ARBA00028655 phosphatidylinositol biosynthetic process (GO:0006661)

id: ARBA00028655
description: Assigns GO:0006661 (phosphatidylinositol biosynthetic process) from eleven alternative condition
  sets covering PI synthase, phosphoinositide kinases and phosphatases, and two lipid-transfer protein
  families.
status: COMPLETE
rule_type: ARBA
rule:
  rule_id: ARBA00028655
  condition_sets:
  - number: 1
    conditions:
    - condition_type: INTERPRO
      value: IPR000387
      label: Tyrosine-specific protein phosphatases domain
    - condition_type: INTERPRO
      value: IPR010569
      label: Myotubularin-like, phosphatase domain
    - condition_type: TAXON
      value: Primates
      curie: NCBITaxon:9443
      label: Primates
    notes: 'Matches myotubularin phosphatases. UniProtKB 2026_04 query (xref:interpro-IPR000387) AND (xref:interpro-IPR010569)
      AND (taxonomy_id:9443): 381 entries, 8 reviewed. Of the reviewed entries, 5 carry GO:0006661 on
      evidence other than ARBA: Q9Y216 (MTMR7) GO:0006661 TAS Reactome:R-HSA-1660517; Q13496 (MTM1) GO:0006661
      TAS Reactome:R-HSA-1660499; Q13614 (MTMR2) GO:0006661 TAS Reactome:R-HSA-1660516; Q9NYA4 (MTMR4)
      GO:0006661 TAS Reactome:R-HSA-1660516; Q13613 (MTMR1) GO:0006661 TAS Reactome:R-HSA-1660499. 3 carry
      it only as IEA GO_REF:0000117 (this rule''s own output), all orthologs of the supported entries.'
  - number: 2
    conditions:
    - condition_type: INTERPRO
      value: IPR002013
      label: SAC domain
    - condition_type: TAXON
      value: Haplorrhini
      curie: NCBITaxon:376913
      label: Haplorrhini
    notes: 'Matches SAC-domain phosphoinositide phosphatases (SAC1, FIG4, synaptojanins). UniProtKB 2026_04
      query (xref:interpro-IPR002013) AND (taxonomy_id:376913): 505 entries, 6 reviewed. Of the reviewed
      entries, 5 carry GO:0006661 on evidence other than ARBA: Q92562 (FIG4) GO:0006661 TAS Reactome:R-HSA-1660516;
      Q9NTJ5 (SAC1) GO:0006661 TAS Reactome:R-HSA-1483248; O43426 (SYNJ1) GO:0006661 TAS Reactome:R-HSA-1660499;
      Q9Y2H2 (SAC2) GO:0006661 TAS Reactome:R-HSA-1660516; O15056 (SYNJ2) GO:0006661 TAS Reactome:R-HSA-1660499.
      1 carry it only as IEA GO_REF:0000117 (this rule''s own output), all orthologs of the supported
      entries.'
  - number: 3
    conditions:
    - condition_type: FUNFAM
      value: 2.30.29.30:FF:000038
      label: Myotubularin 1, isoform CRA_a
    - condition_type: TAXON
      value: Primates
      curie: NCBITaxon:9443
      label: Primates
    notes: 'Matches myotubularins (MTM1, MTMR1, MTMR2). UniProtKB 2026_04 query ("2.30.29.30:FF:000038")
      AND (taxonomy_id:9443): 284 entries, 5 reviewed. Of the reviewed entries, 3 carry GO:0006661 on
      evidence other than ARBA: Q13614 (MTMR2) GO:0006661 TAS Reactome:R-HSA-1660516; Q13613 (MTMR1) GO:0006661
      TAS Reactome:R-HSA-1660499; Q13496 (MTM1) GO:0006661 TAS Reactome:R-HSA-1660499. 2 carry it only
      as IEA GO_REF:0000117 (this rule''s own output), all orthologs of the supported entries.'
  - number: 4
    conditions:
    - condition_type: FUNFAM
      value: 3.30.800.10:FF:000001
      label: phosphatidylinositol 4-phosphate 5-kinase type-1 gamma
    - condition_type: TAXON
      value: Mus
      curie: NCBITaxon:10088
      label: Mus
    notes: 'Matches phosphatidylinositol 4-phosphate 5-kinases type I. UniProtKB 2026_04 query ("3.30.800.10:FF:000001")
      AND (taxonomy_id:10088): 20 entries, 3 reviewed. Of the reviewed entries, 3 carry GO:0006661 on
      evidence other than ARBA: O70161 (PI51C) GO:0006661 IDA PMID:20622009; P70182 (PI51A) GO:0006661
      IGI PMID:20622009; P70181 (PI51B) GO:0006661 IGI PMID:20622009.'
  - number: 5
    conditions:
    - condition_type: FUNFAM
      value: 3.30.505.10:FF:000035
      label: phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 1
    - condition_type: FUNFAM
      value: 3.60.10.10:FF:000005
      label: phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 1
    - condition_type: TAXON
      value: Haplorrhini
      curie: NCBITaxon:376913
      label: Haplorrhini
    notes: 'Matches SHIP1 and SHIP2 inositol 5-phosphatases. UniProtKB 2026_04 query ("3.30.505.10:FF:000035")
      AND ("3.60.10.10:FF:000005") AND (taxonomy_id:376913): 79 entries, 2 reviewed. Of the reviewed entries,
      2 carry GO:0006661 on evidence other than ARBA: O15357 (SHIP2) GO:0006661 TAS Reactome:R-HSA-1660499;
      Q92835 (SHIP1) GO:0006661 TAS Reactome:R-HSA-1660499.'
  - number: 6
    conditions:
    - condition_type: FUNFAM
      value: 3.30.530.20:FF:000001
      label: Phosphatidylinositol transfer protein membrane associated 2
    - condition_type: FUNFAM
      value: 3.40.50.1000:FF:000173
      label: Membrane-associated phosphatidylinositol transfer protein 2
    - condition_type: TAXON
      value: Catarrhini
      curie: NCBITaxon:9526
      label: Catarrhini
    notes: 'Matches membrane-associated phosphatidylinositol transfer proteins. UniProtKB 2026_04 query
      ("3.30.530.20:FF:000001") AND ("3.40.50.1000:FF:000173") AND (taxonomy_id:9526): 64 entries, 2 reviewed.
      Of the reviewed entries, 2 carry GO:0006661 on evidence other than ARBA: O00562 (PITM1) GO:0006661
      TAS Reactome:R-HSA-1483226; Q9BZ72 (PITM2) GO:0006661 TAS Reactome:R-HSA-1483226.'
  - number: 7
    conditions:
    - condition_type: FUNFAM
      value: 1.10.1070.11:FF:000019
      label: Phosphatidylinositol 4-kinase beta 1
    - condition_type: TAXON
      value: Eukaryota
      curie: NCBITaxon:2759
      label: Eukaryota
    notes: 'Matches phosphatidylinositol 4-kinases across Eukaryota; its only reviewed members are the
      two Arabidopsis PI 4-kinases beta. UniProtKB 2026_04 query ("1.10.1070.11:FF:000019") AND (taxonomy_id:2759):
      482 entries, 2 reviewed. Of the reviewed entries, 2 carry GO:0006661 on evidence other than ARBA:
      Q0WPX9 (P4KB2) GO:0006661 TAS PMID:10026194; Q9FMJ0 (P4KB1) GO:0006661 TAS PMID:10026194.'
  - number: 8
    conditions:
    - condition_type: FUNFAM
      value: 1.20.120.1760:FF:000003
      label: CDP-diacylglycerol--inositol 3-phosphatidyltransferase
    - condition_type: TAXON
      value: Chordata
      curie: NCBITaxon:7711
      label: Chordata
    notes: 'Matches CDP-diacylglycerol--inositol 3-phosphatidyltransferase (PI synthase). UniProtKB 2026_04
      query ("1.20.120.1760:FF:000003") AND (taxonomy_id:7711): 527 entries, 3 reviewed. Of the reviewed
      entries, 3 carry GO:0006661 on evidence other than ARBA: O14735 (CDIPT) GO:0006661 IBA GO_REF:0000033;
      P70500 (CDIPT) GO:0006661 IBA GO_REF:0000033; Q8VDP6 (CDIPT) GO:0006661 ISS GO_REF:0000024.'
  - number: 9
    conditions:
    - condition_type: FUNFAM
      value: 1.20.120.1760:FF:000021
      label: CDP-diacylglycerol--inositol 3-phosphatidyltransferase
    - condition_type: TAXON
      value: Fungi
      curie: NCBITaxon:4751
      label: Fungi
    notes: 'Matches fungal PI synthase. UniProtKB 2026_04 query ("1.20.120.1760:FF:000021") AND (taxonomy_id:4751):
      122 entries, 2 reviewed. Of the reviewed entries, 2 carry GO:0006661 on evidence other than ARBA:
      P06197 (PIS) GO:0006661 IBA GO_REF:0000033; Q59RA2 (PIS) GO:0006661 IBA GO_REF:0000033.'
  - number: 10
    conditions:
    - condition_type: FUNFAM
      value: 2.30.29.30:FF:000085
      label: Pleckstrin homology domain-containing family A member 8
    - condition_type: TAXON
      value: Hominidae
      curie: NCBITaxon:9604
      label: Hominidae
    notes: 'Matches PLEKHA3 and PLEKHA8. UniProtKB 2026_04 query ("2.30.29.30:FF:000085") AND (taxonomy_id:9604):
      40 entries, 2 reviewed. Of the reviewed entries, 2 carry GO:0006661 on evidence other than ARBA:
      Q96JA3 (PKHA8) GO:0006661 TAS Reactome:R-HSA-1660499; Q9HB20 (PKHA3) GO:0006661 TAS Reactome:R-HSA-1660499.'
  - number: 11
    conditions:
    - condition_type: FUNFAM
      value: 3.30.40.10:FF:000073
      label: myotubularin-related protein 4 isoform X2
    - condition_type: TAXON
      value: Metazoa
      curie: NCBITaxon:33208
      label: Metazoa
    notes: 'Matches FYVE-domain proteins: MTMR3, MTMR4 and Lst2 homologs. UniProtKB 2026_04 query ("3.30.40.10:FF:000073")
      AND (taxonomy_id:33208): 3192 entries, 19 reviewed. Of the reviewed entries, 2 carry GO:0006661
      on evidence other than ARBA: Q13615 (MTMR3) GO:0006661 TAS Reactome:R-HSA-1660499; Q9NYA4 (MTMR4)
      GO:0006661 TAS Reactome:R-HSA-1660516. 17 carry it only as IEA GO_REF:0000117 (this rule''s own
      output): four MTMR3/MTMR4 orthologs and 13 Lst2 homologs (for example Q9VB70, B4G2G5, Q7QAJ2). Lst2
      proteins have the FYVE zinc finger but no myotubularin phosphatase domain: 126 of the 3,192 matches
      lack IPR010569 (Myotubularin-like, phosphatase domain).'
  go_annotations:
  - go_id: GO:0006661
    go_label: phosphatidylinositol biosynthetic process
    aspect: P
  entries: []
  created_date: '2021-10-20'
  modified_date: '2026-07-18'
  retrieved_date: '2026-11-10'
  source_condition_set_count: 11
review_summary: 'All eleven condition sets of the rule as served on 2026-11-10 were queried in UniProtKB,
  and the reviewed matches of each were looked up in QuickGO. Sets 8 and 9 select PI synthase, the enzyme
  that forms phosphatidylinositol. Sets 1 to 7 and 10 select phosphoinositide kinases, phosphatases and
  transfer proteins. In every one of those sets the reviewed human, mouse or Arabidopsis members carry
  GO:0006661 itself on curated evidence: Reactome TAS from the pathways R-HSA-1660499, R-HSA-1660516,
  R-HSA-1483248 and R-HSA-1483226, MGI IDA and IGI for the mouse PIP5K1 kinases (PMID:20622009), and TIGR
  TAS for the plant PI 4-kinases. The rule therefore reproduces what curators annotated, and transfers
  it to orthologs. Set 11 is the exception: its FunFam is the FYVE zinc finger, and besides MTMR3 and
  MTMR4 it matches Lst2 homologs, which have no phosphatase domain and carry the term only from this rule.'
action: MODIFY
action_rationale: The one defect shown with named proteins is set 11, which puts the term on FYVE proteins
  that are not phosphoinositide enzymes. For the other sets the question is not whether the rule misfires
  but whether GO:0006661 is the right term for enzymes that interconvert phosphoinositides, and that is
  a question about the curated annotations the rule copies, not about the rule. GO keeps phosphatidylinositol
  phosphate biosynthesis (GO:0046854) outside GO:0006661, so the curated annotations may themselves be
  imprecise, but changing them is for Reactome, MGI and GO to decide.
suggested_modifications:
- 'Set 11: add IPR010569 (Myotubularin-like, phosphatase domain) as a required condition, so that Lst2
  homologs (Q9VB70 and 12 other reviewed entries; 126 UniProtKB matches without the domain) are no longer
  annotated.'
- Raise with Reactome and GO whether the "Synthesis of PIPs" pathways (R-HSA-1660499, R-HSA-1660516, R-HSA-1483248)
  should map to GO:0046854 phosphatidylinositol phosphate biosynthetic process and not GO:0006661. If
  the curated annotations change, the consequent of sets 1 to 7 and 10 should follow them.
go_specificity:
  assessment: APPROPRIATE
  notes: 'APPROPRIATE here means only that the rule uses the term its sources use: for sets 8 and 9 the
    term names what PI synthase does, and for the other sets it is the term curators put on the matched
    proteins. It is not a judgement that GO:0006661 is the right term for phosphoinositide kinases and
    phosphatases. QuickGO, 2026-11-09: GO:0006661 has only regulation terms as children, and GO:0046854,
    GO:0006506, GO:0046856, GO:0180047 and GO:0036092 do not have it as an ancestor; so if the curated
    annotations were moved to those terms, this rule would have no more specific child to move to and
    would need separate rules.'
taxonomic_scope:
  assessment: APPROPRIATE
  notes: 'Read from the eleven recorded sets. The narrow restrictions follow the species of the curated
    annotations each set copies: Primates, Haplorrhini, Catarrhini and Hominidae where the support is
    human Reactome TAS (sets 1, 2, 3, 5, 6, 10), and Mus where it is MGI IDA and IGI on the mouse PIP5K1
    kinases (set 4). These are pan-eukaryotic enzyme families, so the rule leaves most orthologs unannotated,
    but that is low coverage, not wrong annotation, and widening a set would carry a term whose fit is
    in question (see go_specificity) to more proteins. The PI synthase sets are scoped to Chordata (set
    8) and Fungi (set 9). Two sets are wider than their evidence: set 7 is Eukaryota (482 matches) on
    the strength of two Arabidopsis entries with TAS annotations, and set 11 is Metazoa and is the one
    that reaches the Lst2 proteins.'
annotation_assessments:
- annotation_kind: GO_TERM
  value: GO:0006661
  label: phosphatidylinositol biosynthetic process
  assessment: PARTIALLY_CORRECT
  matched_protein_count: 5696
  incorrect_protein_count: 126
  correct_examples:
  - O14735
  - P06197
  - O70161
  - Q13496
  - Q9NTJ5
  incorrect_examples:
  - Q9VB70
  notes: 'matched_protein_count is the sum of the eleven set counts and may count an entry more than once.
    incorrect_protein_count is the set 11 matches without IPR010569. Q9VB70 (Drosophila Lst2, reviewed)
    carries GO:0006661 IEA GO_REF:0000117 with ARBA:ARBA00028655 in QuickGO and has no other annotation
    to the term. Correct examples: O14735 CDIPT (IBA), P06197 yeast PIS1 (IBA), O70161 mouse PIP5K1C (IDA
    PMID:20622009), Q13496 MTM1 (TAS Reactome:R-HSA-1660499), Q9NTJ5 SAC1 (TAS Reactome:R-HSA-1483248).'
confidence: 0.7
references:
- id: PMID:30617162
  title: 'Understanding phosphoinositides: rare, dynamic, and essential membrane phospholipids.'
  findings:
  - statement: Phosphoinositides are reversibly phosphorylated derivatives of PI; kinases add and phosphatases
      remove headgroup phosphates, a process chemically distinct from assembling PI from CDP-DAG and myo-inositol.
- id: PMID:32117988
  title: 'CDP-Diacylglycerol Synthases (CDS): Gateway to Phosphatidylinositol and Cardiolipin Synthesis.'
  findings:
  - statement: De novo PI synthesis proceeds via CDS1/CDS2 (phosphatidic acid + CTP -> CDP-diacylglycerol)
      followed by PI synthase; CDP-DAG also feeds phosphatidylglycerol and cardiolipin synthesis.
- id: PMID:18524850
  title: Sequential actions of myotubularin lipid phosphatases regulate endosomal PI(3)P and growth factor
    receptor trafficking.
  findings:
  - statement: Myotubularins act as endosomal phosphoinositide 3-phosphatases that regulate PI3P levels.
      Relevant to condition sets 1, 3 and 11, which select myotubularins.
corrections:
- date: '2026-11-10'
  withdrawn_claim: 'SPLIT at confidence 0.95: 23 of 25 condition sets (PI kinases, phosphoinositide phosphatases,
    GPI-anchor enzymes and others) annotate a chemically different process and are outright incorrect;
    only the two PI synthase sets are right.'
  correction: The live rule has 11 sets, with no GPI-anchor, DPM1, UVRAG or PIK3R1 set. In the kinase,
    phosphatase and transfer-protein sets that remain, the reviewed members carry GO:0006661 itself on
    curated evidence, including experimental evidence for the mouse PIP5K1 kinases. The rule copies those
    annotations; it does not invent them. The earlier review did not look up the matched proteins.
  error_type: REFUTED_BY_CURATED_ANNOTATION
  evidence:
  - O70161 GO:0006661 IDA PMID:20622009 (MGI); P70182 and P70181 GO:0006661 IGI PMID:20622009 (MGI)
  - Q13496, Q13613, Q13614 GO:0006661 TAS Reactome:R-HSA-1660499 / R-HSA-1660516
  - Q9NTJ5 GO:0006661 TAS Reactome:R-HSA-1483248; O43426 GO:0006661 TAS Reactome:R-HSA-1660499
  - Q0WPX9, Q9FMJ0 GO:0006661 TAS PMID:10026194 (TIGR)
- date: '2026-11-10'
  withdrawn_claim: The review describes the rule as it stands, with 25 condition sets.
  correction: The 25 sets were the version modified 2025-12-15, read from a cached copy. UniProt served
    11 sets on 2026-11-10 (modified 2026-07-18). The review is redone against those 11.
  error_type: STALE_RULE_VERSION
  evidence:
  - 'https://rest.uniprot.org/arba/ARBA00028655 on 2026-11-10: 11 condition sets, modifiedDate 2026-07-18'
- date: '2026-11-10'
  withdrawn_claim: literature_support CONTRADICTED, and go_specificity and taxonomic_scope supported by
    quotations from an AI deep-research report and an analysis file in this folder.
  correction: An AI research report is not literature, and those citations are removed. The GO hierarchy
    facts they were cited for were checked directly in QuickGO and are recorded under go_specificity.
  error_type: UNSUPPORTED_SOURCE
  evidence:
  - GO:0006661 has only regulation terms as children (QuickGO, 2026-11-09)
  - GO:0046854, GO:0006506, GO:0046856, GO:0180047 and GO:0036092 do not have GO:0006661 as an ancestor
    (QuickGO, 2026-11-09)
- date: '2026-11-10'
  withdrawn_claim: References on PI3K p85 regulatory subunits (PMID:32677674), GPI-anchor biosynthesis
    (PMID:32156170) and DPM1 (PMID:10642602), each tied to a numbered condition set (15; 12, 22, 23 and
    24; 25), and a myotubularin reference tied to sets 1, 8 and 21.
  correction: Those set numbers belong to the 25-set version. The live rule has no p85, GPI-anchor or
    DPM1 set, so the three references are removed; the myotubularin reference applies to live sets 1,
    3 and 11 (set 8 is PI synthase).
  error_type: STALE_RULE_VERSION
  evidence:
  - 'https://rest.uniprot.org/arba/ARBA00028655 on 2026-11-10: 11 condition sets; none matches PIK3R1,
    PIGL, PIGN, PIGO, MPPE1 or DPM1 families'