TDH2
S. cerevisiae
glyceraldehyde-3-phosphate dehydrogenase (phosphorylating) TDH2
What the model saw
Gene: TDH2 Organism: Saccharomyces cerevisiae Known functions: glyceraldehyde-3-phosphate dehydrogenase (phosphorylating) TDH2. NAD binding. NADP binding. glyceraldehyde-3-phosphate dehydrogenase (NAD+) (phosphorylating) activity. melatonin binding. oxidoreductase activity, acting on the aldehyde or oxo group of donors, NAD or NADP as acceptor. promoter-specific chromatin binding. protein binding.
View unredacted entry
glyceraldehyde-3-phosphate dehydrogenase (phosphorylating) TDH2. NAD binding. NADP binding. glyceraldehyde-3-phosphate dehydrogenase (NAD+) (phosphorylating) activity. melatonin binding. oxidoreductase activity, acting on the aldehyde or oxo group of donors, NAD or NADP as acceptor. promoter-specific chromatin binding. protein binding.
Solver output
TDH2 encodes one of the three yeast GAPDH isoforms, catalyzing the oxidative phosphorylation of glyceraldehyde-3-phosphate to 1,3-bisphosphoglycerate in glycolysis while reducing NAD+ to NADH. This step is central to glycolytic flux and NAD+/NADH redox balance; maintaining adequate NAD+ availability supports sirtuin (Sir2) activity in yeast, which is a well-established pro-longevity pathway. Additionally, GAPDH activity feeds into downstream carbon metabolism that intersects with TOR and AMPK-like nutrient-sensing pathways. The noted melatonin-binding activity suggests a potential antioxidant/redox-regulatory moonlighting role that could further buffer oxidative stress. However, excessive glycolytic flux can also promote replicative aging, so the net effect is moderately pro-longevity through NAD+ homeostasis and nutrient-sensing regulation rather than strongly so.
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 NAD+/NADH balance and sirtuin activation is plausible in general terms but misses the actual mechanism by which TDH2 acts as anti-longevity in yeast. GAPDH/TDH isoforms in yeast are known to be involved in replicative aging - high glycolytic activity and GAPDH expression can actually promote aging rather than extend lifespan. The model acknowledged that "excessive glycolytic flux can also promote replicative aging" but then dismissed this in favor of a pro-longevity conclusion. The mechanistic reasoning is also incorrect - the model focused on NAD+ availability supporting Sir2, but the actual anti-longevity effect likely relates to glycolytic flux promoting aging. The model's confidence of 0.62 is moderate but still wrong. The melatonin-binding moonlighting role mentioned is speculative and not well-established as a longevity mechanism.
Raw API responses
solver
{
"reasoning": "TDH2 encodes one of the three yeast GAPDH isoforms, catalyzing the oxidative phosphorylation of glyceraldehyde-3-phosphate to 1,3-bisphosphoglycerate in glycolysis while reducing NAD+ to NADH. This step is central to glycolytic flux and NAD+/NADH redox balance; maintaining adequate NAD+ availability supports sirtuin (Sir2) activity in yeast, which is a well-established pro-longevity pathway. Additionally, GAPDH activity feeds into downstream carbon metabolism that intersects with TOR and AMPK-like nutrient-sensing pathways. The noted melatonin-binding activity suggests a potential antioxidant/redox-regulatory moonlighting role that could further buffer oxidative stress. However, excessive glycolytic flux can also promote replicative aging, so the net effect is moderately pro-longevity through NAD+ homeostasis and nutrient-sensing regulation rather than strongly so.",
"confidence": 0.62,
"key_pathways": [
"glycolysis / NAD+/NADH redox balance",
"sirtuin (Sir2) activation via NAD+ availability",
"nutrient sensing (TOR/AMPK pathway crosstalk)"
],
"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 NAD+/NADH balance and sirtuin activation is plausible in general terms but misses the actual mechanism by which TDH2 acts as anti-longevity in yeast. GAPDH/TDH isoforms in yeast are known to be involved in replicative aging - high glycolytic activity and GAPDH expression can actually promote aging rather than extend lifespan. The model acknowledged that \"excessive glycolytic flux can also promote replicative aging\" but then dismissed this in favor of a pro-longevity conclusion. The mechanistic reasoning is also incorrect - the model focused on NAD+ availability supporting Sir2, but the actual anti-longevity effect likely relates to glycolytic flux promoting aging. The model's confidence of 0.62 is moderate but still wrong. The melatonin-binding moonlighting role mentioned is speculative and not well-established as a longevity mechanism.",
"failure_mode": "confident_wrong",
"answer_correct": false,
"mechanism_correct": false,
"reasoning_quality": 2,
"ground_truth_questionable": false
}