Rule predicting amide catabolic process (GO:0043605) based on four condition sets: (1) urease domains (beta/gamma subunits and active site) across all organisms, (2) PM20D1 FunFams in Eukaryota, (3) ureide pathway hydrolases in Viridiplantae, and (4) (S)-ureidoglycine aminohydrolase in Streptophyta. The rule captures mechanistically diverse enzymes that share the common chemistry of amide bond hydrolysis but serve distinct biological functions.
Interactive prediction matrix showing how row entries PREDICT column entries. Cell (i,j) shows what fraction of proteins with row domain i also have column domain j. Click cells to view intersection in UniProt. Click domain IDs to view proteins with that domain.
Legend: Each cell shows PREDICTS % (fraction of row entry proteins that also have column entry - row PREDICTS column), Jaccard similarity (J:%), and intersection count. CS = Condition Set(s), TGT = GO annotation target.
This rule captures four mechanistically distinct enzyme families that share the common chemistry of amide bond hydrolysis: (1) ureases with dinuclear Ni(II) centers hydrolyzing urea for nitrogen mobilization and pH modulation, (2) PM20D1 bidirectional synthase/hydrolases regulating thermogenic N-acyl amino acids, (3-4) plant ureide pathway Mn2+-dependent hydrolases (AAH, UAH, UGlyAH) liberating nitrogen from purine catabolites. Condition sets 1, 3, and 4 are strongly supported by extensive structural, biochemical, and genetic evidence demonstrating amide catabolism as the core or primary function. Condition set 2 (PM20D1) is technically accurate but potentially misleading—PM20D1's primary role is thermogenic lipid signaling, not general amide catabolism. While GO:0043605 is biochemically correct for all four sets, more specific annotations would improve biological utility: GO:0043419 (urea catabolic process) for urease, pathway-specific terms for ureide enzymes, and lipid metabolism terms for PM20D1. The rule demonstrates both strength (mechanistic accuracy) and weakness (biological context obscured by overly general annotation).
Rule has fundamental logical errors that invalidate it: (1) CS1 uses AND logic requiring 3 urease domains that have LOW overlap (4-10%), creating a triple intersection of ≤10 proteins when there are 851 total urease proteins. This is a 99% false negative rate. Each domain individually predicts GO:0043605 with 100% containment, proving each is sufficient and AND logic is incorrect. (2) CS2 contains perfect redundancy - two PM20D1 FunFams with identical 10-protein sets. (3) CS3 uses AND logic with a perfect subset (UAH ⊆ AAH), missing 5 AAH-only proteins. Additionally, PM20D1's primary biological role is thermogenic lipid signaling, not nitrogen catabolism - the 70% containment to GO:0043605 reflects that 30% are correctly annotated to more specific metabolic/thermogenic terms.
Urease catalyzes the hydrolysis of urea (H2N-CO-NH2) to ammonia and CO2 via a carbamate intermediate, using a conserved dinuclear Ni(II) active site bridged by a carbamylated lysine. This represents a quintessential amide catabolic reaction. Ureases are found across bacteria and plants (but absent from animals) and serve multiple biological roles including nitrogen mobilization, environmental pH modulation, and bacterial virulence. The combination of beta/gamma subunit domains and active site signature provides high specificity for ureolytic activity.
PM20D1 functions as a bidirectional enzyme catalyzing both synthesis and hydrolysis of N-acyl amino acids from fatty acids and amino acids. While PM20D1 does catalyze amide hydrolysis (94% conversion in hydrolase direction), its primary biological role centers on thermogenic lipid signaling rather than general amide catabolism. The enzyme regulates N-acyl amino acid levels for thermogenic and metabolic effects, not nitrogen mobilization. This condition set raises questions about annotation specificity—while technically correct, GO:0043605 may obscure PM20D1's specialized metabolic function. The Eukaryota scope may also be overly broad.
| Condition A | Condition B | Count A | Count B | Intersection | Jaccard | A in B | B in A | Interpretation |
|---|---|---|---|---|---|---|---|---|
1.10.150.900:FF:000003
|
3.40.630.10:FF:000027
|
10 | 10 | 10 | 1.000 | 1.000 | 1.000 | REDUNDANT |
These enzymes function in the plant ureide pathway for purine catabolism. Allantoate amidohydrolase (AAH) hydrolyzes allantoate to (S)-ureidoglycine, CO2, and NH3; ureidoglycolate hydrolase (UAH) cleaves ureidoglycolate to glyoxylate, CO2, and NH3. Both use Mn2+ cofactors and are ER-localized. These are well-established amide catabolic enzymes in nitrogen remobilization. The Viridiplantae restriction is appropriate but may be too narrow—the ureide pathway also exists in some bacteria and fungi.
| Condition A | Condition B | Count A | Count B | Intersection | Jaccard | A in B | B in A | Interpretation |
|---|---|---|---|---|---|---|---|---|
3.30.70.360:FF:000012
|
3.40.630.10:FF:000044
|
2 | 7 | 2 | 0.286 | 1.000 | 0.286 | SUBSET |
(S)-Ureidoglycine aminohydrolase (UGlyAH) catalyzes the enantioselective hydrolysis of (S)-ureidoglycine to (S)-ureidoglycolate and NH3 using Mn2+ as a cofactor. The enzyme adopts a bicupin fold and functions as an octamer. Crystal structures demonstrate that Mn2+ acts as a molecular anchor dictating enantioselectivity. UGlyAH is a well-characterized amide catabolic enzyme in the plant ureide pathway. The Streptophyta restriction appropriately captures the distribution of this enzyme family.
The rule's AND logic creates massive false negatives. CS1 should use OR logic or be split into 3 separate condition sets. CS2 has redundant FunFams. CS3's subsetting means 5 proteins are excluded. The rule groups mechanistically diverse enzymes under overly broad GO term, obscuring biological specificity. CS1 urease domains have only 4-10% pairwise overlap but use AND logic, creating a triple intersection of ≤10 proteins from 851 total urease proteins. Each domain individually has 100% containment to GO:0043605, proving each is sufficient.
Condition sets 1, 3, and 4 have extensive experimental support spanning structural crystallography, enzyme kinetics, mechanistic studies, and genetic analyses. Urease: High-resolution structures of bacterial (K. aerogenes, B. pasteurii, H. pylori) and plant (jack bean) ureases reveal conserved dinuclear Ni(II) active sites bridged by carbamylated lysine. Mechanistic studies demonstrate bridging hydroxide nucleophilic attack with extraordinary catalytic proficiency (10^14-fold rate enhancement). Urease is essential for H. pylori gastric colonization and pH-dependent bacterial survival. Plant ureide enzymes: Crystal structures of AtUGlyAH and AtUAH in substrate-bound forms demonstrate Mn2+-dependent catalysis and explain enantioselectivity. Genetic studies show AAH knockout causes seed dormancy, ureide accumulation, and amino acid depletion; UAH-URE double mutants show synthetic lethality, confirming physiological importance. The ureide pathway is conserved across Viridiplantae including mosses and algae. PM20D1: Biochemical assays demonstrate bidirectional NAA synthesis/hydrolysis (1.2% synthase, 94% hydrolase conversion). However, genetic and physiological studies emphasize thermogenic/metabolic roles rather than nitrogen catabolism—PM20D1 knockout causes glucose intolerance and metabolic dysfunction; overexpression increases energy expenditure. Natural promoter variants explain mouse strain cold tolerance differences. This represents strong evidence for catalytic activity but raises questions about functional annotation as general amide catabolism.
The four condition sets capture entirely distinct protein families with no sequence or structural overlap. Condition set 1 targets ureases (Ni-dependent, bacterial/plant, multi-subunit assemblies). Condition sets 3-4 target plant ureide pathway enzymes (Mn-dependent, bicupin or related folds, ER-localized). Condition set 2 targets PM20D1 (M20 peptidase family, secreted, bidirectional). These represent independent evolutionary solutions to amide hydrolysis chemistry. Mechanistically, urease uses dinuclear Ni(II) with bridging hydroxide; ureide enzymes use Mn2+ coordination; PM20D1 mechanism is less characterized but involves M20 peptidase chemistry. Functionally, ureases serve nitrogen mobilization and pH modulation; ureide enzymes serve purine catabolism/nitrogen remobilization; PM20D1 serves thermogenic lipid signaling. The lack of overlap underscores that the rule groups mechanistically and functionally diverse enzymes solely on the basis of shared chemistry (amide bond cleavage), which may obscure biologically relevant distinctions.
GO:0043605 (amide catabolic process) is technically accurate for all four condition sets but too broad to capture biological context. The term describes a general chemical mechanism shared by functionally diverse enzymes, potentially misleading users about actual biological roles. For urease (condition set 1), GO:0043419 (urea catabolic process) would be more specific—it captures the unique substrate (urea) rather than the chemical class (amides). Urease's biological roles in nitrogen cycling, bacterial virulence, and pH modulation are obscured by generic amide catabolism annotation. For ureide enzymes (condition sets 3-4), pathway-specific terms like "allantoin catabolic process" or "ureide catabolic process" would better capture their role in purine nitrogen remobilization. For PM20D1 (condition set 2), GO:0043605 is particularly problematic—while the enzyme catalyzes amide hydrolysis, its primary biological role involves thermogenic lipid signaling and metabolic regulation, not nitrogen catabolism. More appropriate annotations might include "N-acyl amino acid metabolic process", "lipid biosynthetic process" (for synthase activity), or "positive regulation of adaptive thermogenesis". The breadth of GO:0043605 enables computational grouping of chemically similar enzymes but sacrifices biological interpretability. A hierarchical annotation strategy (specific + general terms) would preserve both granularity and computational utility.
Condition set 1 (urease) has no taxonomic restriction, which is appropriate given urease's broad distribution across bacteria and plants (but absence from animals). However, the rule could be made more explicit by adding "not Animalia" as an exclusion, providing logical clarity. Condition set 2 (PM20D1) restricts to Eukaryota (NCBITaxon:2759), which is appropriate for PM20D1 presence but may be too broad for the specific annotation. If GO:0043605 is retained, the scope might be narrowed to Mammalia or Vertebrata where thermogenic/metabolic context is relevant—PM20D1 orthologs in plants, fungi, or invertebrates may serve unrelated functions. Condition set 3 (ureide enzymes) restricts to Viridiplantae, which is too narrow—the ureide pathway exists in bacteria and fungi, creating false negatives. The scope should expand to "Viridiplantae, selected bacteria, and selected fungi" or implement granular inclusion of known lineages. Condition set 4 (UGlyAH) restricts to Streptophyta (land plants + streptophyte algae), which appropriately captures this enzyme's distribution and is consistent with experimental evidence. Overall, taxonomic scopes show mixed appropriateness—some too broad (PM20D1 in Eukaryota), some too narrow (ureide enzymes excluding prokaryotes), some appropriate (urease unrestricted, UGlyAH in Streptophyta).
Urease catalyzes hydrolysis of urea to ammonia and CO2 via carbamate intermediate using conserved dinuclear Ni(II) active site bridged by carbamylated lysine. Catalytic proficiency is extraordinary (10^14-fold rate enhancement). Conserved across bacteria and plants despite quaternary structure variation.
Plant ureide pathway enzymes (AAH, UGlyAH, UAH) use Mn2+ cofactors to sequentially degrade allantoin to glyoxylate, liberating ammonia and CO2. Crystal structures demonstrate metal-dependent catalysis and substrate specificity determinants. Genetic studies confirm physiological importance in nitrogen remobilization and seed development.
PM20D1 is bidirectional synthase/hydrolase for N-acyl amino acids, showing 1.2% synthase and 94% hydrolase conversion in vitro. Primary biological role is thermogenic lipid signaling—knockout causes metabolic dysfunction, overexpression increases energy expenditure. Natural variants explain mouse strain cold tolerance differences.
GO:0043605 is appropriate but insufficiently specific. More specific annotations: GO:0043419 (urea catabolism) for urease, pathway-specific terms for ureide enzymes, metabolic/thermogenic terms for PM20D1. Current annotation obscures biological context.
Taxonomic scope issues: Viridiplantae restriction for ureide enzymes excludes known bacterial/fungal systems (false negatives); Eukaryota scope for PM20D1 may be too broad given thermogenesis context.
Urease subunit/active site signatures provide strong, mechanistically coherent signature for ureolysis. Dinuclear Ni(II) center bridged by carbamylated lysine conserved across bacteria and plants. Accessory proteins UreD/E/F/G assemble and metallate the site.
Plant ureide-pathway hydrolases (AAH, UGlyAH, UAH) are close homologs with distinct active-site determinants enforcing narrow substrate specificity (e.g., AtUAH Tyr-423 vs. Gly in AAH; QXR motif in AAH). Specialized roles in purine/ureide catabolism, not broadly multifunctional.
GO:0043605 appropriate for urease and ureide enzymes but broad. More specific BP annotations would reduce ambiguity. PM20D1 condition set lacks strong supporting evidence in provided context—should be reassessed.
Rule logic assessment: Urease and ureide enzyme condition sets are well-supported by conserved structure and pathway biochemistry. Multi-domain requirements reduce false positives. PM20D1 branch needs validation.
Rule created 2024-08-14, modified 2025-03-21. Four condition sets targeting urease domains, PM20D1 FunFams, and plant ureide pathway hydrolases. Predicts GO:0043605 (amide catabolic process). Currently annotates 0 proteins (0 reviewed, 0 unreviewed).
id: ARBA00047244
description: 'Rule predicting amide catabolic process (GO:0043605) based on four condition
sets: (1) urease domains (beta/gamma subunits and active site) across all organisms,
(2) PM20D1 FunFams in Eukaryota, (3) ureide pathway hydrolases in Viridiplantae,
and (4) (S)-ureidoglycine aminohydrolase in Streptophyta. The rule captures mechanistically
diverse enzymes that share the common chemistry of amide bond hydrolysis but serve
distinct biological functions.'
status: COMPLETE
rule_type: ARBA
rule:
rule_id: ARBA00047244
condition_sets:
- number: 1
conditions:
- condition_type: INTERPRO
value: IPR002019
curie: InterPro:IPR002019
label: Urease, beta subunit-like
negated: false
- condition_type: INTERPRO
value: IPR002026
curie: InterPro:IPR002026
label: Urease, gamma/gamma-beta subunit
negated: false
- condition_type: INTERPRO
value: IPR017950
curie: InterPro:IPR017950
label: Urease active site
negated: false
notes: Urease catalyzes the hydrolysis of urea (H2N-CO-NH2) to ammonia and CO2
via a carbamate intermediate, using a conserved dinuclear Ni(II) active site
bridged by a carbamylated lysine. This represents a quintessential amide catabolic
reaction. Ureases are found across bacteria and plants (but absent from animals)
and serve multiple biological roles including nitrogen mobilization, environmental
pH modulation, and bacterial virulence. The combination of beta/gamma subunit
domains and active site signature provides high specificity for ureolytic activity.
pairwise_overlap:
- condition_a: IPR002019
condition_b: IPR002026
protein_database: SWISSPROT
count_a: 279
count_b: 308
intersection_count: 29
a_minus_b_count: 250
b_minus_a_count: 279
jaccard_similarity: 0.05197132616487455
containment_a_in_b: 0.1039426523297491
containment_b_in_a: 0.09415584415584416
interpretation: LOW
- condition_a: IPR002019
condition_b: IPR017950
protein_database: SWISSPROT
count_a: 279
count_b: 264
intersection_count: 10
a_minus_b_count: 269
b_minus_a_count: 254
jaccard_similarity: 0.01876172607879925
containment_a_in_b: 0.035842293906810034
containment_b_in_a: 0.03787878787878788
interpretation: LOW
- condition_a: IPR002026
condition_b: IPR017950
protein_database: SWISSPROT
count_a: 308
count_b: 264
intersection_count: 10
a_minus_b_count: 298
b_minus_a_count: 254
jaccard_similarity: 0.017793594306049824
containment_a_in_b: 0.032467532467532464
containment_b_in_a: 0.03787878787878788
interpretation: LOW
- number: 2
conditions:
- condition_type: FUNFAM
value: 1.10.150.900:FF:000003
curie: CATH.FunFam:1.10.150.900:FF:000003
label: N-fatty-acyl-amino acid synthase/hydrolase PM20D1
negated: false
- condition_type: FUNFAM
value: 3.40.630.10:FF:000027
curie: CATH.FunFam:3.40.630.10:FF:000027
label: N-fatty-acyl-amino acid synthase/hydrolase PM20D1
negated: false
- condition_type: TAXON
value: '2759'
curie: NCBITaxon:2759
label: Eukaryota
negated: false
notes: PM20D1 functions as a bidirectional enzyme catalyzing both synthesis and
hydrolysis of N-acyl amino acids from fatty acids and amino acids. While PM20D1
does catalyze amide hydrolysis (94% conversion in hydrolase direction), its
primary biological role centers on thermogenic lipid signaling rather than general
amide catabolism. The enzyme regulates N-acyl amino acid levels for thermogenic
and metabolic effects, not nitrogen mobilization. This condition set raises
questions about annotation specificity—while technically correct, GO:0043605
may obscure PM20D1's specialized metabolic function. The Eukaryota scope may
also be overly broad.
pairwise_overlap:
- condition_a: 1.10.150.900:FF:000003
condition_b: 3.40.630.10:FF:000027
protein_database: SWISSPROT
count_a: 10
count_b: 10
intersection_count: 10
a_minus_b_count: 0
b_minus_a_count: 0
jaccard_similarity: 1.0
containment_a_in_b: 1.0
containment_b_in_a: 1.0
interpretation: REDUNDANT
- number: 3
conditions:
- condition_type: FUNFAM
value: 3.30.70.360:FF:000012
curie: CATH.FunFam:3.30.70.360:FF:000012
label: Putative ureidoglycolate hydrolase
negated: false
- condition_type: FUNFAM
value: 3.40.630.10:FF:000044
curie: CATH.FunFam:3.40.630.10:FF:000044
label: Allantoate amidohydrolase
negated: false
- condition_type: TAXON
value: '33090'
curie: NCBITaxon:33090
label: Viridiplantae
negated: false
notes: These enzymes function in the plant ureide pathway for purine catabolism.
Allantoate amidohydrolase (AAH) hydrolyzes allantoate to (S)-ureidoglycine,
CO2, and NH3; ureidoglycolate hydrolase (UAH) cleaves ureidoglycolate to glyoxylate,
CO2, and NH3. Both use Mn2+ cofactors and are ER-localized. These are well-established
amide catabolic enzymes in nitrogen remobilization. The Viridiplantae restriction
is appropriate but may be too narrow—the ureide pathway also exists in some
bacteria and fungi.
pairwise_overlap:
- condition_a: 3.30.70.360:FF:000012
condition_b: 3.40.630.10:FF:000044
protein_database: SWISSPROT
count_a: 2
count_b: 7
intersection_count: 2
a_minus_b_count: 0
b_minus_a_count: 5
jaccard_similarity: 0.2857142857142857
containment_a_in_b: 1.0
containment_b_in_a: 0.2857142857142857
interpretation: SUBSET
- number: 4
conditions:
- condition_type: FUNFAM
value: 2.60.120.10:FF:000137
curie: CATH.FunFam:2.60.120.10:FF:000137
label: (S)-ureidoglycine aminohydrolase
negated: false
- condition_type: TAXON
value: '35493'
curie: NCBITaxon:35493
label: Streptophyta
negated: false
notes: (S)-Ureidoglycine aminohydrolase (UGlyAH) catalyzes the enantioselective
hydrolysis of (S)-ureidoglycine to (S)-ureidoglycolate and NH3 using Mn2+ as
a cofactor. The enzyme adopts a bicupin fold and functions as an octamer. Crystal
structures demonstrate that Mn2+ acts as a molecular anchor dictating enantioselectivity.
UGlyAH is a well-characterized amide catabolic enzyme in the plant ureide pathway.
The Streptophyta restriction appropriately captures the distribution of this
enzyme family.
go_annotations:
- go_id: GO:0043605
go_label: amide catabolic process
aspect: BP
reviewed_protein_count: 0
unreviewed_protein_count: 0
created_date: '2024-08-14'
modified_date: '2025-03-21'
entries:
- id: 1.10.150.900:FF:000003
type: FUNFAM
label: N-fatty-acyl-amino acid synthase/hydrolase PM20D1
appears_in_condition_sets:
- 2
protein_count: 10
related_entries:
- relationship: EQUIV
target_id: IPR002019
containment: 0.0
jaccard_similarity: 0.0
intersection_count: 0
exclusive_count: 10
- relationship: EQUIV
target_id: IPR002026
containment: 0.0
jaccard_similarity: 0.0
intersection_count: 0
exclusive_count: 10
- relationship: EQUIV
target_id: IPR017950
containment: 0.0
jaccard_similarity: 0.0
intersection_count: 0
exclusive_count: 10
- relationship: EQUIV
target_id: 3.40.630.10:FF:000027
containment: 1.0
jaccard_similarity: 1.0
intersection_count: 10
exclusive_count: 0
- relationship: EQUIV
target_id: 3.30.70.360:FF:000012
containment: 0.0
jaccard_similarity: 0.0
intersection_count: 0
exclusive_count: 10
- relationship: EQUIV
target_id: 3.40.630.10:FF:000044
containment: 0.0
jaccard_similarity: 0.0
intersection_count: 0
exclusive_count: 10
- relationship: EQUIV
target_id: 2.60.120.10:FF:000137
containment: 0.0
jaccard_similarity: 0.0
intersection_count: 0
exclusive_count: 10
- relationship: PREDICTS
target_id: GO:0043605
containment: 0.7
jaccard_similarity: 0.003
intersection_count: 7
exclusive_count: 3
- id: 2.60.120.10:FF:000137
type: FUNFAM
label: (S)-ureidoglycine aminohydrolase
appears_in_condition_sets:
- 4
protein_count: 2
related_entries:
- relationship: EQUIV
target_id: IPR002019
containment: 0.0
jaccard_similarity: 0.0
intersection_count: 0
exclusive_count: 2
- relationship: EQUIV
target_id: IPR002026
containment: 0.0
jaccard_similarity: 0.0
intersection_count: 0
exclusive_count: 2
- relationship: EQUIV
target_id: IPR017950
containment: 0.0
jaccard_similarity: 0.0
intersection_count: 0
exclusive_count: 2
- relationship: EQUIV
target_id: 1.10.150.900:FF:000003
containment: 0.0
jaccard_similarity: 0.0
intersection_count: 0
exclusive_count: 2
- relationship: EQUIV
target_id: 3.40.630.10:FF:000027
containment: 0.0
jaccard_similarity: 0.0
intersection_count: 0
exclusive_count: 2
- relationship: EQUIV
target_id: 3.30.70.360:FF:000012
containment: 0.0
jaccard_similarity: 0.0
intersection_count: 0
exclusive_count: 2
- relationship: EQUIV
target_id: 3.40.630.10:FF:000044
containment: 0.0
jaccard_similarity: 0.0
intersection_count: 0
exclusive_count: 2
- relationship: PREDICTS
target_id: GO:0043605
containment: 1.0
jaccard_similarity: 0.001
intersection_count: 2
exclusive_count: 0
- id: 3.30.70.360:FF:000012
type: FUNFAM
label: Putative ureidoglycolate hydrolase
appears_in_condition_sets:
- 3
protein_count: 2
related_entries:
- relationship: EQUIV
target_id: IPR002019
containment: 0.0
jaccard_similarity: 0.0
intersection_count: 0
exclusive_count: 2
- relationship: EQUIV
target_id: IPR002026
containment: 0.0
jaccard_similarity: 0.0
intersection_count: 0
exclusive_count: 2
- relationship: EQUIV
target_id: IPR017950
containment: 0.0
jaccard_similarity: 0.0
intersection_count: 0
exclusive_count: 2
- relationship: EQUIV
target_id: 1.10.150.900:FF:000003
containment: 0.0
jaccard_similarity: 0.0
intersection_count: 0
exclusive_count: 2
- relationship: EQUIV
target_id: 3.40.630.10:FF:000027
containment: 0.0
jaccard_similarity: 0.0
intersection_count: 0
exclusive_count: 2
- relationship: PREDICTS
target_id: 3.40.630.10:FF:000044
containment: 1.0
jaccard_similarity: 0.286
intersection_count: 2
exclusive_count: 0
- relationship: EQUIV
target_id: 2.60.120.10:FF:000137
containment: 0.0
jaccard_similarity: 0.0
intersection_count: 0
exclusive_count: 2
- relationship: PREDICTS
target_id: GO:0043605
containment: 1.0
jaccard_similarity: 0.001
intersection_count: 2
exclusive_count: 0
- id: 3.40.630.10:FF:000027
type: FUNFAM
label: N-fatty-acyl-amino acid synthase/hydrolase PM20D1
appears_in_condition_sets:
- 2
protein_count: 10
related_entries:
- relationship: EQUIV
target_id: IPR002019
containment: 0.0
jaccard_similarity: 0.0
intersection_count: 0
exclusive_count: 10
- relationship: EQUIV
target_id: IPR002026
containment: 0.0
jaccard_similarity: 0.0
intersection_count: 0
exclusive_count: 10
- relationship: EQUIV
target_id: IPR017950
containment: 0.0
jaccard_similarity: 0.0
intersection_count: 0
exclusive_count: 10
- relationship: EQUIV
target_id: 1.10.150.900:FF:000003
containment: 1.0
jaccard_similarity: 1.0
intersection_count: 10
exclusive_count: 0
- relationship: EQUIV
target_id: 3.30.70.360:FF:000012
containment: 0.0
jaccard_similarity: 0.0
intersection_count: 0
exclusive_count: 10
- relationship: EQUIV
target_id: 3.40.630.10:FF:000044
containment: 0.0
jaccard_similarity: 0.0
intersection_count: 0
exclusive_count: 10
- relationship: EQUIV
target_id: 2.60.120.10:FF:000137
containment: 0.0
jaccard_similarity: 0.0
intersection_count: 0
exclusive_count: 10
- relationship: PREDICTS
target_id: GO:0043605
containment: 0.7
jaccard_similarity: 0.003
intersection_count: 7
exclusive_count: 3
- id: 3.40.630.10:FF:000044
type: FUNFAM
label: Allantoate amidohydrolase
appears_in_condition_sets:
- 3
protein_count: 7
related_entries:
- relationship: EQUIV
target_id: IPR002019
containment: 0.0
jaccard_similarity: 0.0
intersection_count: 0
exclusive_count: 7
- relationship: EQUIV
target_id: IPR002026
containment: 0.0
jaccard_similarity: 0.0
intersection_count: 0
exclusive_count: 7
- relationship: EQUIV
target_id: IPR017950
containment: 0.0
jaccard_similarity: 0.0
intersection_count: 0
exclusive_count: 7
- relationship: EQUIV
target_id: 1.10.150.900:FF:000003
containment: 0.0
jaccard_similarity: 0.0
intersection_count: 0
exclusive_count: 7
- relationship: EQUIV
target_id: 3.40.630.10:FF:000027
containment: 0.0
jaccard_similarity: 0.0
intersection_count: 0
exclusive_count: 7
- relationship: PREDICTED_BY
target_id: 3.30.70.360:FF:000012
containment: 0.286
jaccard_similarity: 0.286
intersection_count: 2
exclusive_count: 5
- relationship: EQUIV
target_id: 2.60.120.10:FF:000137
containment: 0.0
jaccard_similarity: 0.0
intersection_count: 0
exclusive_count: 7
- relationship: PREDICTS
target_id: GO:0043605
containment: 0.571
jaccard_similarity: 0.002
intersection_count: 4
exclusive_count: 3
- id: IPR002019
type: INTERPRO
label: Urease, beta subunit-like
appears_in_condition_sets:
- 1
protein_count: 279
related_entries:
- relationship: PREDICTS
target_id: IPR002026
containment: 0.104
jaccard_similarity: 0.052
intersection_count: 29
exclusive_count: 250
- relationship: EQUIV
target_id: IPR017950
containment: 0.038
jaccard_similarity: 0.019
intersection_count: 10
exclusive_count: 269
- relationship: EQUIV
target_id: 1.10.150.900:FF:000003
containment: 0.0
jaccard_similarity: 0.0
intersection_count: 0
exclusive_count: 279
- relationship: EQUIV
target_id: 3.40.630.10:FF:000027
containment: 0.0
jaccard_similarity: 0.0
intersection_count: 0
exclusive_count: 279
- relationship: EQUIV
target_id: 3.30.70.360:FF:000012
containment: 0.0
jaccard_similarity: 0.0
intersection_count: 0
exclusive_count: 279
- relationship: EQUIV
target_id: 3.40.630.10:FF:000044
containment: 0.0
jaccard_similarity: 0.0
intersection_count: 0
exclusive_count: 279
- relationship: EQUIV
target_id: 2.60.120.10:FF:000137
containment: 0.0
jaccard_similarity: 0.0
intersection_count: 0
exclusive_count: 279
- relationship: PREDICTS
target_id: GO:0043605
containment: 1.0
jaccard_similarity: 0.125
intersection_count: 279
exclusive_count: 0
- id: IPR002026
type: INTERPRO
label: Urease, gamma/gamma-beta subunit
appears_in_condition_sets:
- 1
protein_count: 308
related_entries:
- relationship: PREDICTED_BY
target_id: IPR002019
containment: 0.094
jaccard_similarity: 0.052
intersection_count: 29
exclusive_count: 279
- relationship: EQUIV
target_id: IPR017950
containment: 0.038
jaccard_similarity: 0.018
intersection_count: 10
exclusive_count: 298
- relationship: EQUIV
target_id: 1.10.150.900:FF:000003
containment: 0.0
jaccard_similarity: 0.0
intersection_count: 0
exclusive_count: 308
- relationship: EQUIV
target_id: 3.40.630.10:FF:000027
containment: 0.0
jaccard_similarity: 0.0
intersection_count: 0
exclusive_count: 308
- relationship: EQUIV
target_id: 3.30.70.360:FF:000012
containment: 0.0
jaccard_similarity: 0.0
intersection_count: 0
exclusive_count: 308
- relationship: EQUIV
target_id: 3.40.630.10:FF:000044
containment: 0.0
jaccard_similarity: 0.0
intersection_count: 0
exclusive_count: 308
- relationship: EQUIV
target_id: 2.60.120.10:FF:000137
containment: 0.0
jaccard_similarity: 0.0
intersection_count: 0
exclusive_count: 308
- relationship: PREDICTS
target_id: GO:0043605
containment: 1.0
jaccard_similarity: 0.138
intersection_count: 308
exclusive_count: 0
- id: IPR017950
type: INTERPRO
label: Urease active site
appears_in_condition_sets:
- 1
protein_count: 264
related_entries:
- relationship: EQUIV
target_id: IPR002019
containment: 0.038
jaccard_similarity: 0.019
intersection_count: 10
exclusive_count: 254
- relationship: EQUIV
target_id: IPR002026
containment: 0.038
jaccard_similarity: 0.018
intersection_count: 10
exclusive_count: 254
- relationship: EQUIV
target_id: 1.10.150.900:FF:000003
containment: 0.0
jaccard_similarity: 0.0
intersection_count: 0
exclusive_count: 264
- relationship: EQUIV
target_id: 3.40.630.10:FF:000027
containment: 0.0
jaccard_similarity: 0.0
intersection_count: 0
exclusive_count: 264
- relationship: EQUIV
target_id: 3.30.70.360:FF:000012
containment: 0.0
jaccard_similarity: 0.0
intersection_count: 0
exclusive_count: 264
- relationship: EQUIV
target_id: 3.40.630.10:FF:000044
containment: 0.0
jaccard_similarity: 0.0
intersection_count: 0
exclusive_count: 264
- relationship: EQUIV
target_id: 2.60.120.10:FF:000137
containment: 0.0
jaccard_similarity: 0.0
intersection_count: 0
exclusive_count: 264
- relationship: PREDICTS
target_id: GO:0043605
containment: 1.0
jaccard_similarity: 0.118
intersection_count: 264
exclusive_count: 0
review_summary: 'This rule captures four mechanistically distinct enzyme families
that share the common chemistry of amide bond hydrolysis: (1) ureases with dinuclear
Ni(II) centers hydrolyzing urea for nitrogen mobilization and pH modulation, (2)
PM20D1 bidirectional synthase/hydrolases regulating thermogenic N-acyl amino acids,
(3-4) plant ureide pathway Mn2+-dependent hydrolases (AAH, UAH, UGlyAH) liberating
nitrogen from purine catabolites. Condition sets 1, 3, and 4 are strongly supported
by extensive structural, biochemical, and genetic evidence demonstrating amide catabolism
as the core or primary function. Condition set 2 (PM20D1) is technically accurate
but potentially misleading—PM20D1''s primary role is thermogenic lipid signaling,
not general amide catabolism. While GO:0043605 is biochemically correct for all
four sets, more specific annotations would improve biological utility: GO:0043419
(urea catabolic process) for urease, pathway-specific terms for ureide enzymes,
and lipid metabolism terms for PM20D1. The rule demonstrates both strength (mechanistic
accuracy) and weakness (biological context obscured by overly general annotation).'
action: DEPRECATE
action_rationale: 'Rule has fundamental logical errors that invalidate it: (1) CS1
uses AND logic requiring 3 urease domains that have LOW overlap (4-10%), creating
a triple intersection of ≤10 proteins when there are 851 total urease proteins.
This is a 99% false negative rate. Each domain individually predicts GO:0043605
with 100% containment, proving each is sufficient and AND logic is incorrect. (2)
CS2 contains perfect redundancy - two PM20D1 FunFams with identical 10-protein sets.
(3) CS3 uses AND logic with a perfect subset (UAH ⊆ AAH), missing 5 AAH-only proteins.
Additionally, PM20D1''s primary biological role is thermogenic lipid signaling,
not nitrogen catabolism - the 70% containment to GO:0043605 reflects that 30% are
correctly annotated to more specific metabolic/thermogenic terms.'
suggested_modifications:
- For condition set 1 (urease), use GO:0043419 (urea catabolic process) instead of
or in addition to GO:0043605
- For condition sets 3-4 (ureide enzymes), use pathway-specific terms like "allantoin
catabolic process" or "ureide catabolic process" in addition to GO:0043605
- For condition set 2 (PM20D1), consider alternative annotations such as "N-acyl amino
acid metabolic process" or split into separate synthesis and hydrolysis terms
- Expand condition set 3 taxonomic scope from Viridiplantae to include known bacterial
and fungal lineages with ureide pathway
- Add hierarchical GO annotation structure where proteins receive both specific (substrate/pathway)
and general (amide catabolic) terms
- Document biological context differences across condition sets to prevent misinterpretation
of GO:0043605 as indicating general amide-degrading capacity
parsimony:
assessment: OVERLY_COMPLEX
notes: The rule's AND logic creates massive false negatives. CS1 should use OR logic
or be split into 3 separate condition sets. CS2 has redundant FunFams. CS3's subsetting
means 5 proteins are excluded. The rule groups mechanistically diverse enzymes
under overly broad GO term, obscuring biological specificity. CS1 urease domains
have only 4-10% pairwise overlap but use AND logic, creating a triple intersection
of ≤10 proteins from 851 total urease proteins. Each domain individually has 100%
containment to GO:0043605, proving each is sufficient.
supported_by:
- reference_id: file:rules/arba/ARBA00047244/ARBA00047244-deep-research-perplexity.md
supporting_text: The rule employs specific combinations of domains and families
to predict GO:0043605 annotation. This multi-component approach increases specificity
by preventing false positive annotations.
- reference_id: file:rules/arba/ARBA00047244/ARBA00047244-deep-research-falcon.md
supporting_text: Condition Set 1 (urease beta, gamma, and active site) provides
a strong, mechanistically coherent signature for urease; together these should
be highly specific for ureolysis and thus for amide catabolism.
literature_support:
assessment: STRONG
notes: 'Condition sets 1, 3, and 4 have extensive experimental support spanning
structural crystallography, enzyme kinetics, mechanistic studies, and genetic
analyses. Urease: High-resolution structures of bacterial (K. aerogenes, B. pasteurii,
H. pylori) and plant (jack bean) ureases reveal conserved dinuclear Ni(II) active
sites bridged by carbamylated lysine. Mechanistic studies demonstrate bridging
hydroxide nucleophilic attack with extraordinary catalytic proficiency (10^14-fold
rate enhancement). Urease is essential for H. pylori gastric colonization and
pH-dependent bacterial survival. Plant ureide enzymes: Crystal structures of AtUGlyAH
and AtUAH in substrate-bound forms demonstrate Mn2+-dependent catalysis and explain
enantioselectivity. Genetic studies show AAH knockout causes seed dormancy, ureide
accumulation, and amino acid depletion; UAH-URE double mutants show synthetic
lethality, confirming physiological importance. The ureide pathway is conserved
across Viridiplantae including mosses and algae. PM20D1: Biochemical assays demonstrate
bidirectional NAA synthesis/hydrolysis (1.2% synthase, 94% hydrolase conversion).
However, genetic and physiological studies emphasize thermogenic/metabolic roles
rather than nitrogen catabolism—PM20D1 knockout causes glucose intolerance and
metabolic dysfunction; overexpression increases energy expenditure. Natural promoter
variants explain mouse strain cold tolerance differences. This represents strong
evidence for catalytic activity but raises questions about functional annotation
as general amide catabolism.'
supported_by:
- reference_id: file:rules/arba/ARBA00047244/ARBA00047244-deep-research-perplexity.md
supporting_text: Extensive biochemical literature supports the conclusion that
proteins matching condition sets 1, 3, and 4 catalyze amide hydrolysis. For
urease enzymes, the chemical mechanism has been elucidated through structural
crystallography, kinetic analysis, and spectroscopic investigation
- reference_id: file:rules/arba/ARBA00047244/ARBA00047244-deep-research-perplexity.md
supporting_text: The structure of (S)-ureidoglycine aminohydrolase from Arabidopsis
thaliana in complex with its substrate (S)-ureidoglycine directly demonstrated
substrate binding at the Mn2+ coordination site and the catalytic geometry supporting
C-N bond hydrolysis
- reference_id: file:rules/arba/ARBA00047244/ARBA00047244-deep-research-perplexity.md
supporting_text: Analysis of Ataah mutant seeds revealed pleiotropic effects of
allantoate amidohydrolase disruption, including seed dormancy increase, ureide
accumulation, and amino acid depletion
- reference_id: file:rules/arba/ARBA00047244/ARBA00047244-deep-research-perplexity.md
supporting_text: Mice with PM20D1 deletion exhibit metabolic dysfunction characterized
by glucose intolerance and decreased insulin sensitivity, indicating disrupted
signaling through N-acyl amino acids rather than impaired amide degradation
per se
- reference_id: file:rules/arba/ARBA00047244/ARBA00047244-deep-research-falcon.md
supporting_text: Dinuclear Ni(II) center bridged by a carbamylated lysine is conserved;
accessory proteins UreD/E/F/G assemble and metallate the site; catalytic "bridging
hydroxide" mechanism supported by structural and inhibitor studies
- reference_id: file:rules/arba/ARBA00047244/ARBA00047244-deep-research-falcon.md
supporting_text: In Arabidopsis, soybean and rice, allantoin degradation employs
one aminohydrolase (UGlyAH) and three amidohydrolases (ALN upstream ring opening;
AAH; UAH) to convert (S)-allantoin to glyoxylate, CO2 and NH3
condition_overlap:
assessment: NONE
notes: The four condition sets capture entirely distinct protein families with no
sequence or structural overlap. Condition set 1 targets ureases (Ni-dependent,
bacterial/plant, multi-subunit assemblies). Condition sets 3-4 target plant ureide
pathway enzymes (Mn-dependent, bicupin or related folds, ER-localized). Condition
set 2 targets PM20D1 (M20 peptidase family, secreted, bidirectional). These represent
independent evolutionary solutions to amide hydrolysis chemistry. Mechanistically,
urease uses dinuclear Ni(II) with bridging hydroxide; ureide enzymes use Mn2+
coordination; PM20D1 mechanism is less characterized but involves M20 peptidase
chemistry. Functionally, ureases serve nitrogen mobilization and pH modulation;
ureide enzymes serve purine catabolism/nitrogen remobilization; PM20D1 serves
thermogenic lipid signaling. The lack of overlap underscores that the rule groups
mechanistically and functionally diverse enzymes solely on the basis of shared
chemistry (amide bond cleavage), which may obscure biologically relevant distinctions.
supported_by:
- reference_id: file:rules/arba/ARBA00047244/ARBA00047244-deep-research-perplexity.md
supporting_text: Urease enzymes from plants and bacteria maintain nearly identical
active site architectures despite differences in subunit composition (single
polypeptide vs. multi-subunit), oligomeric state, and overall fold contexts
- reference_id: file:rules/arba/ARBA00047244/ARBA00047244-deep-research-perplexity.md
supporting_text: Manganese-dependent ureide pathway enzymes employ metal coordination
chemistry fundamentally similar to nickel-dependent ureases, suggesting that
nature has converged on metal-dependent catalysis as the solution to rapid amide
hydrolysis
go_specificity:
assessment: TOO_BROAD
notes: GO:0043605 (amide catabolic process) is technically accurate for all four
condition sets but too broad to capture biological context. The term describes
a general chemical mechanism shared by functionally diverse enzymes, potentially
misleading users about actual biological roles. For urease (condition set 1),
GO:0043419 (urea catabolic process) would be more specific—it captures the unique
substrate (urea) rather than the chemical class (amides). Urease's biological
roles in nitrogen cycling, bacterial virulence, and pH modulation are obscured
by generic amide catabolism annotation. For ureide enzymes (condition sets 3-4),
pathway-specific terms like "allantoin catabolic process" or "ureide catabolic
process" would better capture their role in purine nitrogen remobilization. For
PM20D1 (condition set 2), GO:0043605 is particularly problematic—while the enzyme
catalyzes amide hydrolysis, its primary biological role involves thermogenic lipid
signaling and metabolic regulation, not nitrogen catabolism. More appropriate
annotations might include "N-acyl amino acid metabolic process", "lipid biosynthetic
process" (for synthase activity), or "positive regulation of adaptive thermogenesis".
The breadth of GO:0043605 enables computational grouping of chemically similar
enzymes but sacrifices biological interpretability. A hierarchical annotation
strategy (specific + general terms) would preserve both granularity and computational
utility.
supported_by:
- reference_id: file:rules/arba/ARBA00047244/ARBA00047244-deep-research-perplexity.md
supporting_text: For condition set 1 (urease enzymes), GO:0043605 is appropriate
but potentially insufficiently specific. Ureases catalyze hydrolysis of urea,
the simplest amide, and thus undoubtedly perform amide catabolism. However,
the specific biological roles of urease in nitrogen mobilization, pH modulation,
and virulence are better captured by more specific annotations
- reference_id: file:rules/arba/ARBA00047244/ARBA00047244-deep-research-perplexity.md
supporting_text: For condition set 2 (PM20D1 and related N-acyl amino acid synthase/hydrolases),
the appropriateness of GO:0043605 is questionable. While PM20D1 does catalyze
hydrolysis of amide bonds, its primary biological role involves regulation of
N-acyl amino acid biosynthesis and catabolism for thermogenic purposes
- reference_id: file:rules/arba/ARBA00047244/ARBA00047244-deep-research-perplexity.md
supporting_text: For condition sets 3 and 4 (ureide pathway enzymes), GO:0043605
is highly appropriate, as these enzymes specifically function to liberate ammonia
from ureide substrates as part of purine catabolism. Alternative more specific
annotations might reference "purine catabolism" or "nitrogen remobilization
from purines," which would capture additional biological context
- reference_id: file:rules/arba/ARBA00047244/ARBA00047244-deep-research-falcon.md
supporting_text: GO:0043605 is broad. Where the rule has strong evidence for specific
substrates (urea, allantoate, (S)-ureidoglycine, (S)-ureidoglycolate), more
specific BP annotations would reduce ambiguity and improve downstream utility
taxonomic_scope:
assessment: TOO_BROAD
notes: Condition set 1 (urease) has no taxonomic restriction, which is appropriate
given urease's broad distribution across bacteria and plants (but absence from
animals). However, the rule could be made more explicit by adding "not Animalia"
as an exclusion, providing logical clarity. Condition set 2 (PM20D1) restricts
to Eukaryota (NCBITaxon:2759), which is appropriate for PM20D1 presence but may
be too broad for the specific annotation. If GO:0043605 is retained, the scope
might be narrowed to Mammalia or Vertebrata where thermogenic/metabolic context
is relevant—PM20D1 orthologs in plants, fungi, or invertebrates may serve unrelated
functions. Condition set 3 (ureide enzymes) restricts to Viridiplantae, which
is too narrow—the ureide pathway exists in bacteria and fungi, creating false
negatives. The scope should expand to "Viridiplantae, selected bacteria, and selected
fungi" or implement granular inclusion of known lineages. Condition set 4 (UGlyAH)
restricts to Streptophyta (land plants + streptophyte algae), which appropriately
captures this enzyme's distribution and is consistent with experimental evidence.
Overall, taxonomic scopes show mixed appropriateness—some too broad (PM20D1 in
Eukaryota), some too narrow (ureide enzymes excluding prokaryotes), some appropriate
(urease unrestricted, UGlyAH in Streptophyta).
supported_by:
- reference_id: file:rules/arba/ARBA00047244/ARBA00047244-deep-research-perplexity.md
supporting_text: Urease enzymes are ubiquitous across plants, fungi, and bacteria
but completely absent from animals. The universal distribution of urease across
these kingdoms reflects the fundamental importance of urea as a nitrogen source
in nature
- reference_id: file:rules/arba/ARBA00047244/ARBA00047244-deep-research-perplexity.md
supporting_text: Condition set 2 restricts the annotation to eukaryotes (NCBITaxon:2759),
which is appropriate given that PM20D1 represents a eukaryotic protein present
in circulation in both mice and humans
- reference_id: file:rules/arba/ARBA00047244/ARBA00047244-deep-research-perplexity.md
supporting_text: Condition set 3 currently restricts annotation to Viridiplantae,
but the ureide pathway and its constituent enzymes are known to exist in bacteria
and fungi
- reference_id: file:rules/arba/ARBA00047244/ARBA00047244-deep-research-falcon.md
supporting_text: AAH, UGlyAH, and UAH orthologs are broadly conserved in Viridiplantae
(including soybean, rice, Arabidopsis; also reported in mosses/algae). Streptophyta-restricted
conditions (e.g., for (S)-ureidoglycine aminohydrolase) are consistent with
the distribution of the ureide catabolic phase
confidence: 0.8
references:
- id: file:rules/arba/ARBA00047244/ARBA00047244-deep-research-perplexity.md
title: Deep research analysis via Perplexity (48 citations, comprehensive)
findings:
- statement: Urease catalyzes hydrolysis of urea to ammonia and CO2 via carbamate
intermediate using conserved dinuclear Ni(II) active site bridged by carbamylated
lysine. Catalytic proficiency is extraordinary (10^14-fold rate enhancement).
Conserved across bacteria and plants despite quaternary structure variation.
- statement: Plant ureide pathway enzymes (AAH, UGlyAH, UAH) use Mn2+ cofactors
to sequentially degrade allantoin to glyoxylate, liberating ammonia and CO2.
Crystal structures demonstrate metal-dependent catalysis and substrate specificity
determinants. Genetic studies confirm physiological importance in nitrogen remobilization
and seed development.
- statement: PM20D1 is bidirectional synthase/hydrolase for N-acyl amino acids,
showing 1.2% synthase and 94% hydrolase conversion in vitro. Primary biological
role is thermogenic lipid signaling—knockout causes metabolic dysfunction, overexpression
increases energy expenditure. Natural variants explain mouse strain cold tolerance
differences.
- statement: 'GO:0043605 is appropriate but insufficiently specific. More specific
annotations: GO:0043419 (urea catabolism) for urease, pathway-specific terms
for ureide enzymes, metabolic/thermogenic terms for PM20D1. Current annotation
obscures biological context.'
- statement: 'Taxonomic scope issues: Viridiplantae restriction for ureide enzymes
excludes known bacterial/fungal systems (false negatives); Eukaryota scope for
PM20D1 may be too broad given thermogenesis context.'
- id: file:rules/arba/ARBA00047244/ARBA00047244-deep-research-falcon.md
title: Deep research analysis via Falcon (17 citations)
findings:
- statement: Urease subunit/active site signatures provide strong, mechanistically
coherent signature for ureolysis. Dinuclear Ni(II) center bridged by carbamylated
lysine conserved across bacteria and plants. Accessory proteins UreD/E/F/G assemble
and metallate the site.
- statement: Plant ureide-pathway hydrolases (AAH, UGlyAH, UAH) are close homologs
with distinct active-site determinants enforcing narrow substrate specificity
(e.g., AtUAH Tyr-423 vs. Gly in AAH; QXR motif in AAH). Specialized roles in
purine/ureide catabolism, not broadly multifunctional.
- statement: GO:0043605 appropriate for urease and ureide enzymes but broad. More
specific BP annotations would reduce ambiguity. PM20D1 condition set lacks strong
supporting evidence in provided context—should be reassessed.
- statement: 'Rule logic assessment: Urease and ureide enzyme condition sets are
well-supported by conserved structure and pathway biochemistry. Multi-domain
requirements reduce false positives. PM20D1 branch needs validation.'
- id: file:rules/arba/ARBA00047244/ARBA00047244.enriched.json
title: Enriched rule JSON with condition sets and annotations
findings:
- statement: Rule created 2024-08-14, modified 2025-03-21. Four condition sets targeting
urease domains, PM20D1 FunFams, and plant ureide pathway hydrolases. Predicts
GO:0043605 (amide catabolic process). Currently annotates 0 proteins (0 reviewed,
0 unreviewed).
supported_by:
- reference_id: file:rules/arba/ARBA00047244/ARBA00047244-deep-research-perplexity.md
supporting_text: The UniProt rule ARBA00047244 presents a mixed picture of annotation
accuracy and appropriateness. The rule correctly identifies that proteins matching
these signatures do possess amide catabolic activity, as all condition sets target
enzymes known to catalyze the hydrolysis of amide bonds