ALG3
S. cerevisiae
dolichyl-P-Man:Man(5)GlcNAc(2)-PP-dolichol alpha-1,3-mannosyltransferase
What the model saw
Gene: ALG3 Organism: Saccharomyces cerevisiae Known functions: dolichyl-P-Man:Man(5)GlcNAc(2)-PP-dolichol alpha-1,3-mannosyltransferase. dol-P-Man:Man(5)GlcNAc(2)-PP-Dol alpha-1,3-mannosyltransferase activity. mannosyltransferase activity.
View unredacted entry
dolichyl-P-Man:Man(5)GlcNAc(2)-PP-dolichol alpha-1,3-mannosyltransferase. dol-P-Man:Man(5)GlcNAc(2)-PP-Dol alpha-1,3-mannosyltransferase activity. mannosyltransferase activity.
Solver output
ALG3 encodes a dolichyl-phosphate-mannose (Dol-P-Man) dependent alpha-1,3-mannosyltransferase that catalyzes a critical step in the dolichol-linked oligosaccharide (LLO) assembly pathway in the ER lumen, specifically adding the first mannose on the B-arm of the Man5GlcNAc2-PP-dolichol intermediate. This reaction is essential for proper N-linked glycosylation of nascent proteins in the secretory pathway. Correct N-glycosylation is required for proper protein folding, ER quality control (via calnexin/calreticulin cycles), and proteostasis. Loss of ALG3 function leads to hypoglycosylation, accumulation of misfolded proteins, ER stress, and activation of the unfolded protein response (UPR), all of which are associated with accelerated aging and reduced lifespan. Therefore, the normal function of ALG3 supports proteostasis and is expected to be 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 but the ground truth is anti_longevity. The model's reasoning is plausible on the surface - it argues that ALG3 supports proteostasis via N-glycosylation and therefore should be pro-longevity. However, in yeast longevity studies, deletion of ALG3 (and other N-glycosylation genes) can actually extend lifespan, making ALG3 anti-longevity (its presence shortens life, or its deletion extends life). The model's mechanistic reasoning about ER stress and UPR is partially relevant but leads to the wrong conclusion. The model assumed that because ALG3 supports proteostasis, it must be pro-longevity, but failed to consider that in yeast, disruption of N-glycosylation pathways can activate stress responses (like UPR/hormesis) that actually extend lifespan. The confidence of 0.62 is moderate but still wrong.
Raw API responses
solver
{
"reasoning": "ALG3 encodes a dolichyl-phosphate-mannose (Dol-P-Man) dependent alpha-1,3-mannosyltransferase that catalyzes a critical step in the dolichol-linked oligosaccharide (LLO) assembly pathway in the ER lumen, specifically adding the first mannose on the B-arm of the Man5GlcNAc2-PP-dolichol intermediate. This reaction is essential for proper N-linked glycosylation of nascent proteins in the secretory pathway. Correct N-glycosylation is required for proper protein folding, ER quality control (via calnexin/calreticulin cycles), and proteostasis. Loss of ALG3 function leads to hypoglycosylation, accumulation of misfolded proteins, ER stress, and activation of the unfolded protein response (UPR), all of which are associated with accelerated aging and reduced lifespan. Therefore, the normal function of ALG3 supports proteostasis and is expected to be pro-longevity.",
"confidence": 0.62,
"key_pathways": [
"N-linked glycosylation / dolichol-linked oligosaccharide biosynthesis",
"ER protein quality control and unfolded protein response (UPR)",
"Proteostasis maintenance"
],
"mechanism_class": "loss_of_proteostasis",
"longevity_influence": "pro_longevity"
}advisor
{
"notes": "The model predicted pro_longevity but the ground truth is anti_longevity. The model's reasoning is plausible on the surface - it argues that ALG3 supports proteostasis via N-glycosylation and therefore should be pro-longevity. However, in yeast longevity studies, deletion of ALG3 (and other N-glycosylation genes) can actually extend lifespan, making ALG3 anti-longevity (its presence shortens life, or its deletion extends life). The model's mechanistic reasoning about ER stress and UPR is partially relevant but leads to the wrong conclusion. The model assumed that because ALG3 supports proteostasis, it must be pro-longevity, but failed to consider that in yeast, disruption of N-glycosylation pathways can activate stress responses (like UPR/hormesis) that actually extend lifespan. The confidence of 0.62 is moderate but still wrong.",
"failure_mode": "confident_wrong",
"answer_correct": false,
"mechanism_correct": false,
"reasoning_quality": 2,
"ground_truth_questionable": false
}