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6246724f00000549 Renin angiotensin pathway Human

Based on the documentation I've reviewed and the model details, let me now perform a thorough review of the renin-angiotensin pathway GO-CAM model (gomodel:6246724f00000549).

GO-CAM Model Review: Renin-angiotensin pathway (Human)

Model Overview:

This GO-CAM model represents the renin-angiotensin pathway in humans, a critical biological system for regulating blood pressure, fluid balance, and electrolyte homeostasis. The model includes four key activities connected in a causal chain:

  1. Renin (UniProtKB:P00797-1) with aspartic-type endopeptidase activity (GO:0004190)
  2. Angiotensin-converting enzyme/ACE (UniProtKB:P12821) with peptidyl-dipeptidase activity (GO:0008241)
  3. Angiotensinogen (UniProtKB:P01019) with hormone activity (GO:0005179)
  4. Angiotensin II type 1 receptor/AGTR1 (UniProtKB:P30556) with angiotensin type I receptor activity (GO:0001596)

Strengths of the Model:

  1. The model accurately captures the key components of the renin-angiotensin pathway, including the enzyme-substrate relationships and signal transduction.
  2. The cellular compartments for each protein are appropriately specified, with:
  3. Renin occurring in extracellular space (GO:0005615)
  4. ACE occurring in extracellular space (GO:0005615)
  5. Angiotensinogen occurring in extracellular space (GO:0005615)
  6. AGTR1 occurring in plasma membrane (GO:0005886)
  7. The causal relationships between activities are correctly represented with appropriate relation predicates:
  8. Renin directly positively regulates (RO:0002629) ACE
  9. ACE causally upstream with positive effect (RO:0002304) on angiotensinogen
  10. Angiotensinogen directly positively regulates (RO:0002629) AGTR1
  11. Each activity is appropriately associated with its corresponding biological process:
  12. Renin with angiotensin maturation (GO:0002003)
  13. ACE with angiotensin maturation (GO:0002003)
  14. Angiotensinogen with maintenance of blood vessel diameter homeostasis by renin-angiotensin (GO:0002034)
  15. AGTR1 with angiotensin-activated signaling pathway (GO:0038166)
  16. Evidence codes and PMIDs are included for each activity and relationship.

Issues and Suggestions for Improvement:

  1. Substrate-Enzyme Relationships: According to the Signaling Receptor Activity Guidelines, the model should specify "has input" relationships for substrates. Currently, the causal relationships are correctly shown, but the substrate input relationships could be more explicit.

  2. Activation Mechanism Clarification: The relationship between angiotensinogen (AGT) and AGTR1 should be clarified. Based on the literature, angiotensinogen is cleaved by renin to produce angiotensin I, which is then cleaved by ACE to produce angiotensin II, which is the actual ligand that activates AGTR1. The model correctly shows the causal chain but may benefit from explicit representation of these intermediate peptides (Angiotensin I and Angiotensin II).

  3. Molecular Function Specificity: For angiotensinogen (AGT), the molecular function is currently annotated as "hormone activity" (GO:0005179), but a more specific term related to its role as a precursor for the angiotensin peptides might be more appropriate. According to UniProt, its function is as an essential component of the renin-angiotensin system.

  4. Downstream Effects: The model could be expanded to include the downstream effects of AGTR1 activation, such as G-protein coupling and subsequent signaling cascades, which ultimately lead to vasoconstriction, aldosterone release, and other physiological effects.

  5. Alternative Pathways: The model could also represent alternative processing pathways, such as the action of ACE2 on angiotensin peptides, which produces peptides with different biological activities, as mentioned in the UniProt entries.

Biological Validation:

  1. Cleavage Specificity: The UniProt entries confirm that renin specifically cleaves angiotensinogen to release angiotensin I, and ACE then converts angiotensin I to angiotensin II by removing a dipeptide. This sequential processing is implied but not explicitly represented in the model.

  2. Receptor Specificity: The model correctly identifies AGTR1 as the receptor for angiotensin II, consistent with the literature (including PMID:32079768 and PMID:30639100 cited in the model).

  3. Cellular Localization: The cellular locations specified in the model align with those described in the UniProt entries:

  4. Renin is secreted and acts in the extracellular space
  5. ACE is a membrane protein with an extracellular catalytic domain
  6. Angiotensinogen is secreted into the bloodstream
  7. AGTR1 is a cell surface receptor in the plasma membrane

Overall Assessment:

This GO-CAM model provides a sound representation of the core components and relationships in the renin-angiotensin pathway. The model adheres to GO-CAM best practices for representing signaling pathways involving protein ligands and receptors.

The model could be enhanced by: 1. More explicit representation of the peptide intermediates (Angiotensin I and II) 2. Including downstream signaling effects of AGTR1 activation 3. Adding alternative processing pathways (e.g., ACE2)

These suggestions would make the model more comprehensive, but the current representation is accurate and captures the essential aspects of the renin-angiotensin pathway.

Recommendation:

This model is biologically accurate and follows GO-CAM best practices. It can be approved, potentially with minor suggestions for future enhancements as noted above.