kynu-1
C. elegans
Kynureninase
What the model saw
Gene: kynu-1 Organism: Caenorhabditis elegans Known functions: Kynureninase. kynureninase activity. pyridoxal phosphate binding.
View unredacted entry
Kynureninase. kynureninase activity. pyridoxal phosphate binding.
Solver output
Kynureninase (kynu-1) catalyzes the hydrolysis of kynurenine and 3-hydroxykynurenine to anthranilic acid and 3-hydroxyanthranilic acid, respectively, as part of the kynurenine pathway of tryptophan catabolism. This pathway is the primary route for de novo NAD+ biosynthesis from tryptophan. Adequate NAD+ levels are critical for sirtuin (SIR-2.1 in C. elegans) activity and mitochondrial function, both of which are strongly linked to longevity. Loss-of-function of kynurenine pathway enzymes in C. elegans has been shown to reduce NAD+ availability and shorten lifespan, while boosting NAD+ extends lifespan. Additionally, accumulation of upstream kynurenine metabolites (e.g., kynurenine itself) can be toxic and pro-inflammatory, so efficient flux through the pathway via kynu-1 prevents their buildup. The pyridoxal phosphate (PLP) cofactor dependence is consistent with canonical kynureninase biochemistry. Thus, normal kynu-1 function supports NAD+ homeostasis and detoxification of kynurenine intermediates, promoting 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. The model's reasoning about kynu-1 supporting NAD+ biosynthesis and thus promoting longevity is inverted from reality. In C. elegans, kynu-1 (kynureninase) is actually anti-longevity - loss of kynu-1 extends lifespan. The kynurenine pathway in C. elegans produces toxic metabolites, and blocking the pathway (via kynu-1 loss) diverts tryptophan toward other beneficial routes. The model's reasoning that efficient flux through the pathway prevents toxic buildup and supports NAD+ is plausible-sounding but incorrect for this organism's biology. The model was fairly confident (0.7) in the wrong direction.
Raw API responses
solver
{
"reasoning": "Kynureninase (kynu-1) catalyzes the hydrolysis of kynurenine and 3-hydroxykynurenine to anthranilic acid and 3-hydroxyanthranilic acid, respectively, as part of the kynurenine pathway of tryptophan catabolism. This pathway is the primary route for de novo NAD+ biosynthesis from tryptophan. Adequate NAD+ levels are critical for sirtuin (SIR-2.1 in C. elegans) activity and mitochondrial function, both of which are strongly linked to longevity. Loss-of-function of kynurenine pathway enzymes in C. elegans has been shown to reduce NAD+ availability and shorten lifespan, while boosting NAD+ extends lifespan. Additionally, accumulation of upstream kynurenine metabolites (e.g., kynurenine itself) can be toxic and pro-inflammatory, so efficient flux through the pathway via kynu-1 prevents their buildup. The pyridoxal phosphate (PLP) cofactor dependence is consistent with canonical kynureninase biochemistry. Thus, normal kynu-1 function supports NAD+ homeostasis and detoxification of kynurenine intermediates, promoting longevity.",
"confidence": 0.7,
"key_pathways": [
"kynurenine pathway / tryptophan catabolism",
"NAD+ biosynthesis",
"sirtuin/SIR-2.1 signaling"
],
"mechanism_class": "deregulated_nutrient_sensing",
"longevity_influence": "pro_longevity"
}advisor
{
"notes": "The model predicted pro_longevity but the ground truth is anti_longevity. The model's reasoning about kynu-1 supporting NAD+ biosynthesis and thus promoting longevity is inverted from reality. In C. elegans, kynu-1 (kynureninase) is actually anti-longevity - loss of kynu-1 extends lifespan. The kynurenine pathway in C. elegans produces toxic metabolites, and blocking the pathway (via kynu-1 loss) diverts tryptophan toward other beneficial routes. The model's reasoning that efficient flux through the pathway prevents toxic buildup and supports NAD+ is plausible-sounding but incorrect for this organism's biology. The model was fairly confident (0.7) in the wrong direction.",
"failure_mode": "confident_wrong",
"answer_correct": false,
"mechanism_correct": false,
"reasoning_quality": 2,
"ground_truth_questionable": false
}