URH1
S. cerevisiae
trifunctional uridine nucleosidase/nicotinamide riboside hydrolase/nicotinic acid riboside hydrolase
What the model saw
Gene: URH1 Organism: Saccharomyces cerevisiae Known functions: trifunctional uridine nucleosidase/nicotinamide riboside hydrolase/nicotinic acid riboside hydrolase. hydrolase activity, hydrolyzing N-glycosyl compounds. nicotinamide riboside hydrolase activity. nicotinic acid riboside hydrolase activity. purine nucleosidase activity. ribosylpyrimidine nucleosidase activity. uridine nucleosidase activity.
View unredacted entry
trifunctional uridine nucleosidase/nicotinamide riboside hydrolase/nicotinic acid riboside hydrolase. hydrolase activity, hydrolyzing N-glycosyl compounds. nicotinamide riboside hydrolase activity. nicotinic acid riboside hydrolase activity. purine nucleosidase activity. ribosylpyrimidine nucleosidase activity. uridine nucleosidase activity.
Solver output
URH1 encodes a trifunctional nucleosidase with nicotinamide riboside (NR) hydrolase activity, meaning it cleaves NR into nicotinamide and ribose, thereby degrading a key NAD+ precursor. NAD+ is a central metabolite in the Sir2/sirtuin deacetylase pathway, which is a major pro-longevity axis in yeast. By catabolizing NR before it can be salvaged into NAD+, URH1 reduces the intracellular NAD+ pool available to Sir2 (SIRT1 ortholog), dampening sirtuin-dependent longevity signaling. Consistent with this, deletion of URH1 in yeast has been shown to elevate NR-derived NAD+ levels and extend replicative lifespan. The nicotinic acid riboside hydrolase activity similarly degrades another NAD+ precursor, compounding the anti-longevity effect through depletion of the NAD+ salvage pathway.
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 correctly predicted anti_longevity for URH1. The mechanistic reasoning is well-grounded: URH1 hydrolyzes nicotinamide riboside (NR), depleting a key NAD+ precursor, which reduces NAD+ availability for Sir2/sirtuin-dependent longevity signaling. The model correctly notes that URH1 deletion elevates NR-derived NAD+ and extends replicative lifespan, which is consistent with published literature (e.g., Belenky et al. work on NR and NAD+ salvage in yeast). The confidence level of 0.72 is appropriate given the specificity of the functional annotation. Overall, both the answer and the mechanistic reasoning are correct and well-articulated.
Raw API responses
solver
{
"reasoning": "URH1 encodes a trifunctional nucleosidase with nicotinamide riboside (NR) hydrolase activity, meaning it cleaves NR into nicotinamide and ribose, thereby degrading a key NAD+ precursor. NAD+ is a central metabolite in the Sir2/sirtuin deacetylase pathway, which is a major pro-longevity axis in yeast. By catabolizing NR before it can be salvaged into NAD+, URH1 reduces the intracellular NAD+ pool available to Sir2 (SIRT1 ortholog), dampening sirtuin-dependent longevity signaling. Consistent with this, deletion of URH1 in yeast has been shown to elevate NR-derived NAD+ levels and extend replicative lifespan. The nicotinic acid riboside hydrolase activity similarly degrades another NAD+ precursor, compounding the anti-longevity effect through depletion of the NAD+ salvage pathway.",
"confidence": 0.72,
"key_pathways": [
"NAD+ salvage pathway",
"Sir2/sirtuin deacetylase signaling",
"nicotinamide riboside catabolism"
],
"mechanism_class": "deregulated_nutrient_sensing",
"longevity_influence": "anti_longevity"
}advisor
{
"notes": "The model correctly predicted anti_longevity for URH1. The mechanistic reasoning is well-grounded: URH1 hydrolyzes nicotinamide riboside (NR), depleting a key NAD+ precursor, which reduces NAD+ availability for Sir2/sirtuin-dependent longevity signaling. The model correctly notes that URH1 deletion elevates NR-derived NAD+ and extends replicative lifespan, which is consistent with published literature (e.g., Belenky et al. work on NR and NAD+ salvage in yeast). The confidence level of 0.72 is appropriate given the specificity of the functional annotation. Overall, both the answer and the mechanistic reasoning are correct and well-articulated.",
"failure_mode": "correct",
"answer_correct": true,
"mechanism_correct": true,
"reasoning_quality": 5,
"ground_truth_questionable": false
}