id: ARBA00026372 description: 'This rule predicts GO:0051998 (protein carboxyl O-methyltransferase activity) using 5 condition sets that identify two mechanistically distinct enzyme families: isoprenylcysteine carboxyl methyltransferases (ICMT) and protein-L-isoaspartate methyltransferases (PIMT). These enzymes share a common chemistry (methylating carboxyl groups on proteins) but differ fundamentally in substrate specificity, cellular location, biological function, and mechanism.' status: COMPLETE rule_type: ARBA rule: rule_id: ARBA00026372 condition_sets: - number: 1 conditions: - condition_type: INTERPRO value: IPR007269 curie: InterPro:IPR007269 label: Isoprenylcysteine carboxyl methyltransferase negated: false - condition_type: INTERPRO value: IPR025770 curie: InterPro:IPR025770 label: Protein-S-isoprenylcysteine O-methyltransferase negated: false - condition_type: PANTHER value: PTHR12714 curie: PTHR12714 label: '' negated: false notes: Condition set 1 identifies ICMT enzymes through InterPro and PANTHER signatures. These are integral ER membrane proteins (8 transmembrane domains) that methylate prenylated cysteine residues at the C-terminus of CaaX proteins. IPR025770 is completely contained within IPR007269 (12 of 12 proteins overlap, Jaccard=0.750), indicating redundancy within this condition set. pairwise_overlap: - condition_a: IPR007269 condition_b: IPR025770 protein_database: SWISSPROT count_a: 16 count_b: 12 intersection_count: 12 a_minus_b_count: 4 b_minus_a_count: 0 jaccard_similarity: 0.75 containment_a_in_b: 0.75 containment_b_in_a: 1.0 interpretation: SUBSET - condition_a: IPR007269 condition_b: PTHR12714 protein_database: SWISSPROT count_a: 16 count_b: 19 intersection_count: 14 a_minus_b_count: 2 b_minus_a_count: 5 jaccard_similarity: 0.6666666666666666 containment_a_in_b: 0.875 containment_b_in_a: 0.7368421052631579 interpretation: HIGH_OVERLAP - condition_a: IPR025770 condition_b: PTHR12714 protein_database: SWISSPROT count_a: 12 count_b: 19 intersection_count: 12 a_minus_b_count: 0 b_minus_a_count: 7 jaccard_similarity: 0.631578947368421 containment_a_in_b: 1.0 containment_b_in_a: 0.631578947368421 interpretation: SUBSET - number: 2 conditions: - condition_type: FUNFAM value: 3.40.50.150:FF:000027 curie: CATH.FunFam:3.40.50.150:FF:000027 label: Protein-L-isoaspartate O-methyltransferase negated: false - condition_type: TAXON value: '2759' curie: NCBITaxon:2759 label: Eukaryota negated: false notes: Condition set 2 identifies PIMT enzymes in eukaryotes. These are cytosolic protein repair enzymes that methylate isoaspartyl residues in damaged proteins. This condition set is completely DISJOINT from condition set 1 (0 protein overlap), representing a mechanistically distinct enzyme family. - number: 3 conditions: - condition_type: FUNFAM value: 1.20.120.1630:FF:000007 curie: CATH.FunFam:1.20.120.1630:FF:000007 label: Protein-S-isoprenylcysteine O-methyltransferase negated: false notes: Condition set 3 identifies additional ICMT-family proteins (6 proteins in SwissProt). All 6 proteins are subsets of the IPR007269 and IPR025770 sets from CS1, but this FunFam captures only a portion of the ICMT family. No taxonomic restriction is applied. - number: 4 conditions: - condition_type: FUNFAM value: 1.20.120.1630:FF:000018 curie: CATH.FunFam:1.20.120.1630:FF:000018 label: Protein-S-isoprenylcysteine O-methyltransferase negated: false - condition_type: TAXON value: '4751' curie: NCBITaxon:4751 label: Fungi negated: false notes: Condition set 4 identifies fungal ICMT proteins (2 proteins in SwissProt). These 2 proteins are subsets of IPR025770 and IPR007269 from CS1, but are DISJOINT from the 6 proteins in CS3 (1.20.120.1630:FF:000007), suggesting these FunFams partition the ICMT family. - number: 5 conditions: - condition_type: FUNFAM value: 3.40.50.150:FF:000235 curie: CATH.FunFam:3.40.50.150:FF:000235 label: Protein-L-isoaspartate O-methyltransferase negated: false - condition_type: TAXON value: '33208' curie: NCBITaxon:33208 label: Metazoa negated: false notes: Condition set 5 identifies metazoan PIMT proteins (2 proteins in SwissProt). This condition set is completely DISJOINT from all ICMT-related condition sets (CS1, CS3, CS4) and also DISJOINT from the eukaryotic PIMT set in CS2, indicating these FunFams partition the PIMT family by taxonomy. go_annotations: - go_id: GO:0051998 go_label: protein carboxyl O-methyltransferase activity aspect: MF entries: - id: 1.20.120.1630:FF:000007 type: FUNFAM label: Protein-S-isoprenylcysteine O-methyltransferase appears_in_condition_sets: - 3 protein_count: 6 related_entries: - relationship: PREDICTS target_id: IPR007269 containment: 0.375 jaccard_similarity: 0.375 intersection_count: 6 exclusive_count: 10 - relationship: PREDICTS target_id: IPR025770 containment: 0.5 jaccard_similarity: 0.5 intersection_count: 6 exclusive_count: 6 - relationship: PREDICTS target_id: PTHR12714 containment: 0.316 jaccard_similarity: 0.316 intersection_count: 6 exclusive_count: 13 - relationship: EQUIV target_id: 3.40.50.150:FF:000027 containment: 0.0 jaccard_similarity: 0.0 intersection_count: 0 exclusive_count: 6 - relationship: EQUIV target_id: 1.20.120.1630:FF:000018 containment: 0.0 jaccard_similarity: 0.0 intersection_count: 0 exclusive_count: 6 - relationship: EQUIV target_id: 3.40.50.150:FF:000235 containment: 0.0 jaccard_similarity: 0.0 intersection_count: 0 exclusive_count: 6 - relationship: PREDICTS target_id: GO:0051998 containment: 1.0 jaccard_similarity: 0.015 intersection_count: 6 exclusive_count: 0 - id: 1.20.120.1630:FF:000018 type: FUNFAM label: Protein-S-isoprenylcysteine O-methyltransferase appears_in_condition_sets: - 4 protein_count: 2 related_entries: - relationship: PREDICTS target_id: IPR007269 containment: 0.125 jaccard_similarity: 0.125 intersection_count: 2 exclusive_count: 14 - relationship: PREDICTS target_id: IPR025770 containment: 0.167 jaccard_similarity: 0.167 intersection_count: 2 exclusive_count: 10 - relationship: PREDICTS target_id: PTHR12714 containment: 0.105 jaccard_similarity: 0.105 intersection_count: 2 exclusive_count: 17 - relationship: EQUIV target_id: 3.40.50.150:FF:000027 containment: 0.0 jaccard_similarity: 0.0 intersection_count: 0 exclusive_count: 2 - relationship: EQUIV target_id: 1.20.120.1630:FF:000007 containment: 0.0 jaccard_similarity: 0.0 intersection_count: 0 exclusive_count: 2 - relationship: EQUIV target_id: 3.40.50.150:FF:000235 containment: 0.0 jaccard_similarity: 0.0 intersection_count: 0 exclusive_count: 2 - relationship: PREDICTS target_id: GO:0051998 containment: 1.0 jaccard_similarity: 0.005 intersection_count: 2 exclusive_count: 0 - id: 3.40.50.150:FF:000027 type: FUNFAM label: Protein-L-isoaspartate O-methyltransferase appears_in_condition_sets: - 2 protein_count: 12 related_entries: - relationship: EQUIV target_id: IPR007269 containment: 0.0 jaccard_similarity: 0.0 intersection_count: 0 exclusive_count: 12 - relationship: EQUIV target_id: IPR025770 containment: 0.0 jaccard_similarity: 0.0 intersection_count: 0 exclusive_count: 12 - relationship: EQUIV target_id: PTHR12714 containment: 0.0 jaccard_similarity: 0.0 intersection_count: 0 exclusive_count: 12 - relationship: EQUIV target_id: 1.20.120.1630:FF:000007 containment: 0.0 jaccard_similarity: 0.0 intersection_count: 0 exclusive_count: 12 - relationship: EQUIV target_id: 1.20.120.1630:FF:000018 containment: 0.0 jaccard_similarity: 0.0 intersection_count: 0 exclusive_count: 12 - relationship: EQUIV target_id: 3.40.50.150:FF:000235 containment: 0.0 jaccard_similarity: 0.0 intersection_count: 0 exclusive_count: 12 - relationship: PREDICTS target_id: GO:0051998 containment: 1.0 jaccard_similarity: 0.029 intersection_count: 12 exclusive_count: 0 - id: 3.40.50.150:FF:000235 type: FUNFAM label: Protein-L-isoaspartate O-methyltransferase appears_in_condition_sets: - 5 protein_count: 2 related_entries: - relationship: EQUIV target_id: IPR007269 containment: 0.0 jaccard_similarity: 0.0 intersection_count: 0 exclusive_count: 2 - relationship: EQUIV target_id: IPR025770 containment: 0.0 jaccard_similarity: 0.0 intersection_count: 0 exclusive_count: 2 - relationship: EQUIV target_id: PTHR12714 containment: 0.0 jaccard_similarity: 0.0 intersection_count: 0 exclusive_count: 2 - relationship: EQUIV target_id: 3.40.50.150:FF:000027 containment: 0.0 jaccard_similarity: 0.0 intersection_count: 0 exclusive_count: 2 - relationship: EQUIV target_id: 1.20.120.1630:FF:000007 containment: 0.0 jaccard_similarity: 0.0 intersection_count: 0 exclusive_count: 2 - relationship: EQUIV target_id: 1.20.120.1630:FF:000018 containment: 0.0 jaccard_similarity: 0.0 intersection_count: 0 exclusive_count: 2 - relationship: PREDICTS target_id: GO:0051998 containment: 1.0 jaccard_similarity: 0.005 intersection_count: 2 exclusive_count: 0 - id: IPR007269 type: INTERPRO label: Isoprenylcysteine carboxyl methyltransferase appears_in_condition_sets: - 1 protein_count: 16 related_entries: - relationship: PREDICTED_BY target_id: IPR025770 containment: 1.0 jaccard_similarity: 0.75 intersection_count: 12 exclusive_count: 0 - relationship: PREDICTS target_id: PTHR12714 containment: 0.875 jaccard_similarity: 0.667 intersection_count: 14 exclusive_count: 2 - relationship: EQUIV target_id: 3.40.50.150:FF:000027 containment: 0.0 jaccard_similarity: 0.0 intersection_count: 0 exclusive_count: 16 - relationship: PREDICTED_BY target_id: 1.20.120.1630:FF:000007 containment: 1.0 jaccard_similarity: 0.375 intersection_count: 6 exclusive_count: 0 - relationship: PREDICTED_BY target_id: 1.20.120.1630:FF:000018 containment: 1.0 jaccard_similarity: 0.125 intersection_count: 2 exclusive_count: 0 - relationship: EQUIV target_id: 3.40.50.150:FF:000235 containment: 0.0 jaccard_similarity: 0.0 intersection_count: 0 exclusive_count: 16 - relationship: PREDICTS target_id: GO:0051998 containment: 1.0 jaccard_similarity: 0.039 intersection_count: 16 exclusive_count: 0 - id: IPR025770 type: INTERPRO label: Protein-S-isoprenylcysteine O-methyltransferase appears_in_condition_sets: - 1 protein_count: 12 related_entries: - relationship: PREDICTS target_id: IPR007269 containment: 0.75 jaccard_similarity: 0.75 intersection_count: 12 exclusive_count: 4 - relationship: PREDICTS target_id: PTHR12714 containment: 1.0 jaccard_similarity: 0.632 intersection_count: 12 exclusive_count: 0 - relationship: EQUIV target_id: 3.40.50.150:FF:000027 containment: 0.0 jaccard_similarity: 0.0 intersection_count: 0 exclusive_count: 12 - relationship: PREDICTED_BY target_id: 1.20.120.1630:FF:000007 containment: 1.0 jaccard_similarity: 0.5 intersection_count: 6 exclusive_count: 0 - relationship: PREDICTED_BY target_id: 1.20.120.1630:FF:000018 containment: 1.0 jaccard_similarity: 0.167 intersection_count: 2 exclusive_count: 0 - relationship: EQUIV target_id: 3.40.50.150:FF:000235 containment: 0.0 jaccard_similarity: 0.0 intersection_count: 0 exclusive_count: 12 - relationship: PREDICTS target_id: GO:0051998 containment: 1.0 jaccard_similarity: 0.029 intersection_count: 12 exclusive_count: 0 - id: PTHR12714 type: PANTHER appears_in_condition_sets: - 1 protein_count: 19 related_entries: - relationship: PREDICTED_BY target_id: IPR007269 containment: 0.737 jaccard_similarity: 0.667 intersection_count: 14 exclusive_count: 5 - relationship: PREDICTED_BY target_id: IPR025770 containment: 0.632 jaccard_similarity: 0.632 intersection_count: 12 exclusive_count: 7 - relationship: EQUIV target_id: 3.40.50.150:FF:000027 containment: 0.0 jaccard_similarity: 0.0 intersection_count: 0 exclusive_count: 19 - relationship: PREDICTED_BY target_id: 1.20.120.1630:FF:000007 containment: 1.0 jaccard_similarity: 0.316 intersection_count: 6 exclusive_count: 0 - relationship: PREDICTED_BY target_id: 1.20.120.1630:FF:000018 containment: 1.0 jaccard_similarity: 0.105 intersection_count: 2 exclusive_count: 0 - relationship: EQUIV target_id: 3.40.50.150:FF:000235 containment: 0.0 jaccard_similarity: 0.0 intersection_count: 0 exclusive_count: 19 - relationship: PREDICTS target_id: GO:0051998 containment: 0.737 jaccard_similarity: 0.034 intersection_count: 14 exclusive_count: 5 review_summary: ARBA00026372 exhibits severe structural flaws that undermine its biological validity. The rule conflates two mechanistically distinct enzyme families - isoprenylcysteine carboxyl methyltransferases (ICMT) and protein-L-isoaspartate methyltransferases (PIMT) - under a single overly broad GO term. While both enzymes methylate carboxyl groups on proteins, they differ fundamentally in substrate specificity, cellular location, biological function, and mechanism. ICMT enzymes are integral ER membrane proteins that modify prenylated C-terminal cysteines to enhance membrane affinity of signaling proteins like Ras. PIMT enzymes are cytosolic repair enzymes that methylate isoaspartyl residues in damaged proteins as part of a repair cycle. The complete DISJOINT nature of condition sets identifying these two families (Jaccard=0.000 between CS1 and CS2, CS1 and CS5) confirms they represent separate protein families that should not be annotated with the same specific GO term. Additionally, condition set 1 contains internal redundancy (IPR025770 is a complete subset of IPR007269), and the rule uses the generic parent term GO:0051998 when specific child terms GO:0004671 (for ICMT) and GO:0004719 (for PIMT) exist. The average Jaccard similarity of 0.097 across domain pairs reflects the fundamental heterogeneity of this rule. action: DEPRECATE action_rationale: 'This rule should be REMOVED and replaced with two separate rules, each using appropriate specific GO terms. The conflation of ICMT and PIMT enzymes under GO:0051998 represents a fundamental violation of the principle that automated rules should capture proteins with shared mechanistic and functional characteristics. While both enzyme families perform carboxyl O-methylation, this shared chemistry is insufficient justification for a single annotation rule given their profound differences in substrate, mechanism, cellular context, and biological role. The complete protein-level disjointness between ICMT and PIMT condition sets (0% overlap) definitively demonstrates these are distinct enzyme families that evolution has specialized for different purposes. Using a broad parent GO term to paper over mechanistic differences creates misleading annotations that obscure rather than clarify protein function. Furthermore, the internal redundancy within condition set 1 (IPR025770 completely contained in IPR007269) indicates poor rule design. This rule should be deprecated and replaced with two parsimonious rules: one annotating ICMT proteins to GO:0004671 (protein C-terminal S-isoprenylcysteine carboxyl O-methyltransferase activity) and one annotating PIMT proteins to GO:0004719 (protein-L-isoaspartate (D-aspartate) O-methyltransferase activity).' suggested_modifications: - Create ARBA rule for ICMT family using InterPro:IPR007269, PANTHER:PTHR12714, and relevant FunFams (1.20.120.1630:FF:000007, 1.20.120.1630:FF:000018), annotating to GO:0004671 (protein C-terminal S-isoprenylcysteine carboxyl O-methyltransferase activity) - Create separate ARBA rule for PIMT family using FunFams 3.40.50.150:FF:000027 and 3.40.50.150:FF:000235 with appropriate taxonomic restrictions, annotating to GO:0004719 (protein-L-isoaspartate (D-aspartate) O-methyltransferase activity) - Remove IPR025770 from ICMT rule as it is completely redundant with IPR007269 - Deprecate current ARBA00026372 rule to prevent future false annotations parsimony: assessment: OVERLY_COMPLEX notes: The rule contains 5 condition sets attempting to capture two distinct enzyme families, with significant redundancy and unnecessary complexity. Condition set 1 alone contains redundant InterPro domains (IPR025770 is a complete subset of IPR007269 with 100% containment). The inclusion of multiple taxonomically restricted FunFam condition sets (CS2 for Eukaryota, CS4 for Fungi, CS5 for Metazoa) adds complexity without biological justification when these could be consolidated within family-specific rules. The fundamental issue is not complexity per se, but rather that the rule attempts to unify mechanistically distinct enzyme families that should be handled by separate rules. The average Jaccard similarity of 0.097 across all domain pairs reflects this inappropriate grouping rather than acceptable biological diversity within a single enzyme family. supported_by: - reference_id: file:rules/arba/ARBA00026372/ARBA00026372-analysis.yaml supporting_text: '"IPR007269 ↔ IPR025770: Jaccard similarity: 0.75, Containment: A in B = 0.750, B in A = 1.000, Interpretation: SUBSET. Summary: Analyzed 15 domain-domain pairs and 6 domain-GO pairs across entire rule. Average Jaccard similarity: 0.097. 1 pairs with >50% overlap, 11 subset relationships."' literature_support: assessment: CONTRADICTED notes: Literature clearly establishes that ICMT and PIMT are mechanistically distinct enzyme families despite sharing a common chemistry. ICMT is an integral ER membrane protein with 8 transmembrane domains that methylates the alpha-carboxyl group of prenylated cysteine residues at the C-terminus of CaaX proteins. This modification is permanent and increases membrane affinity of signaling proteins like Ras. In contrast, PIMT is a cytosolic enzyme that methylates the alpha-carboxyl group of isoaspartyl residues in damaged or aging proteins. This methylation is transient and initiates a repair cycle through a succinimide intermediate. The substrates differ (prenylated C-terminal cysteine vs. internal isoaspartyl residues), the cellular locations differ (ER membrane vs. cytosol), the biological functions differ (signal protein modification vs. protein repair), and the outcomes differ (permanent membrane targeting vs. transient repair intermediate). These fundamental differences contradict the premise that these enzymes should receive identical GO annotations simply because they both methylate carboxyl groups. The literature supports using specific child GO terms that capture these mechanistic distinctions. supported_by: - reference_id: web:https://pubmed.ncbi.nlm.nih.gov/22195972/ supporting_text: '"ICMT is a highly conserved enzyme that methyl esterifies the alpha carboxyl group of prenylated proteins including Ras and related GTPases. Methyl esterification neutralizes the negative charge of the prenylcysteine and thereby increases membrane affinity. Icmt is an integral membrane protein restricted to the endoplasmic reticulum (ER). Human Icmt traverses the ER membrane eight times, with both N and C termini disposed toward the cytosol."' - reference_id: web:https://pubmed.ncbi.nlm.nih.gov/31234761/ supporting_text: '"PIMT acts to transfer methyl groups from S-adenosyl-L-methionine to the alpha side chain carboxyl groups of damaged L-isoaspartyl and D-aspartyl amino acids. Under physiological conditions, deamidation of asparagine residues or dehydration of aspartic acid residues results in formation of a metastable intermediate succinimide that spontaneously hydrolyzes to form a mixture of normal L-aspartyl and atypical L-isoaspartyl linkages. PIMT, using AdoMet as a methyl donor, selectively methylates the isoaspartyl α-carboxyl group to form a highly labile methyl ester. Spontaneous demethylation occurs within minutes to reform the original succinimide, and further cycles of repair result in near complete conversion of the isoaspartyl β-linkages to normal aspartyl α-linkages."' - reference_id: web:https://en.wikipedia.org/wiki/Protein-S-isoprenylcysteine_O-methyltransferase supporting_text: '"A C-terminal CaaX motif targets eukaryotic proteins to posttranslational modifications. Processing is initiated by covalent attachment of a 15-carbon farnesyl or a 20-carbon geranylgeranyl lipid to the cysteine, followed by removal of the C-terminal three amino acids by CaaX protease Rce1, and then methylation of the prenylcysteine by ICMT."' condition_overlap: assessment: SIGNIFICANT notes: 'The rule exhibits severe overlap issues at multiple levels. Within condition set 1, IPR025770 is completely contained within IPR007269 (100% containment, 75% Jaccard), indicating unnecessary redundancy. More critically, the rule shows systematic DISJOINT relationships between major condition set groups. Condition sets identifying ICMT enzymes (CS1, CS3, CS4) are completely DISJOINT from condition sets identifying PIMT enzymes (CS2, CS5), with 0% protein overlap. For example, IPR007269 (CS1) vs. 3.40.50.150:FF:000027 (CS2) shows Jaccard=0.000 with 0 shared proteins out of 28 total. Similarly, IPR025770 (CS1) vs. 3.40.50.150:FF:000235 (CS5) shows Jaccard=0.000 with 0 shared proteins out of 14 total. Even within enzyme families, FunFam condition sets show suspicious disjointness: 1.20.120.1630:FF:000007 (CS3) and 1.20.120.1630:FF:000018 (CS4) are completely DISJOINT despite both being labeled as protein-S-isoprenylcysteine O-methyltransferase. The systematic pattern of DISJOINT relationships (9 out of 15 domain pairs show Jaccard=0.000) indicates this rule groups unrelated protein families rather than capturing a single coherent enzyme family with some structural diversity.' supported_by: - reference_id: file:rules/arba/ARBA00026372/ARBA00026372-analysis.yaml supporting_text: '"IPR007269 ↔ 3.40.50.150:FF:000027: Counts: 16 / 12, Intersection: 0, Jaccard similarity: 0.0, Containment: A in B = 0.0, B in A = 0.0, Interpretation: DISJOINT. IPR025770 ↔ 3.40.50.150:FF:000027: Counts: 12 / 12, Intersection: 0, Jaccard similarity: 0.0, Interpretation: DISJOINT. IPR025770 ↔ 3.40.50.150:FF:000235: Counts: 12 / 2, Intersection: 0, Jaccard similarity: 0.0, Interpretation: DISJOINT. 3.40.50.150:FF:000027 ↔ 1.20.120.1630:FF:000007: Counts: 12 / 6, Intersection: 0, Jaccard similarity: 0.0, Interpretation: DISJOINT. 1.20.120.1630:FF:000007 ↔ 1.20.120.1630:FF:000018: Counts: 6 / 2, Intersection: 0, Jaccard similarity: 0.0, Interpretation: DISJOINT."' - reference_id: file:rules/arba/ARBA00026372/ARBA00026372-analysis.txt supporting_text: '"Summary: Analyzed 15 domain-domain pairs and 6 domain-GO pairs across entire rule. Average Jaccard similarity: 0.097. 1 pairs with >50% overlap, 11 subset relationships."' go_specificity: assessment: TOO_BROAD notes: 'GO:0051998 (protein carboxyl O-methyltransferase activity) is a generic parent term that obscures critical mechanistic and functional differences between the enzyme families captured by this rule. The GO hierarchy includes specific child terms that accurately reflect the distinct substrate specificities and biological roles of these enzymes: GO:0004671 (protein C-terminal S-isoprenylcysteine carboxyl O-methyltransferase activity) for ICMT enzymes and GO:0004719 (protein-L-isoaspartate (D-aspartate) O-methyltransferase activity) for PIMT enzymes. Using the broad parent term GO:0051998 for both enzyme families is analogous to annotating all kinases with "protein kinase activity" despite their diverse substrate specificities and regulatory roles. The choice of this broad term appears to be a workaround to justify combining mechanistically unrelated enzymes in a single rule, rather than a biologically appropriate annotation level. Proper curation practice would split this rule and use the specific child terms that capture the distinct mechanistic features of ICMT vs. PIMT enzymes. The definition of GO:0051998 ("Catalysis of the transfer of a methyl group to a carboxyl group on a protein") is accurate but insufficiently specific to be informative given that specific child terms exist for the different target residues and contexts.' supported_by: - reference_id: file:rules/arba/ARBA00026372/ARBA00026372.enriched.json supporting_text: '"annotations: [{annotationType: ANNOTATION, dbReference: {database: GO, id: GO:0051998, properties: [{key: GoTerm, value: -}, {key: GoEvidenceType, value: :-}], label: protein carboxyl O-methyltransferase activity}}]"' - reference_id: web:GO_term_search supporting_text: '"GO:0004671 (protein C-terminal S-isoprenylcysteine carboxyl O-methyltransferase activity): Catalysis of the reaction: S-adenosyl-L-methionine + protein C-terminal S-farnesyl-L-cysteine = S-adenosyl-L-homocysteine + protein C-terminal S-farnesyl-L-cysteine methyl ester. GO:0004719 (protein-L-isoaspartate (D-aspartate) O-methyltransferase activity): Catalysis of the reaction: S-adenosyl-L-methionine + protein L-beta-aspartate = S-adenosyl-L-homocysteine + protein L-beta-aspartate methyl ester."' taxonomic_scope: assessment: MISSING notes: The taxonomic restrictions in this rule are inconsistent and incoherent. Condition set 1 (ICMT enzymes via InterPro domains) lacks any taxonomic restriction and would annotate all domains of life, while condition set 4 (also ICMT enzymes but via a different FunFam) is restricted to Fungi (NCBITaxon:4751). This creates an illogical situation where the same enzyme family receives universal annotation in one condition set but fungi-specific annotation in another. Similarly, condition set 2 restricts PIMT enzymes to Eukaryota (NCBITaxon:2759) while condition set 5 restricts PIMT enzymes to Metazoa (NCBITaxon:33208), creating overlapping redundant taxonomic coverage. The fundamental issue is that this multi-family rule conflates two distinct enzyme families that likely have different phylogenetic distributions. ICMT enzymes appear to be primarily eukaryotic (involved in CaaX protein processing), while PIMT enzymes are more broadly distributed across bacteria and eukaryotes. Condition set 1 is MISSING an appropriate taxonomic restriction for ICMT, which should likely be restricted to Eukaryota. If the rule were properly split into separate ICMT and PIMT rules, each could have internally consistent taxonomic restrictions based on the actual phylogenetic distribution of each enzyme family. supported_by: - reference_id: file:rules/arba/ARBA00026372/ARBA00026372.enriched.json supporting_text: '"Condition set 1: No taxon restriction. Condition set 2: taxon restriction to Eukaryota (2759). Condition set 4: taxon restriction to Fungi (4751). Condition set 5: taxon restriction to Metazoa (33208)."' confidence: 0.95 references: - id: file:rules/arba/ARBA00026372/ARBA00026372-analysis.yaml title: Domain overlap analysis for ARBA00026372 findings: - statement: IPR025770 is a complete subset of IPR007269 with 100% containment - statement: Average Jaccard similarity across all domain pairs is 0.097 - statement: 9 out of 15 domain pairs show complete disjointness (Jaccard=0.000) - statement: ICMT-related domains (IPR007269, IPR025770) are completely DISJOINT from PIMT-related domains (3.40.50.150:FF:000027, 3.40.50.150:FF:000235) - id: file:rules/arba/ARBA00026372/ARBA00026372-analysis.txt title: Human-readable domain analysis report findings: - statement: Rule contains 5 condition sets with significant structural issues - statement: Only 1 pair shows >50% overlap (the redundant IPR007269/IPR025770 pair within CS1) - id: file:rules/arba/ARBA00026372/ARBA00026372.enriched.json title: Original ARBA rule definition with enriched annotations findings: - statement: Rule annotates to GO:0051998 (protein carboxyl O-methyltransferase activity) - statement: Rule created 2021-10-20, last modified 2025-03-21 - statement: Condition sets mix ICMT and PIMT enzyme families with inconsistent taxonomic restrictions - id: web:https://pubmed.ncbi.nlm.nih.gov/22195972/ title: Mechanism of isoprenylcysteine carboxyl methylation from the crystal structure of ICMT findings: - statement: ICMT is an integral ER membrane protein with 8 transmembrane domains - statement: ICMT methylates prenylated cysteine residues at C-terminus of CaaX proteins - statement: Methylation increases membrane affinity by neutralizing negative charge - id: web:https://pubmed.ncbi.nlm.nih.gov/31234761/ title: PIMT-Mediated Protein Repair Mechanism and Implications findings: - statement: PIMT is a cytosolic repair enzyme for damaged proteins - statement: PIMT methylates isoaspartyl residues formed from asparagine deamidation or aspartate dehydration - statement: Methylation is transient and initiates repair cycle through succinimide intermediate - id: web:https://en.wikipedia.org/wiki/Protein-S-isoprenylcysteine_O-methyltransferase title: Overview of ICMT structure and function findings: - statement: ICMT performs the third step of CaaX protein processing after prenylation and proteolysis - statement: Modification is permanent and enhances membrane localization of signaling proteins - id: web:https://en.wikipedia.org/wiki/L-isoaspartyl_methyltransferase title: Overview of PIMT/PCMT1 structure and function findings: - statement: PIMT is highly conserved across eukaryotes, archaebacteria, and Gram-negative bacteria - statement: Enzyme recognizes and repairs damaged L-isoaspartyl and D-aspartyl residues in aging proteins