LEU2
S. cerevisiae
3-isopropylmalate dehydrogenase
What the model saw
Gene: LEU2 Organism: Saccharomyces cerevisiae Known functions: 3-isopropylmalate dehydrogenase. 3-isopropylmalate dehydrogenase activity. NAD binding. magnesium ion binding. oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor.
View unredacted entry
3-isopropylmalate dehydrogenase. 3-isopropylmalate dehydrogenase activity. NAD binding. magnesium ion binding. oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor.
Solver output
LEU2 encodes 3-isopropylmalate dehydrogenase, a key enzyme in the leucine biosynthesis pathway in S. cerevisiae. Leucine is a potent activator of TORC1 signaling via the Rag GTPase complex; thus, LEU2 activity directly influences intracellular leucine availability, which in turn modulates TOR pathway activity. However, LEU2 is most commonly used as an auxotrophic selectable marker in yeast genetics, and its primary molecular function is biosynthetic rather than a direct regulator of aging. Leucine limitation (as in leu2 mutants) could paradoxically mimic dietary restriction and extend lifespan by reducing TORC1 activity, but the wild-type gene's role in supplying leucine for normal growth does not straightforwardly map to a pro- or anti-longevity function. The NAD-binding oxidoreductase activity is a secondary biochemical feature of the enzyme mechanism and does not independently implicate NAD metabolism in aging here. Because the longevity effect depends heavily on the genetic background and leucine availability in the environment rather than the intrinsic function of the enzyme, the influence is genuinely ambiguous.
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 "unclear" while the ground truth is "anti_longevity." LEU2 is classified as anti-longevity, meaning its deletion (loss of function) extends lifespan. The model actually touched on this possibility — noting that leu2 mutants could mimic dietary restriction and extend lifespan by reducing TORC1 activity — but then retreated to "unclear" rather than committing to anti_longevity. The mechanistic reasoning about leucine/TORC1 is partially relevant but speculative and not well-grounded in the actual experimental evidence for LEU2's role in yeast aging. The model also failed to recognize that LEU2 is commonly used as an auxotrophic marker and that its deletion in standard lab strains (which are leu2 auxotrophs) is associated with lifespan extension, making it anti-longevity. The model's hedging led it to the wrong classification despite having some relevant reasoning elements.
Raw API responses
solver
{
"reasoning": "LEU2 encodes 3-isopropylmalate dehydrogenase, a key enzyme in the leucine biosynthesis pathway in S. cerevisiae. Leucine is a potent activator of TORC1 signaling via the Rag GTPase complex; thus, LEU2 activity directly influences intracellular leucine availability, which in turn modulates TOR pathway activity. However, LEU2 is most commonly used as an auxotrophic selectable marker in yeast genetics, and its primary molecular function is biosynthetic rather than a direct regulator of aging. Leucine limitation (as in leu2 mutants) could paradoxically mimic dietary restriction and extend lifespan by reducing TORC1 activity, but the wild-type gene's role in supplying leucine for normal growth does not straightforwardly map to a pro- or anti-longevity function. The NAD-binding oxidoreductase activity is a secondary biochemical feature of the enzyme mechanism and does not independently implicate NAD metabolism in aging here. Because the longevity effect depends heavily on the genetic background and leucine availability in the environment rather than the intrinsic function of the enzyme, the influence is genuinely ambiguous.",
"confidence": 0.72,
"key_pathways": [
"leucine biosynthesis",
"TORC1/nutrient sensing via amino acid availability",
"NAD-dependent oxidoreduction"
],
"mechanism_class": "deregulated_nutrient_sensing",
"longevity_influence": "unclear"
}advisor
{
"notes": "The model predicted \"unclear\" while the ground truth is \"anti_longevity.\" LEU2 is classified as anti-longevity, meaning its deletion (loss of function) extends lifespan. The model actually touched on this possibility — noting that leu2 mutants could mimic dietary restriction and extend lifespan by reducing TORC1 activity — but then retreated to \"unclear\" rather than committing to anti_longevity. The mechanistic reasoning about leucine/TORC1 is partially relevant but speculative and not well-grounded in the actual experimental evidence for LEU2's role in yeast aging. The model also failed to recognize that LEU2 is commonly used as an auxotrophic marker and that its deletion in standard lab strains (which are leu2 auxotrophs) is associated with lifespan extension, making it anti-longevity. The model's hedging led it to the wrong classification despite having some relevant reasoning elements.",
"failure_mode": "confident_wrong",
"answer_correct": false,
"mechanism_correct": false,
"reasoning_quality": 2,
"ground_truth_questionable": true
}