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Based on all the information I've gathered, I'll now provide a comprehensive review of the GO-CAM model gomodel:613aae0000000500 "cobalamin metabolic process 3, methylation of cobalamin (Mouse)".

Review of GO-CAM Model: Cobalamin Metabolic Process 3, Methylation of Cobalamin (Mouse)

Overview

This GO-CAM model (gomodel:613aae0000000500) represents the "cobalamin metabolic process 3, methylation of cobalamin" pathway in mouse. It models the conversion of cobalamin (vitamin B12) to its active methylcobalamin form and its subsequent use in methionine synthesis.

Model Structure Analysis

The model includes five activities with the following gene products: 1. MMACHC (MGI:MGI:1914346) - oxidoreductase activity 2. MMADHC (MGI:MGI:1923786) - molecular carrier activity 3. MTRR (MGI:MGI:1891037) - [methionine synthase] reductase (NADPH) activity 4. MTR (MGI:MGI:894292) - methionine synthase activity 5. A second MTR activity with output CHEBI:16304 (cob(II)alamin)

Causal flow analysis

The causal flow of the model appears to be: - MMACHC (oxidoreductase) → MMADHC (molecular carrier) - MMADHC → MTR (methionine synthase) AND MTR (with cob(II)alamin output) - MTR (with cob(II)alamin output) → MTRR (methionine synthase reductase) - MTRR → MTR (methionine synthase)

This represents a circular pathway where MTR activity produces cob(II)alamin, which is then a substrate for MTRR, which in turn produces methylcobalamin (CHEBI:28115) that enables the methionine synthase activity of MTR again.

Evaluation Against GO-CAM Best Practices

1. Biological accuracy

The model accurately represents the current understanding of the methylcobalamin pathway: - MMACHC acts as an oxidoreductase to prepare cobalamin for further processing - MMADHC functions as a molecular carrier to deliver cobalamin to the appropriate enzymes - MTR uses methylcobalamin as a cofactor for methionine synthesis - MTRR regenerates the active methylcobalamin form when MTR's cobalamin cofactor becomes oxidized to cob(II)alamin

The molecular species (CHEBI:28115, methylcobalamin; CHEBI:16304, cob(II)alamin) are appropriately included.

2. Appropriate use of causal relations

The model uses the appropriate causal relations: - "RO:0002413" (provides input for) is used consistently to link activities in the pathway - The relations accurately reflect that each protein's activity provides input for the downstream protein's activity

3. Cellular component annotations

The model includes "GO:0005829" (cytosol) as the location for MMACHC and MMADHC activities, which is correct based on their known subcellular localization.

4. Use of evidence codes

The model uses appropriate evidence codes: - ECO:0000266 (sequence orthology evidence used in manual assertion) - correctly used with human Uniprot IDs as with_objects - ECO:0000315 (mutant phenotype evidence used in manual assertion) - appropriately used with mouse genes

5. Completeness of the model

The model appears to include all the essential components of the methylcobalamin metabolic pathway. It correctly represents: - Initial processing of cobalamin by MMACHC/MMADHC - The role of methionine synthase (MTR) - The regeneration of the active methylcobalamin form by MTRR

Recommendations for Improvement

While the model is generally well-constructed, I recommend the following improvements:

  1. Add cellular component annotation for MTRR and MTR: Both activities should have "occurs_in" relationships with the cytosol (GO:0005829) as they are cytosolic proteins.

  2. Clarify input/output relationships: Add explicit "has_input" and "has_output" annotations for MMACHC to show what form of cobalamin it processes.

  3. Complete molecular details: Consider adding the "has_input" relationship for MMADHC that would show it receives cobalamin from MMACHC.

  4. Add homocysteine and methionine molecules: The model would benefit from including homocysteine as input and methionine as output for the MTR activity to complete the biochemical context.

  5. Consider using a complex representation: Since MMACHC and MMADHC are known to form a functional complex, as per the document "How to annotate complexes in GO-CAM", this interaction could be represented.

  6. Add additional evidence: Some of the causal associations lack evidence annotations. Adding evidence for these relationships would strengthen the model.

Conclusion

The GO-CAM model "cobalamin metabolic process 3, methylation of cobalamin (Mouse)" (gomodel:613aae0000000500) is a well-constructed representation of vitamin B12 metabolism. It accurately captures the key activities and relationships in the methylcobalamin pathway and uses appropriate ontology terms and evidence codes.

The model is biologically accurate, following the known pathway where cobalamin is processed by MMACHC, transported by MMADHC, utilized by methionine synthase (MTR), and regenerated by methionine synthase reductase (MTRR). The circular nature of the pathway is correctly represented through the causal flow of activities.

With the suggested minor improvements, particularly regarding cellular components and molecular inputs/outputs, the model would provide an even more comprehensive representation of this important metabolic pathway.