ADH2
S. cerevisiae
alcohol dehydrogenase ADH2
What the model saw
Gene: ADH2 Organism: Saccharomyces cerevisiae Known functions: alcohol dehydrogenase ADH2. alcohol dehydrogenase (NAD+) activity. butanol dehydrogenase (NAD+) activity. ethanol dehydrogenase (NAD+) activity. oxidoreductase activity. zinc ion binding.
View unredacted entry
alcohol dehydrogenase ADH2. alcohol dehydrogenase (NAD+) activity. butanol dehydrogenase (NAD+) activity. ethanol dehydrogenase (NAD+) activity. oxidoreductase activity. zinc ion binding.
Solver output
ADH2 encodes the glucose-repressed alcohol dehydrogenase in S. cerevisiae that catalyzes the reverse reaction: oxidation of ethanol back to acetaldehyde (and then acetate) using NAD+. Unlike ADH1 (which produces ethanol during fermentation), ADH2 is expressed during gluconeogenic/respiratory growth when glucose is limiting, promoting ethanol re-assimilation and mitochondrial respiration. This metabolic shift away from fermentation toward respiration is associated with caloric restriction-like signaling, reduced TOR activity, and extended chronological and replicative lifespan. By regenerating NAD+ and channeling carbon through the TCA cycle rather than fermentative pathways, ADH2 activity supports the metabolic state linked to longevity in yeast. Additionally, reduced ethanol accumulation lowers acetaldehyde/reactive aldehyde stress, mitigating oxidative damage.
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 ADH2's biochemical role is largely accurate (it is indeed the glucose-repressed alcohol dehydrogenase that oxidizes ethanol during respiratory growth), but the conclusion about its longevity effect is wrong. In yeast chronological lifespan studies, ethanol re-assimilation via ADH2 actually produces acetic acid as a byproduct, which has been shown to be toxic and to shorten chronological lifespan. The model incorrectly assumed that the metabolic shift toward respiration associated with ADH2 expression would be pro-longevity, missing the key finding that acetic acid production (a downstream product of ethanol oxidation via ADH2) is anti-longevity. The model was fairly confident (0.72) in its wrong answer. The mechanistic reasoning, while plausible on the surface, missed the critical anti-longevity mechanism (acetic acid toxicity/acidification of the medium shortening chronological lifespan).
Raw API responses
solver
{
"reasoning": "ADH2 encodes the glucose-repressed alcohol dehydrogenase in S. cerevisiae that catalyzes the reverse reaction: oxidation of ethanol back to acetaldehyde (and then acetate) using NAD+. Unlike ADH1 (which produces ethanol during fermentation), ADH2 is expressed during gluconeogenic/respiratory growth when glucose is limiting, promoting ethanol re-assimilation and mitochondrial respiration. This metabolic shift away from fermentation toward respiration is associated with caloric restriction-like signaling, reduced TOR activity, and extended chronological and replicative lifespan. By regenerating NAD+ and channeling carbon through the TCA cycle rather than fermentative pathways, ADH2 activity supports the metabolic state linked to longevity in yeast. Additionally, reduced ethanol accumulation lowers acetaldehyde/reactive aldehyde stress, mitigating oxidative damage.",
"confidence": 0.72,
"key_pathways": [
"ethanol re-assimilation / gluconeogenesis",
"NAD+ regeneration and redox balance",
"caloric restriction / TOR 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 about ADH2's biochemical role is largely accurate (it is indeed the glucose-repressed alcohol dehydrogenase that oxidizes ethanol during respiratory growth), but the conclusion about its longevity effect is wrong. In yeast chronological lifespan studies, ethanol re-assimilation via ADH2 actually produces acetic acid as a byproduct, which has been shown to be toxic and to shorten chronological lifespan. The model incorrectly assumed that the metabolic shift toward respiration associated with ADH2 expression would be pro-longevity, missing the key finding that acetic acid production (a downstream product of ethanol oxidation via ADH2) is anti-longevity. The model was fairly confident (0.72) in its wrong answer. The mechanistic reasoning, while plausible on the surface, missed the critical anti-longevity mechanism (acetic acid toxicity/acidification of the medium shortening chronological lifespan).",
"failure_mode": "confident_wrong",
"answer_correct": false,
"mechanism_correct": false,
"reasoning_quality": 3,
"ground_truth_questionable": false
}