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61f34dd300000981 Regulation of gluconeogenesis by SIRT6 FOXO1 and KAT2A GCN5 Human

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Model Review for gomodel:61f34dd300000981 (Regulation of gluconeogenesis by SIRT6, FOXO1 and KAT2A/GCN5 (Human))

Based on my review of the model and the relevant literature, I'm ready to provide a thorough assessment of this GO-CAM.

Model Overview:

This model represents the regulatory pathway by which SIRT6, FOXO1, and KAT2A/GCN5 interact to regulate gluconeogenesis in the human liver. The model consists of 6 molecular activities connected by causal relationships.

Model Strengths:

  1. The model correctly represents the key molecular functions of the main players:
  2. SIRT6 (Q8N6T7) with NAD-dependent protein lysine deacetylase activity (GO:0034979)
  3. FOXO1 (Q12778) with DNA-binding transcription factor activity (GO:0003700)
  4. KAT2A/GCN5 (Q92830) with peptide-lysine-N-acetyltransferase activity (GO:0061733)

  5. PPARGC1A (Q9UBK2) with transcription coactivator activity (GO:0003713)

  6. The model correctly places all activities in the nucleus (GO:0005634), which matches the subcellular localization information from UniProt.

  7. The model correctly connects the activities with causal relationships that are supported by the literature:

  8. SIRT6 directly negatively regulates FOXO1 (supported by PMID:25009184)
  9. SIRT6 directly positively regulates KAT2A (supported by PMID:23142079)
  10. KAT2A directly negatively regulates PPARGC1A (supported by PMID:23142079, PMID:16753578)

  11. FOXO1 directly positively regulates PPARGC1A (supported by references)

  12. The biological process annotations are appropriate:

  13. SIRT6 activities are associated with negative regulation of gluconeogenesis (GO:0045721)
  14. FOXO1 activity is associated with positive regulation of gluconeogenesis (GO:0045722)
  15. PPARGC1A activity is associated with gluconeogenesis (GO:0006094)

Areas for Improvement:

  1. Missing Mechanistic Details: The model could be more explicit about the specific mechanisms:
  2. SIRT6 deacetylates FOXO1, leading to its nuclear exclusion (PMID:25009184)
  3. SIRT6 specifically deacetylates KAT2A at Lys-549, which enhances KAT2A's acetyltransferase activity (PMID:23142079)

  4. KAT2A then acetylates PPARGC1A, which inhibits its transcriptional coactivator activity (PMID:16753578, PMID:23142079)

  5. Potential Missing Activities:

  6. The model doesn't include SIRT1, which was shown in the literature (PMID:23142079) to have opposing effects to SIRT6 on PPARGC1A acetylation and could be relevant for a complete understanding of the pathway.

  7. The model doesn't represent the positive regulation of SIRT6 by p53 as described in PMID:25009184, though this may be outside the specific scope of this model.

  8. Biological Process Association for KAT2A:

  9. Although KAT2A's activity is correctly associated with negative regulation of gluconeogenesis (GO:0045721), this connection could be strengthened by explicitly showing how KAT2A's acetylation of PPARGC1A leads to suppression of gluconeogenic genes.

  10. Additional Evidence:

  11. The model would benefit from citing PMID:25009184 as evidence for the relationship between SIRT6 and FOXO1, as this is a key paper establishing this connection.

Suggested Specific Improvements:

  1. Add molecular details to the causal relationships:
  2. SIRT6 → FOXO1: Add that SIRT6 deacetylates FOXO1 at Lys-423, promoting its nuclear exclusion
  3. SIRT6 → KAT2A: Add that SIRT6 deacetylates KAT2A at Lys-549

  4. KAT2A → PPARGC1A: Add that KAT2A acetylates PPARGC1A at multiple lysine residues

  5. Consider adding SIRT1 as a counterpart to SIRT6 in the regulation of PPARGC1A, showing its opposing effect (deacetylating PPARGC1A), which would provide a more complete picture of the regulatory circuit.

  6. Add downstream effects: The model could be extended to show the downstream effects on specific gluconeogenic genes (G6PC and PCK1) that are regulated by PPARGC1A and FOXO1.

Conclusion:

Overall, gomodel:61f34dd300000981 is a well-constructed model that accurately represents the key molecular activities and causal relationships involved in the regulation of gluconeogenesis by SIRT6, FOXO1, and KAT2A/GCN5. The model is consistent with the literature and reflects the current understanding of this regulatory pathway. The suggested improvements would add more mechanistic detail and provide a more complete representation of the regulatory circuit, but the existing model is scientifically accurate and appropriately structured according to GO-CAM best practices.

The model effectively illustrates how SIRT6 can suppress gluconeogenesis through two complementary mechanisms: (1) by directly promoting FOXO1 nuclear exclusion and (2) by activating KAT2A to acetylate and inhibit PPARGC1A. This dual mechanism provides robust regulation of the gluconeogenic program in the liver.