SHM2
S. cerevisiae
glycine hydroxymethyltransferase SHM2
What the model saw
Gene: SHM2 Organism: Saccharomyces cerevisiae Known functions: glycine hydroxymethyltransferase SHM2. glycine hydroxymethyltransferase activity. pyridoxal phosphate binding.
View unredacted entry
glycine hydroxymethyltransferase SHM2. glycine hydroxymethyltransferase activity. pyridoxal phosphate binding.
Solver output
SHM2 encodes the cytoplasmic serine hydroxymethyltransferase (SHMT) in S. cerevisiae, which catalyzes the reversible interconversion of serine and glycine using pyridoxal phosphate (PLP) as a cofactor. This reaction is the primary entry point into one-carbon (folate) metabolism, supplying 5,10-methylenetetrahydrofolate for nucleotide biosynthesis, methylation reactions, and redox balance. Robust one-carbon metabolism supports S-adenosylmethionine (SAM) production, which feeds into epigenetic methylation and polyamine synthesis pathways that are tightly linked to nutrient sensing and longevity in yeast. Loss of one-carbon flux impairs nucleotide pools and methylation capacity, which can accelerate genomic instability and reduce replicative lifespan. Additionally, adequate glycine/serine balance and folate cycle activity have been associated with mitochondrial function and NAD+ metabolism, both pro-longevity factors in yeast.
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 0.65 confidence, but the ground truth is anti_longevity. SHM2 is classified as anti-longevity in GenAge, meaning its deletion or reduction extends lifespan. The model's reasoning focused on why SHM2 activity would be beneficial (one-carbon metabolism, SAM production, nucleotide biosynthesis), but failed to consider that SHM2 deletion could extend lifespan - perhaps by redirecting metabolic flux, reducing serine consumption, or through other mechanisms. The mechanistic reasoning is plausible in isolation but leads to the wrong conclusion. The model did not consider the possibility that SHM2 is anti-longevity (i.e., its loss extends lifespan), which is the actual finding.
Raw API responses
solver
{
"reasoning": "SHM2 encodes the cytoplasmic serine hydroxymethyltransferase (SHMT) in S. cerevisiae, which catalyzes the reversible interconversion of serine and glycine using pyridoxal phosphate (PLP) as a cofactor. This reaction is the primary entry point into one-carbon (folate) metabolism, supplying 5,10-methylenetetrahydrofolate for nucleotide biosynthesis, methylation reactions, and redox balance. Robust one-carbon metabolism supports S-adenosylmethionine (SAM) production, which feeds into epigenetic methylation and polyamine synthesis pathways that are tightly linked to nutrient sensing and longevity in yeast. Loss of one-carbon flux impairs nucleotide pools and methylation capacity, which can accelerate genomic instability and reduce replicative lifespan. Additionally, adequate glycine/serine balance and folate cycle activity have been associated with mitochondrial function and NAD+ metabolism, both pro-longevity factors in yeast.",
"confidence": 0.65,
"key_pathways": [
"one-carbon (folate) metabolism",
"serine-glycine interconversion",
"S-adenosylmethionine biosynthesis and methylation"
],
"mechanism_class": "deregulated_nutrient_sensing",
"longevity_influence": "pro_longevity"
}advisor
{
"notes": "The model predicted pro_longevity with 0.65 confidence, but the ground truth is anti_longevity. SHM2 is classified as anti-longevity in GenAge, meaning its deletion or reduction extends lifespan. The model's reasoning focused on why SHM2 activity would be beneficial (one-carbon metabolism, SAM production, nucleotide biosynthesis), but failed to consider that SHM2 deletion could extend lifespan - perhaps by redirecting metabolic flux, reducing serine consumption, or through other mechanisms. The mechanistic reasoning is plausible in isolation but leads to the wrong conclusion. The model did not consider the possibility that SHM2 is anti-longevity (i.e., its loss extends lifespan), which is the actual finding.",
"failure_mode": "confident_wrong",
"answer_correct": false,
"mechanism_correct": false,
"reasoning_quality": 2,
"ground_truth_questionable": false
}