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6446bfcb00001243 Thiamine diphosphate biosynthetic process 2 Mouse

Now I'll review the GO-CAM model with ID gomodel:6446bfcb00001243, which is titled "Thiamine diphosphate biosynthetic process 2 (Mouse)" focused on mouse thiamine metabolism.

Overview of the GO-CAM Model

This model describes the thiamine diphosphate biosynthetic pathway in mouse cells, including: - 5 molecular activities carried out by different proteins - 3 causal relationships between activities - Multiple cellular compartments (plasma membrane, cytosol, mitochondrial inner membrane)

Evaluation of Biological Content

The model describes a pathway for thiamine (vitamin B1) uptake, transport, and metabolism in mouse cells, focusing on the following key steps:

  1. Thiamine transmembrane transporters (Slc19a2 and Slc19a3) on the plasma membrane import thiamine into the cell
  2. Thiamine is phosphorylated to thiamine diphosphate (TPP) by thiamine diphosphokinase (Tpk1) in the cytosol
  3. TPP is transported into mitochondria by the mitochondrial TPP transporter (Slc25a19)
  4. Thiamine triphosphate phosphatase (Thtpa) dephosphorylates thiamine triphosphate

The model is well supported by literature evidence and properly annotated with relevant PMIDs. The publications confirm:

  • The function of Slc19a2 and Slc19a3 as thiamine transporters
  • The role of Tpk1 in phosphorylating thiamine to thiamine diphosphate
  • The mitochondrial transport of thiamine diphosphate by Slc25a19
  • The thiamine triphosphate phosphatase activity of Thtpa

Review of Model Structure and GO-CAM Compliance

The model follows GO-CAM best practices with:

  1. Proper use of "enabled by" relationships: Each activity is correctly annotated with the gene product that enables it
  2. Proper cellular location: Each activity is located in the appropriate cellular compartment
  3. Proper use of causal relations: Activities are connected with appropriate causal relations using "provides input for" (RO:0002413)
  4. Appropriate evidence codes: Experimental evidence codes (ECO:0000314 and ECO:0000315) are used with relevant PMIDs
  5. Correct biological process associations: All activities are part of the thiamine diphosphate biosynthetic process (GO:0009229)

Causal Relationships Analysis

The model contains three causal relationships: 1. Slc19a2 (thiamine transmembrane transporter) provides input for Tpk1 (thiamine diphosphokinase) 2. Slc19a3 (another thiamine transmembrane transporter) provides input for Tpk1 3. Thtpa (thiamine triphosphate phosphatase) provides input for Slc25a19 (thiamine pyrophosphate transmembrane transporter)

The first two relationships make biological sense - thiamine transporters import thiamine, which is then a substrate for thiamine diphosphokinase.

However, the third causal relationship (from Thtpa to Slc25a19) appears problematic: - Thtpa dephosphorylates thiamine triphosphate to thiamine diphosphate (TPP) - Slc25a19 is a mitochondrial TPP transporter - The directionality suggests that the output of Thtpa is used by Slc25a19, but the literature doesn't clearly support this relationship - Based on the literature, Slc25a19 transports TPP into mitochondria, while Thtpa dephosphorylates thiamine triphosphate to TPP in the cytosol

Suggestions for Improvement

  1. Reconsider the causal relationship between Thtpa and Slc25a19:
  2. The current relationship suggests Thtpa activity provides input for Slc25a19, but the direction of thiamine metabolism in cells suggests Slc25a19 activity should come after Tpk1 (which produces TPP) and before Thtpa.

  3. The model would be more accurate if restructured to show:

    • Tpk1 (thiamine diphosphokinase) provides input for Slc25a19 (TPP transporter)
    • Slc25a19 potentially provides input for other mitochondrial TPP-dependent enzymes (not currently in the model)

  4. Consider adding other key enzymes in thiamine metabolism:

  5. Thiamine pyrophosphokinase, which converts thiamine diphosphate to thiamine triphosphate (the substrate for Thtpa)

  6. TPP-dependent enzymes that use TPP as a cofactor (e.g., pyruvate dehydrogenase, α-ketoglutarate dehydrogenase)

  7. Add annotations indicating the role of thiamine diphosphate as a cofactor:

  8. The model currently focuses on the biosynthesis of TPP but doesn't capture its role as an essential cofactor for metabolic enzymes

Conclusion

The GO-CAM model "Thiamine diphosphate biosynthetic process 2 (Mouse)" (gomodel:6446bfcb00001243) presents a mostly accurate representation of thiamine transport and metabolism in mouse cells, with well-supported evidence from the literature. The model follows GO-CAM best practices in terms of structure and annotation.

The main issue is the questionable causal relationship between the thiamine triphosphate phosphatase (Thtpa) and the mitochondrial thiamine pyrophosphate transporter (Slc25a19), which doesn't seem to accurately reflect the sequence of events in thiamine metabolism based on the literature. Reorganizing this relationship and potentially adding more enzymes involved in thiamine metabolism would make the model more complete and biologically accurate.