PKH1
S. cerevisiae
serine/threonine protein kinase PKH1
What the model saw
Gene: PKH1 Organism: Saccharomyces cerevisiae Known functions: serine/threonine protein kinase PKH1. ATP binding. protein binding. protein kinase activity. protein serine kinase activity. protein serine/threonine kinase activity.
View unredacted entry
serine/threonine protein kinase PKH1. ATP binding. protein binding. protein kinase activity. protein serine kinase activity. protein serine/threonine kinase activity.
Solver output
PKH1 is the yeast ortholog of mammalian PDK1 (3-phosphoinositide-dependent protein kinase 1) and functions upstream of Ypk1/Ypk2 (SGK/PKB-related kinases) and Pkc1 in the sphingolipid-mediated signaling cascade. PKH1 activates Sch9 (the yeast S6K/Akt ortholog) through direct phosphorylation, placing it within the TORC1/nutrient-sensing axis. Reduced Sch9 activity — achieved by loss of upstream activating kinases or direct deletion — is well established to extend chronological and replicative lifespan in yeast by mimicking caloric restriction and downregulating pro-aging anabolic signaling. PKH1 also regulates sphingolipid-dependent signaling that feeds into stress responses and membrane homeostasis. Because PKH1 promotes Sch9 activity (a pro-aging kinase), its normal function sustains nutrient-sensing signaling that shortens lifespan, making PKH1 itself anti-longevity; however, PKH1 also has partially redundant roles with PKH2 and contributes to cell wall integrity and stress survival, which could be pro-longevity. On balance, its primary role as an activator of the Sch9/TORC1 downstream axis places it as pro-aging (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 "pro_longevity" but the ground truth is "anti_longevity." Interestingly, the model's own reasoning correctly identifies PKH1 as anti-longevity (it explicitly states "its normal function sustains nutrient-sensing signaling that shortens lifespan, making PKH1 itself anti-longevity"), but then contradicts itself by outputting "pro_longevity" as the final answer. This is a case where the reasoning actually arrives at the correct mechanistic conclusion but the final answer label is wrong. The mechanistic reasoning about PKH1 activating Sch9 (a pro-aging kinase) and thus being anti-longevity is sound, but the model then flips its conclusion in the final output. The reasoning quality is moderate — it shows good knowledge of the pathway but fails to reconcile the contradiction in its own logic before outputting the final answer.
Raw API responses
solver
{
"reasoning": "PKH1 is the yeast ortholog of mammalian PDK1 (3-phosphoinositide-dependent protein kinase 1) and functions upstream of Ypk1/Ypk2 (SGK/PKB-related kinases) and Pkc1 in the sphingolipid-mediated signaling cascade. PKH1 activates Sch9 (the yeast S6K/Akt ortholog) through direct phosphorylation, placing it within the TORC1/nutrient-sensing axis. Reduced Sch9 activity — achieved by loss of upstream activating kinases or direct deletion — is well established to extend chronological and replicative lifespan in yeast by mimicking caloric restriction and downregulating pro-aging anabolic signaling. PKH1 also regulates sphingolipid-dependent signaling that feeds into stress responses and membrane homeostasis. Because PKH1 promotes Sch9 activity (a pro-aging kinase), its normal function sustains nutrient-sensing signaling that shortens lifespan, making PKH1 itself anti-longevity; however, PKH1 also has partially redundant roles with PKH2 and contributes to cell wall integrity and stress survival, which could be pro-longevity. On balance, its primary role as an activator of the Sch9/TORC1 downstream axis places it as pro-aging (anti-longevity).",
"confidence": 0.62,
"key_pathways": [
"TORC1-Sch9 nutrient sensing axis",
"Sphingolipid signaling via PKH1-Ypk1",
"PKC1 cell wall integrity pathway"
],
"mechanism_class": "deregulated_nutrient_sensing",
"longevity_influence": "pro_longevity"
}advisor
{
"notes": "The model predicted \"pro_longevity\" but the ground truth is \"anti_longevity.\" Interestingly, the model's own reasoning correctly identifies PKH1 as anti-longevity (it explicitly states \"its normal function sustains nutrient-sensing signaling that shortens lifespan, making PKH1 itself anti-longevity\"), but then contradicts itself by outputting \"pro_longevity\" as the final answer. This is a case where the reasoning actually arrives at the correct mechanistic conclusion but the final answer label is wrong. The mechanistic reasoning about PKH1 activating Sch9 (a pro-aging kinase) and thus being anti-longevity is sound, but the model then flips its conclusion in the final output. The reasoning quality is moderate — it shows good knowledge of the pathway but fails to reconcile the contradiction in its own logic before outputting the final answer.",
"failure_mode": "confident_wrong",
"answer_correct": false,
"mechanism_correct": false,
"reasoning_quality": 3,
"ground_truth_questionable": false
}