Pgam5
D. melanogaster
Phosphoglycerate mutase 5
What the model saw
Gene: Pgam5 Organism: Drosophila melanogaster Known functions: Phosphoglycerate mutase 5. phosphoglycerate mutase 5. phosphatase activity. phosphoglycerate mutase activity. protein binding. protein serine/threonine kinase activator activity. protein serine/threonine phosphatase activity.
View unredacted entry
Phosphoglycerate mutase 5. phosphoglycerate mutase 5. phosphatase activity. phosphoglycerate mutase activity. protein binding. protein serine/threonine kinase activator activity. protein serine/threonine phosphatase activity.
Solver output
PGAM5 is a mitochondria-localized serine/threonine phosphatase that activates PINK1/Parkin-independent mitophagy and necroptosis pathways. Its phosphatase activity dephosphorylates and activates downstream substrates including FUNDC1 (mitophagy receptor) and RIPK3/MLKL (necroptosis effectors), promoting regulated necrotic cell death and mitochondrial fragmentation via DRP1 dephosphorylation. In Drosophila, PGAM5 acts as a protein serine/threonine phosphatase that can activate stress kinase cascades (e.g., ASK1/MAPK), amplifying mitochondrial stress signaling. Overactivation of these pathways drives mitochondrial dysfunction, excessive cell death, and tissue degeneration, which are hallmarks associated with shortened lifespan. Its role as a serine/threonine kinase activator further suggests it amplifies pro-death signaling rather than pro-survival pathways, making its normal function net anti-longevity.
GenAge curators classify each gene's normal function as promoting (Pro-Longevity) or opposing (Anti-Longevity) longevity, based on synthesis across studies. Loss-of-function effects can vary from this depending on the manipulation.
Advisor judgment
The model predicted anti_longevity with 0.72 confidence, but the ground truth is pro_longevity. The model's reasoning focused on PGAM5's role in necroptosis, mitochondrial fragmentation, and pro-death signaling pathways, concluding it would shorten lifespan. However, in Drosophila, Pgam5 appears to have a pro-longevity role. The mechanistic reasoning is also likely incorrect for the Drosophila context - while some of the mammalian biology described (RIPK3, MLKL necroptosis) may be accurate in mammals, these pathways don't directly translate to Drosophila, and the model failed to consider that PGAM5's phosphatase activity in Drosophila may serve protective/pro-survival functions (e.g., maintaining mitochondrial homeostasis, supporting PINK1 pathway in a beneficial way). The model was confidently wrong in both direction and mechanism.
Raw API responses
solver
{
"reasoning": "PGAM5 is a mitochondria-localized serine/threonine phosphatase that activates PINK1/Parkin-independent mitophagy and necroptosis pathways. Its phosphatase activity dephosphorylates and activates downstream substrates including FUNDC1 (mitophagy receptor) and RIPK3/MLKL (necroptosis effectors), promoting regulated necrotic cell death and mitochondrial fragmentation via DRP1 dephosphorylation. In Drosophila, PGAM5 acts as a protein serine/threonine phosphatase that can activate stress kinase cascades (e.g., ASK1/MAPK), amplifying mitochondrial stress signaling. Overactivation of these pathways drives mitochondrial dysfunction, excessive cell death, and tissue degeneration, which are hallmarks associated with shortened lifespan. Its role as a serine/threonine kinase activator further suggests it amplifies pro-death signaling rather than pro-survival pathways, making its normal function net anti-longevity.",
"confidence": 0.72,
"key_pathways": [
"PINK1/Parkin mitophagy and mitochondrial fragmentation via DRP1 dephosphorylation",
"Necroptosis/regulated necrosis via RIPK3 activation",
"ASK1-MAPK stress kinase signaling"
],
"mechanism_class": "mitochondrial_dysfunction",
"longevity_influence": "anti_longevity"
}advisor
{
"notes": "The model predicted anti_longevity with 0.72 confidence, but the ground truth is pro_longevity. The model's reasoning focused on PGAM5's role in necroptosis, mitochondrial fragmentation, and pro-death signaling pathways, concluding it would shorten lifespan. However, in Drosophila, Pgam5 appears to have a pro-longevity role. The mechanistic reasoning is also likely incorrect for the Drosophila context - while some of the mammalian biology described (RIPK3, MLKL necroptosis) may be accurate in mammals, these pathways don't directly translate to Drosophila, and the model failed to consider that PGAM5's phosphatase activity in Drosophila may serve protective/pro-survival functions (e.g., maintaining mitochondrial homeostasis, supporting PINK1 pathway in a beneficial way). The model was confidently wrong in both direction and mechanism.",
"failure_mode": "confident_wrong",
"answer_correct": false,
"mechanism_correct": false,
"reasoning_quality": 2,
"ground_truth_questionable": false
}