kgd1
S. pombe
alpha-ketoglutarate dehydrogenase
What the model saw
Gene: kgd1 Organism: Schizosaccharomyces pombe Known functions: alpha-ketoglutarate dehydrogenase. oxidoreductase activity, acting on the aldehyde or oxo group of donors, disulfide as acceptor. oxoglutarate dehydrogenase (succinyl-transferring) activity. thiamine pyrophosphate binding.
View unredacted entry
alpha-ketoglutarate dehydrogenase. oxidoreductase activity, acting on the aldehyde or oxo group of donors, disulfide as acceptor. oxoglutarate dehydrogenase (succinyl-transferring) activity. thiamine pyrophosphate binding.
Solver output
kgd1 encodes the E1 subunit of the alpha-ketoglutarate dehydrogenase complex (KGDHC), which catalyzes the oxidative decarboxylation of alpha-ketoglutarate to succinyl-CoA in the TCA cycle, using thiamine pyrophosphate as a cofactor. This reaction is a critical step in mitochondrial energy metabolism, and its proper function supports efficient oxidative phosphorylation and ATP production. Loss of KGDHC activity leads to impaired TCA cycle flux, mitochondrial dysfunction, accumulation of alpha-ketoglutarate, and increased reactive oxygen species (ROS) generation — all hallmarks of mitochondrial deterioration associated with aging. In yeast models, intact TCA cycle function is generally required for healthy chronological and replicative lifespan. Additionally, alpha-ketoglutarate itself is a substrate for prolyl hydroxylases and other dioxygenases involved in epigenetic regulation, but the primary role here is mitochondrial energy metabolism, making functional KGDHC pro-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 with 0.72 confidence, but the ground truth is anti_longevity. The model's reasoning is plausible on the surface — it correctly identifies kgd1 as encoding the E1 subunit of the alpha-ketoglutarate dehydrogenase complex and correctly describes its biochemical role. However, the model's mechanistic conclusion is wrong: it assumes that because KGDHC supports TCA cycle function, it must be pro-longevity. In reality, kgd1 is anti_longevity in S. pombe, meaning its deletion or loss likely extends lifespan. This is consistent with findings in other organisms where reduced TCA cycle flux (particularly at the alpha-ketoglutarate dehydrogenase step) can extend lifespan, possibly through metabolic reprogramming, increased alpha-ketoglutarate levels (which can inhibit mTOR or activate epigenetic regulators), or reduced mitochondrial ROS production from a less active KGDHC. The model failed to consider that reduced KGDHC activity could be beneficial for longevity, and instead defaulted to the assumption that functional mitochondrial metabolism = pro-longevity, which is not always the case.
Raw API responses
solver
{
"reasoning": "kgd1 encodes the E1 subunit of the alpha-ketoglutarate dehydrogenase complex (KGDHC), which catalyzes the oxidative decarboxylation of alpha-ketoglutarate to succinyl-CoA in the TCA cycle, using thiamine pyrophosphate as a cofactor. This reaction is a critical step in mitochondrial energy metabolism, and its proper function supports efficient oxidative phosphorylation and ATP production. Loss of KGDHC activity leads to impaired TCA cycle flux, mitochondrial dysfunction, accumulation of alpha-ketoglutarate, and increased reactive oxygen species (ROS) generation — all hallmarks of mitochondrial deterioration associated with aging. In yeast models, intact TCA cycle function is generally required for healthy chronological and replicative lifespan. Additionally, alpha-ketoglutarate itself is a substrate for prolyl hydroxylases and other dioxygenases involved in epigenetic regulation, but the primary role here is mitochondrial energy metabolism, making functional KGDHC pro-longevity.",
"confidence": 0.72,
"key_pathways": [
"TCA cycle / mitochondrial oxidative metabolism",
"alpha-ketoglutarate to succinyl-CoA conversion",
"mitochondrial ROS homeostasis"
],
"mechanism_class": "mitochondrial_dysfunction",
"longevity_influence": "pro_longevity"
}advisor
{
"notes": "The model predicted pro_longevity with 0.72 confidence, but the ground truth is anti_longevity. The model's reasoning is plausible on the surface — it correctly identifies kgd1 as encoding the E1 subunit of the alpha-ketoglutarate dehydrogenase complex and correctly describes its biochemical role. However, the model's mechanistic conclusion is wrong: it assumes that because KGDHC supports TCA cycle function, it must be pro-longevity. In reality, kgd1 is anti_longevity in S. pombe, meaning its deletion or loss likely extends lifespan. This is consistent with findings in other organisms where reduced TCA cycle flux (particularly at the alpha-ketoglutarate dehydrogenase step) can extend lifespan, possibly through metabolic reprogramming, increased alpha-ketoglutarate levels (which can inhibit mTOR or activate epigenetic regulators), or reduced mitochondrial ROS production from a less active KGDHC. The model failed to consider that reduced KGDHC activity could be beneficial for longevity, and instead defaulted to the assumption that functional mitochondrial metabolism = pro-longevity, which is not always the case.",
"failure_mode": "confident_wrong",
"answer_correct": false,
"mechanism_correct": false,
"reasoning_quality": 3,
"ground_truth_questionable": false
}