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Based on all the information I've gathered, I can now review the GO-CAM model (gomodel:639bc18f00000430) for accuracy and adherence to best practices.

Review of GO-CAM Model 639bc18f00000430

Model Title

"Negative regulation of glycolytic process through fructose-6-phosphate 2 (Mouse)"

Overview

This model describes a regulatory pathway in mouse that involves the negative regulation of glycolysis through a pathway that includes: 1. Glucose-6-phosphate isomerase (Gpi1) 2. Fructose-2,6-bisphosphate 2-phosphatase activity (Pfkfb1) 3. cAMP-dependent protein kinase activity (Prkaca) 4. 6-phosphofructokinase activity (Pfkl)

The model shows the relationship between these activities and their role in the negative regulation of glycolysis through fructose-6-phosphate.

Structure and Accuracy Assessment

Molecular Functions and Proteins:

  1. Pfkl (MGI:MGI:97547) - 6-phosphofructokinase activity (GO:0003872)
  2. This is correctly annotated as participating in glycolytic process through fructose-6-phosphate (GO:0061615)

  3. The UniProt information confirms this is appropriate, as Pfkl is a key enzyme that catalyzes the phosphorylation of fructose-6-phosphate to fructose-1,6-bisphosphate

  4. Prkaca (MGI:MGI:97592) - cAMP-dependent protein kinase activity (GO:0004691)

  5. Correctly annotated as participating in negative regulation of glycolytic process (GO:0045820)

  6. The literature (PMID:16155866) supports this function, showing that PKA activity from this catalytic subunit can lead to decreased glycolysis

  7. Pfkfb1 (MGI:MGI:107816) - fructose-2,6-bisphosphate 2-phosphatase activity (GO:0004331)

  8. Correctly annotated as participating in negative regulation of glycolytic process (GO:0045820)
  9. Located in cytosol (GO:0005829)
  10. Has input of beta-D-fructose 2,6-bisphosphate(4-) (CHEBI:58579)

  11. The UniProt entry confirms Pfkfb1 has both kinase and phosphatase activities, and phosphorylation by PKA shifts it toward phosphatase activity

  12. Gpi1 (MGI:MGI:95797) - glucose-6-phosphate isomerase activity (GO:0004347)

  13. Correctly annotated as being located in the cytosol (GO:0005829)

Causal Relationships:

  1. Causal relationship 1: Prkaca directly positively regulates (RO:0002629) Pfkfb1
  2. This is supported by the literature. PMID:16155866 shows that PKA phosphorylates Pfkfb1, which shifts its activity toward the phosphatase function.

  3. The UniProt entry for Pfkfb1 confirms that "phosphorylation at Ser-33 inhibits the kinase and activates the bisphosphatase"

  4. Causal relationship 2: Pfkfb1 directly negatively regulates (RO:0002630) Pfkl

  5. This is accurate as the phosphatase activity of Pfkfb1 degrades fructose-2,6-bisphosphate, which is an activator of Pfkl

  6. The decrease in F-2,6-P2 levels leads to decreased activity of phosphofructokinase, inhibiting glycolysis

  7. Causal relationship 3: Gpi1 provides input for (RO:0002413) Pfkfb1

  8. This is accurate as glucose-6-phosphate isomerase produces fructose-6-phosphate, which is a substrate for Pfkfb1

Biological Accuracy

The pathway described in this model is biologically accurate and consistent with current knowledge:

  1. PKA (Prkaca) phosphorylates and activates the phosphatase activity of Pfkfb1
  2. Activated phosphatase activity of Pfkfb1 decreases the levels of fructose-2,6-bisphosphate
  3. Decreased fructose-2,6-bisphosphate leads to decreased activity of phosphofructokinase (Pfkl)
  4. This ultimately leads to negative regulation of glycolysis

This is consistent with the literature, including PMID:16155866, which demonstrates that constitutively active PKA leads to decreased levels of fructose-2,6-bisphosphate and inhibition of glycolysis.

Adherence to GO-CAM Best Practices

  1. Representation of molecule activities: The model correctly represents the molecular functions of each protein and their roles in biological processes.

  2. Causal relationships: The model uses appropriate causal relationship predicates:

  3. RO:0002413 (provides input for) for enzymatic reactions where one enzyme produces a substrate for another
  4. RO:0002629 (directly positively regulates) for positive regulation

  5. RO:0002630 (directly negatively regulates) for negative regulation

  6. Cellular components: The model includes appropriate cellular locations (cytosol for Pfkfb1 and Gpi1).

  7. Evidence: Each annotation has appropriate evidence codes and references to literature.

  8. Use of complexes: This model does not involve complexes, so the complex annotation guidelines do not apply here.

Suggestions for Improvement

While the model is accurate and well-constructed, a few potential improvements could be considered:

  1. Additional molecular details: The model could potentially include the fact that Prkaca phosphorylates Pfkfb1 at Ser-33, which is a specific mechanism that shifts the activity of Pfkfb1.

  2. Additional biochemical context: The model could include ATP as an input for both Prkaca and Pfkl activities, as both are kinases that use ATP.

  3. Expanded pathway context: The model could be expanded to include how this regulation fits into the broader context of metabolic regulation, possibly including:

  4. The role of glucagon in activating PKA
  5. The connection to gluconeogenesis, which is often upregulated when glycolysis is downregulated

Summary

This is a well-constructed GO-CAM model that accurately represents the negative regulation of glycolysis through the PKA-Pfkfb1-Pfkl axis. It adheres to the GO-CAM best practices for representing molecular activities and their causal relationships. The model is supported by appropriate evidence from the literature and provides a clear representation of the pathway in mouse. No significant errors or issues were found in the model.