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Based on all this information, I'll now provide a comprehensive review of the GO-CAM model gomodel:60e7989d00001485.

Review of GO-CAM Model gomodel:60e7989d00001485

Model Overview

Title: Tetrahydrofolate interconversion 1a (Mouse)
Taxon: NCBITaxon:10090 (Mouse)
Status: Production
Source: gomodel:R-HSA-196757
Model ID: gomodel:60e7989d00001485

Model Content Analysis

This GO-CAM model represents the tetrahydrofolate interconversion pathway in mouse, with a focus on four key enzymes participating in this interconnected metabolic network:

  1. Dihydrofolate reductase (DHFR) - MGI:MGI:94890 (Dhfr)
  2. Serine hydroxymethyltransferase 1, cytosolic (SHMT1) - MGI:MGI:98299 (Shmt1)
  3. Serine hydroxymethyltransferase 2, mitochondrial (SHMT2) - MGI:MGI:1277989 (Shmt2)
  4. Thymidylate synthase (TYMS) - MGI:MGI:98878 (Tyms)

The model shows these enzymes operating in the nucleus (all have occurs_in: GO:0005634), which is consistent with the literature finding that folate-dependent nuclear dTMP synthesis occurs in the liver, with the required enzymes localizing to the nucleus during S-phase and G2/M phases of the cell cycle (as supported by PMID:19513116).

Causal Connections

The model correctly represents the flow of metabolites through the tetrahydrofolate interconversion pathway using the RO:0002413 "provides input for" relationship. The causal connections depicted are:

  1. DHFR (MGI:94890) with dihydrofolate reductase activity (GO:0004146) provides input for both:
  2. SHMT1 (MGI:98299) with glycine hydroxymethyltransferase activity (GO:0004372)

  3. SHMT2 (MGI:1277989) with glycine hydroxymethyltransferase activity (GO:0004372)

  4. SHMT1 (MGI:98299) provides input for:

  5. TYMS (MGI:98878) with thymidylate synthase activity (GO:0004799)

  6. SHMT2 (MGI:1277989) provides input for:

  7. TYMS (MGI:98878) with thymidylate synthase activity (GO:0004799)

  8. TYMS (MGI:98878) provides input for:

  9. DHFR (MGI:94890) with dihydrofolate reductase activity (GO:0004146)

This creates a cycle that accurately represents how DHFR regenerates tetrahydrofolate, which is then used by SHMT1/SHMT2 to produce 5,10-methylenetetrahydrofolate, which is in turn used by TYMS to convert dUMP to dTMP while generating dihydrofolate that returns to DHFR.

Evidence and References

The model uses appropriate evidence codes and references:

  • ECO:0000315 (mutant phenotype evidence used in manual assertion) with PMID:19513116
  • ECO:0000314 (direct assay evidence used in manual assertion) with PMID:360074 and PMID:22057276

These references, particularly PMID:19513116, strongly support the nuclear localization of these enzymes and their roles in nuclear thymidylate biosynthesis.

Biological Context

This model accurately represents a critical pathway in one-carbon metabolism necessary for DNA synthesis and cellular division. As described in PMID:19513116, these enzymes are SUMOylated and translocate to the nucleus during S-phase, where they form a metabolically coupled complex for de novo thymidylate synthesis directly at the replication fork, ensuring proper DNA synthesis.

Assessment of Model Accuracy

The model adheres well to the biological understanding of tetrahydrofolate interconversion:

  1. Appropriate molecular functions: Each protein is annotated with its correct enzymatic activity.

  2. Subcellular localization: The nuclear localization is supported by the cited literature.

  3. Proper process annotation: All activities are correctly indicated as part of tetrahydrofolate interconversion (GO:0035999).

  4. Causal relationships: The "provides input for" relationships accurately represent the metabolic flow in this pathway.

Areas for Potential Improvement

While the model is scientifically sound, there are some aspects that could be enhanced:

  1. More detailed process context: The model could potentially benefit from indicating these activities are specifically involved in dTMP biosynthesis, in addition to general tetrahydrofolate interconversion.

  2. Consideration of cytoplasmic versus nuclear roles: The literature indicates that these enzymes function both in the cytoplasm and nucleus, with specific nuclear translocation during S-phase. The model focuses only on the nuclear aspect, which is valid but could be noted as specific to certain cell cycle phases.

  3. Inclusion of metabolites: While GO-CAM focuses on activity flow rather than metabolites, a note about the key metabolites (tetrahydrofolate, 5,10-methylenetetrahydrofolate, etc.) could provide additional context.

Conclusion

The GO-CAM model gomodel:60e7989d00001485 accurately represents the tetrahydrofolate interconversion pathway in mouse, with a focus on the nuclear localization of these activities as supported by the scientific literature. The model adheres to GO-CAM best practices and provides a coherent representation of this metabolic process.

The model effectively captures the key findings from PMID:19513116 which demonstrated that these enzymes localize to the nucleus during specific cell cycle phases to support nuclear thymidylate biosynthesis, contributing to proper DNA replication. The cycle of reactions is represented appropriately with causal relationships that reflect the metabolic dependencies between these enzymes.