.

2. Model Structure and Completeness

The model includes the core components necessary to understand the positive regulation of glycolysis through fructose-2,6-bisphosphate:

  • All activities are appropriately enabled by specific gene products.
  • Cellular locations are specified when known (e.g., Pfkfb1 and Gpi1 in cytosol).
  • Molecular functions are correctly assigned (e.g., 6-phosphofructo-2-kinase activity for Pfkfb1).
  • Biological processes are properly indicated (e.g., Pfkl's participation in glycolytic process through fructose-6-phosphate).
  • Causal relationships are clearly defined using appropriate relationship predicates.

Strengths:

  • The model includes the output molecule (beta-D-fructofuranose 2,6-bisphosphate) for Pfkfb1 activity.
  • The model uses appropriate causal relationship predicates (RO:0002629 for direct positive regulation and RO:0002413 for provides input for).
  • The model includes occurrences in cellular components where known.

Potential improvements:

  • The model could potentially include more detail on the phosphorylation state of Pfkfb1 that is regulated by Ppp2ca.
  • Additional details about the inputs and outputs for Pfkl activity could enhance completeness.

3. Evidence and References

The model has robust evidential support:

  • Appropriate evidence codes are used throughout (ECO:0000266, ECO:0000314, ECO:0000315).
  • All activities are backed by literature references (PMIDs).
  • Where homology-based evidence is used, appropriate "with" references are included.

4. GO-CAM Best Practices

The model follows GO-CAM best practices:

  • Complex representation: The model appropriately represents individual proteins rather than complexes since the activities are carried out by specific subunits.
  • Causal relationships: The model correctly uses the "directly positively regulates" predicate (RO:0002629) for the regulatory relationships and "provides input for" (RO:0002413) for metabolic input relationships.
  • Activity flow: The activities are connected in a logical flow that represents the biological pathway.
  • Parsimony: The model is concise while capturing the essential regulatory relationships.

5. Validation Against Literature

The scientific literature supports the relationships depicted in the model:

  • PMID:12230553 describes the role of Fru-2,6-P2 in regulating hepatic carbohydrate metabolism, supporting the positive regulatory role of Pfkfb1 on glycolysis.
  • PMID:8172601 supports the role of Pfkl in the phosphorylation of fructose-6-phosphate, an essential step in glycolysis.
  • PMID:2344351 validates the role of Gpi1 (glucose-6-phosphate isomerase) in the early steps of glycolysis.
  • PMID:26080680 provides evidence for the cytosolic localization of Gpi1.
  • PMID:35530161 supports the involvement of Pfkl in the glycolytic process through fructose-6-phosphate.

6. Isoform Specificity and Tissue Context

The model appropriately represents:

  • The specific mouse isoforms of the proteins involved (Pfkfb1, Pfkl, Gpi1, Ppp2ca).
  • The tissue context is implied to be liver-specific based on the liver-type Pfkl and the evidence used.

Recommendations

Based on my review, this model is scientifically accurate and adheres to GO-CAM best practices. It provides a clear representation of the positive regulation of glycolysis through fructose-2,6-bisphosphate in mouse.

Minor Suggestions for Enhancement:

  1. Add metabolic inputs/outputs for Pfkl: While the model shows Pfkl participating in glycolysis, adding its specific substrate (fructose-6-phosphate) and product (fructose-1,6-bisphosphate) would enhance clarity.

  2. Include the phosphorylation state details: The model could specify that Ppp2ca regulates Pfkfb1 by dephosphorylating specific residues, shifting the kinase/phosphatase activity ratio.

  3. Consider expanding the model: The model could be expanded to include additional regulatory inputs to Pfkfb1 (e.g., hormone signaling) or to show downstream glycolytic steps affected by increased Pfkl activity.

Conclusion

The GO-CAM model gomodel:63894f2500002043 is a high-quality representation of the positive regulation of glycolysis via fructose-2,6-bisphosphate in mouse. It is scientifically accurate, well-evidenced, and follows GO-CAM best practices. The model effectively captures the key molecular activities and causal relationships involved in this regulatory pathway, making it a valuable resource for understanding glycolytic regulation.