Hard cases — pseudoenzymes & disputed-function human genes (batch 4)
The earlier cohorts used mostly well-behaved genes. This cohort (batch4-genes.txt;
results) deliberately picks human genes flagged as
hard-to-curate in our own project docs (HUMAN_GENES_RE_REVIEW.md,
UNIPROT_CAUTION_NOTE/, PSEUDOENZYMES.md, TOP_NOTS.md, TRANSCRIPTION_FACTORS/):
pseudoenzymes, literature-contested activities, "was-X-actually-Y" reclassifications,
and family-label misdirection. It asks two questions the easy cohorts couldn't:
(a) does the GO layer assign the ancestral/dead/disputed activity? and (b) does
the narrative acknowledge the pseudoenzyme status or the controversy?
GO capture stays low (1/12). But the two-layer behaviour is the real result.
The narrative is genuinely pseudoenzyme- and reclassification-aware
Because Affinage reasons from the literature (not from domain/family labels), its
narrative repeatedly gets the hard call right — verbatim:
| Gene | Curation challenge | Narrative verdict (verbatim) |
|---|---|---|
| ILK | pseudokinase (scaffold) | "Despite its kinase-like domain, ILK is a bona fide pseudokinase: recombinant ILK has no detectable activity toward GSK-3beta" |
| ROR1 | pseudokinase | "Although it adopts a kinase fold, ROR1 is a pseudokinase devoid of intrinsic catalytic activity and is instead transphosphorylated by partner kinases" |
| CPT1C | pseudo-transferase | "it retains weak carnitine palmitoyltransferase activity… catalytic efficiency 20–300 times lower than CPT1A, and it localizes to the ER" |
| HDAC6 | not a histone deacetylase | "cytoplasmic class IIb deacetylase… deacetylating a broad set of non-histone substrates… alpha-tubulin" |
| PARK7 | glyoxalase vs deglycase controversy | "A reported nucleotide/protein deglycase activity is reframed by rigorous kinetics as glyoxalase-like with only a minor role in neuronal methylglyoxal defense" |
This is markedly better than a domain-based tool: on KEAP1, InterPro2GO→BioReason
assigned actin binding (from the BTB-Kelch fold); Affinage's literature grounding
instead lands on molecular adaptor/molecular sensor/ligase — the correct
E3-adaptor/NRF2-sensor zone, not actin.
…but the GO layer is a lossy down-cast that can contradict its own narrative
The mechanism_profile does not inherit the narrative's nuance. The sharpest case:
- ROR1 — narrative: "pseudokinase devoid of intrinsic catalytic activity";
GO layer:catalytic activity, acting on a protein. The two layers directly
contradict each other. - CPT1C — narrative: "weak… 20–300× lower"; GO layer: flat
transferase activity(no hint of the pseudo/weak status).
Where the narrative itself de-emphasises catalysis, the GO layer more often follows
and avoids the ancestral-activity trap — literature-grounding paying off:
| Gene | Trap (ancestral/wrong activity) | Affinage GO top terms | Avoided? |
|---|---|---|---|
| ILK | protein kinase activity | molecular adaptor, cytoskeletal protein binding | ✅ |
| RASA1 | GTPase activity | molecular function regulator activity | ✅ (it's a GAP) |
| PLD3 | phospholipase D activity | catalytic activity acting on DNA, DNA binding | ✅ (leans exonuclease) |
| KEAP1 | actin binding | molecular adaptor / sensor, ligase | ✅ |
| CASP12 | cysteine endopeptidase activity | (empty — no MF grounded) | ✅ by omission |
| ROR1 | (pseudo)kinase catalysis | catalytic activity, acting on a protein | ❌ |
| CPT1C | carnitine transferase | transferase activity | ❌ |
Controversy handling: mixed
- PARK7 — the narrative engages the glyoxalase-vs-deglycase dispute and
adjudicates it (deglycase "reframed… as glyoxalase-like"), matching our caution-note
reading. Good. - UCHL1 — the narrative presents a confident deubiquitinase and omits the
contested ubiquitin-ligase activity entirely. A curator's positive-vs-NOT pair
records the dispute; the single "current model" flattens it.
So the "current model" format can represent a controversy when the literature has a
clear resolution (PARK7), but tends to flatten genuinely unresolved ones (UCHL1) —
it has no slot for "annotated both positively and NOT," which is exactly how GOA/our
reviews encode contested functions.
Bottom line
On the hardest human genes, Affinage's narrative is impressively literature-faithful
— it names pseudokinases as catalytically dead, reclassifies HDAC6, and adjudicates
PARK7 — and beats domain-based tools on family-label misdirection (KEAP1). Its GO
layer, by contrast, is coarse (1/12 specific capture), sometimes assigns the dead
ancestral activity (ROR1, CPT1C), and in ROR1's case flatly contradicts the very
narrative it is derived from. The gap between the two layers is widest exactly where
curation is hardest — reinforcing the project's core result: judge Affinage by its
narrative, not its GO grounding, and even the narrative cannot encode a live dispute.