PKH3
S. cerevisiae
protein kinase PKH3
What the model saw
Gene: PKH3 Organism: Saccharomyces cerevisiae Known functions: protein kinase PKH3. ATP binding. protein binding. protein kinase activity. protein serine kinase activity. protein serine/threonine kinase activity.
View unredacted entry
protein kinase PKH3. ATP binding. protein binding. protein kinase activity. protein serine kinase activity. protein serine/threonine kinase activity.
Solver output
PKH3 is a yeast ortholog of mammalian PDK1 (3-phosphoinositide-dependent protein kinase 1), belonging to the PKH kinase family (PKH1/2/3) that activates downstream AGC-family kinases including Sch9 (the yeast S6K ortholog) and Ypk1/2. Sch9 is a central effector of TORC1 signaling, and its activation promotes growth and suppresses stress responses and autophagy, thereby shortening chronological and replicative lifespan. By phosphorylating and activating Sch9 and related AGC kinases, PKH3 feeds into the TOR/Sch9 nutrient-sensing axis, which is a well-established pro-aging pathway in yeast. Reduction of TOR-Sch9 signaling is one of the most robust lifespan-extending interventions in S. cerevisiae, so a kinase that activates this pathway would be expected to oppose longevity. PKH3 also has partially redundant roles with PKH1/2 in sphingolipid-mediated signaling, further linking it to nutrient and stress sensing networks relevant to aging.
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 correctly predicted anti_longevity for PKH3. The mechanistic reasoning is sound and well-grounded: PKH3 as a PDK1 ortholog activating AGC kinases (Sch9) in the TOR/nutrient-sensing pathway is a legitimate pro-aging mechanism in yeast. The model also correctly notes the sphingolipid signaling connection. The confidence of 0.62 is appropriately moderate given PKH3's partial redundancy with PKH1/2 and its less-studied role compared to its paralogs. The reasoning is biologically coherent and consistent with the known anti-longevity classification.
Raw API responses
solver
{
"reasoning": "PKH3 is a yeast ortholog of mammalian PDK1 (3-phosphoinositide-dependent protein kinase 1), belonging to the PKH kinase family (PKH1/2/3) that activates downstream AGC-family kinases including Sch9 (the yeast S6K ortholog) and Ypk1/2. Sch9 is a central effector of TORC1 signaling, and its activation promotes growth and suppresses stress responses and autophagy, thereby shortening chronological and replicative lifespan. By phosphorylating and activating Sch9 and related AGC kinases, PKH3 feeds into the TOR/Sch9 nutrient-sensing axis, which is a well-established pro-aging pathway in yeast. Reduction of TOR-Sch9 signaling is one of the most robust lifespan-extending interventions in S. cerevisiae, so a kinase that activates this pathway would be expected to oppose longevity. PKH3 also has partially redundant roles with PKH1/2 in sphingolipid-mediated signaling, further linking it to nutrient and stress sensing networks relevant to aging.",
"confidence": 0.62,
"key_pathways": [
"TOR/Sch9 nutrient-sensing signaling",
"PDK1-AGC kinase cascade",
"sphingolipid-mediated stress signaling"
],
"mechanism_class": "deregulated_nutrient_sensing",
"longevity_influence": "anti_longevity"
}advisor
{
"notes": "The model correctly predicted anti_longevity for PKH3. The mechanistic reasoning is sound and well-grounded: PKH3 as a PDK1 ortholog activating AGC kinases (Sch9) in the TOR/nutrient-sensing pathway is a legitimate pro-aging mechanism in yeast. The model also correctly notes the sphingolipid signaling connection. The confidence of 0.62 is appropriately moderate given PKH3's partial redundancy with PKH1/2 and its less-studied role compared to its paralogs. The reasoning is biologically coherent and consistent with the known anti-longevity classification.",
"failure_mode": "correct",
"answer_correct": true,
"mechanism_correct": true,
"reasoning_quality": 4,
"ground_truth_questionable": false
}