LYS12
S. cerevisiae
homoisocitrate dehydrogenase
What the model saw
Gene: LYS12 Organism: Saccharomyces cerevisiae Known functions: homoisocitrate dehydrogenase. NAD binding. homoisocitrate dehydrogenase activity. magnesium ion binding. oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor.
View unredacted entry
homoisocitrate dehydrogenase. NAD binding. homoisocitrate dehydrogenase activity. magnesium ion binding. oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor.
Solver output
LYS12 encodes homoisocitrate dehydrogenase, which catalyzes the NAD⁺-dependent oxidative decarboxylation of homoisocitrate to α-ketoadipate, a key step in the α-aminoadipate pathway for lysine biosynthesis in yeast. This reaction consumes NAD⁺ and produces NADH, directly coupling amino acid anabolism to cellular redox balance. Lysine biosynthesis is an energetically costly process regulated by nutrient availability, and its flux is tightly linked to TOR pathway activity and nitrogen sensing. Proper function of LYS12 supports balanced amino acid metabolism; loss of lysine biosynthesis genes can trigger amino acid starvation responses (e.g., Gcn4 activation) that paradoxically extend lifespan via reduced TOR signaling. However, the normal enzymatic activity of LYS12 sustains proteostasis and metabolic homeostasis by ensuring adequate lysine supply for protein synthesis, which is broadly pro-longevity. The NAD⁺-consuming nature of the reaction also places it within the broader NAD⁺/NADH redox network that governs sirtuin activity and mitochondrial function.
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 is speculative and ultimately leads to the wrong conclusion. The model correctly identifies LYS12's biochemical function (homoisocitrate dehydrogenase in the lysine biosynthesis pathway) but then constructs a narrative around why it would be pro-longevity (supporting proteostasis, metabolic homeostasis, NAD+ balance). The actual anti-longevity classification suggests that deletion of LYS12 extends lifespan, likely because disrupting lysine biosynthesis triggers amino acid starvation responses that reduce TOR signaling — a mechanism the model actually mentions as a possibility but then dismisses in favor of the pro-longevity interpretation. The model's confidence of 0.62 is moderate but still wrong. The mechanistic reasoning is also incorrect in its final conclusion, even though it touches on the correct underlying biology (GCN4 activation, reduced TOR signaling) before dismissing it.
Raw API responses
solver
{
"reasoning": "LYS12 encodes homoisocitrate dehydrogenase, which catalyzes the NAD⁺-dependent oxidative decarboxylation of homoisocitrate to α-ketoadipate, a key step in the α-aminoadipate pathway for lysine biosynthesis in yeast. This reaction consumes NAD⁺ and produces NADH, directly coupling amino acid anabolism to cellular redox balance. Lysine biosynthesis is an energetically costly process regulated by nutrient availability, and its flux is tightly linked to TOR pathway activity and nitrogen sensing. Proper function of LYS12 supports balanced amino acid metabolism; loss of lysine biosynthesis genes can trigger amino acid starvation responses (e.g., Gcn4 activation) that paradoxically extend lifespan via reduced TOR signaling. However, the normal enzymatic activity of LYS12 sustains proteostasis and metabolic homeostasis by ensuring adequate lysine supply for protein synthesis, which is broadly pro-longevity. The NAD⁺-consuming nature of the reaction also places it within the broader NAD⁺/NADH redox network that governs sirtuin activity and mitochondrial function.",
"confidence": 0.62,
"key_pathways": [
"lysine biosynthesis (α-aminoadipate pathway)",
"NAD+/NADH redox balance",
"TOR-mediated nutrient sensing"
],
"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 is speculative and ultimately leads to the wrong conclusion. The model correctly identifies LYS12's biochemical function (homoisocitrate dehydrogenase in the lysine biosynthesis pathway) but then constructs a narrative around why it would be pro-longevity (supporting proteostasis, metabolic homeostasis, NAD+ balance). The actual anti-longevity classification suggests that deletion of LYS12 extends lifespan, likely because disrupting lysine biosynthesis triggers amino acid starvation responses that reduce TOR signaling — a mechanism the model actually mentions as a possibility but then dismisses in favor of the pro-longevity interpretation. The model's confidence of 0.62 is moderate but still wrong. The mechanistic reasoning is also incorrect in its final conclusion, even though it touches on the correct underlying biology (GCN4 activation, reduced TOR signaling) before dismissing it.",
"failure_mode": "confident_wrong",
"answer_correct": false,
"mechanism_correct": false,
"reasoning_quality": 2,
"ground_truth_questionable": false
}