Keap1
D. melanogaster
Keap1
What the model saw
Gene: Keap1 Organism: Drosophila melanogaster Known functions: Keap1. ubiquitin-like ligase-substrate adaptor activity.
View unredacted entry
Keap1. ubiquitin-like ligase-substrate adaptor activity.
Solver output
Keap1 (Kelch-like ECH-associated protein 1) functions as a ubiquitin-like ligase-substrate adaptor that targets the transcription factor Nrf2 (CncC in Drosophila) for ubiquitin-mediated proteasomal degradation. By acting as the substrate adaptor for the Cullin3-based E3 ubiquitin ligase complex, Keap1 constitutively suppresses Nrf2/CncC activity under basal conditions. Nrf2/CncC is the master regulator of the antioxidant response element (ARE)-driven gene expression program, including genes encoding superoxide dismutases, glutathione S-transferases, and other cytoprotective enzymes. Loss-of-function of Keap1 in Drosophila leads to constitutive Nrf2/CncC activation and extended lifespan, while Keap1's normal function — degrading Nrf2/CncC — suppresses this pro-longevity oxidative stress response. Thus, Keap1's normal molecular activity opposes longevity by limiting the organism's capacity to neutralize reactive oxygen species and maintain redox homeostasis.
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 Keap1 as anti_longevity in Drosophila melanogaster. The mechanistic reasoning is accurate and detailed: Keap1 acts as a substrate adaptor for the CRL3 E3 ubiquitin ligase complex, targeting Nrf2/CncC for proteasomal degradation, thereby suppressing the antioxidant response. Loss of Keap1 leads to constitutive Nrf2/CncC activation and extended lifespan, making Keap1 anti-longevity. The mechanism class of "chronic_inflammation" is slightly off — the primary mechanism is oxidative stress response/antioxidant signaling rather than inflammation per se — but the textual reasoning correctly identifies the Keap1-Nrf2 pathway as the key mechanism. The confidence level of 0.82 is appropriate.
Raw API responses
solver
{
"reasoning": "Keap1 (Kelch-like ECH-associated protein 1) functions as a ubiquitin-like ligase-substrate adaptor that targets the transcription factor Nrf2 (CncC in Drosophila) for ubiquitin-mediated proteasomal degradation. By acting as the substrate adaptor for the Cullin3-based E3 ubiquitin ligase complex, Keap1 constitutively suppresses Nrf2/CncC activity under basal conditions. Nrf2/CncC is the master regulator of the antioxidant response element (ARE)-driven gene expression program, including genes encoding superoxide dismutases, glutathione S-transferases, and other cytoprotective enzymes. Loss-of-function of Keap1 in Drosophila leads to constitutive Nrf2/CncC activation and extended lifespan, while Keap1's normal function — degrading Nrf2/CncC — suppresses this pro-longevity oxidative stress response. Thus, Keap1's normal molecular activity opposes longevity by limiting the organism's capacity to neutralize reactive oxygen species and maintain redox homeostasis.",
"confidence": 0.82,
"key_pathways": [
"Keap1-Nrf2/CncC antioxidant signaling",
"Cullin3-RING ubiquitin ligase (CRL3) complex",
"oxidative stress response / ARE-driven gene expression"
],
"mechanism_class": "chronic_inflammation",
"longevity_influence": "anti_longevity"
}advisor
{
"notes": "The model correctly predicted Keap1 as anti_longevity in Drosophila melanogaster. The mechanistic reasoning is accurate and detailed: Keap1 acts as a substrate adaptor for the CRL3 E3 ubiquitin ligase complex, targeting Nrf2/CncC for proteasomal degradation, thereby suppressing the antioxidant response. Loss of Keap1 leads to constitutive Nrf2/CncC activation and extended lifespan, making Keap1 anti-longevity. The mechanism class of \"chronic_inflammation\" is slightly off — the primary mechanism is oxidative stress response/antioxidant signaling rather than inflammation per se — but the textual reasoning correctly identifies the Keap1-Nrf2 pathway as the key mechanism. The confidence level of 0.82 is appropriate.",
"failure_mode": "correct",
"answer_correct": true,
"mechanism_correct": true,
"reasoning_quality": 5,
"ground_truth_questionable": false
}