id: ARBA00089391
description: 'ARBA00089391 predicts spermidine transmembrane transport (GO:1903711)
  for fungal proteins containing either MFS multidrug transporter domains (in Taphrinomycotina)
  or urea active transporter domains (in all Fungi). The rule combines taxonomic
  restrictions with functionally distinct transporter families.'
status: COMPLETE
rule_type: ARBA
rule:
  rule_id: ARBA00089391
  condition_sets:
  - number: 1
    conditions:
    - condition_type: FUNFAM
      value: 1.20.1250.20:FF:000011
      curie: CATH.FunFam:1.20.1250.20:FF:000011
      label: MFS multidrug transporter, putative
      negated: false
    - condition_type: TAXON
      value: Taphrinomycotina
      curie: NCBITaxon:451866
      label: Taphrinomycotina
      negated: false
    notes: ''
  - number: 2
    conditions:
    - condition_type: FUNFAM
      value: 1.20.1730.10:FF:000006
      curie: CATH.FunFam:1.20.1730.10:FF:000006
      label: Urea active transporter
      negated: false
    - condition_type: TAXON
      value: Fungi
      curie: NCBITaxon:4751
      label: Fungi
      negated: false
    notes: ''
  go_annotations:
  - go_id: GO:1903711
    go_label: spermidine transmembrane transport
    aspect: BP
  reviewed_protein_count: 0
  unreviewed_protein_count: 0
  created_date: ''
  modified_date: ''
  entries:
  - id: 1.20.1250.20:FF:000011
    type: FUNFAM
    label: MFS multidrug transporter, putative
    appears_in_condition_sets:
    - 1
    protein_count: 55
    related_entries:
    - relationship: EQUIV
      target_id: 1.20.1730.10:FF:000006
      containment: 0.0
      jaccard_similarity: 0.0
      intersection_count: 0
      exclusive_count: 55
    - relationship: PREDICTS
      target_id: GO:1903711
      containment: 0.218
      jaccard_similarity: 0.058
      intersection_count: 12
      exclusive_count: 43
  - id: 1.20.1730.10:FF:000006
    type: FUNFAM
    label: Urea active transporter
    appears_in_condition_sets:
    - 2
    protein_count: 5
    related_entries:
    - relationship: EQUIV
      target_id: 1.20.1250.20:FF:000011
      containment: 0.0
      jaccard_similarity: 0.0
      intersection_count: 0
      exclusive_count: 5
    - relationship: PREDICTS
      target_id: GO:1903711
      containment: 0.6
      jaccard_similarity: 0.018
      intersection_count: 3
      exclusive_count: 2
review_summary: 'This rule should be deprecated because the specific FunFam domains
  used are too broad and non-specific to reliably predict spermidine transport. While
  some MFS transporters (notably the DHA1-family Tpo1-5 in S. cerevisiae) are bona
  fide polyamine transporters, the FunFam 1.20.1250.20:FF:000011 is labeled as a
  generic "MFS multidrug transporter, putative" and captures a heterogeneous group
  of MFS proteins, most of which are not polyamine transporters. Only 21.8% of
  proteins matching this FunFam have existing GO:1903711 annotations. The urea
  active transporter domain (1.20.1730.10:FF:000006) belongs to a functionally
  distinct family with no established connection to polyamine transport. The two
  condition sets are completely disjoint (Jaccard = 0.0), indicating this rule
  conflates unrelated protein families. As noted in geneontology/go-annotation#5896,
  this rule results in biologically implausible predictions such as S. pombe having
  10-11 spermidine transporters, exceeding even its hexose transporter count.'
action: DEPRECATE
action_rationale: 'The rule should be deprecated because the FunFam domains used
  are insufficiently specific to predict spermidine transport function. Known fungal
  spermidine transporters (e.g. Tpo1-5 in S. cerevisiae) belong to the DHA1 subfamily
  of MFS transporters, but the FunFam 1.20.1250.20:FF:000011 captures a broader,
  heterogeneous set of MFS multidrug transporters. The low coverage (21.8%) for
  condition set 1 confirms poor specificity. Condition set 2 uses a urea active
  transporter domain with no established polyamine transport function. The rule
  generates biologically implausible annotations, as documented in
  geneontology/go-annotation#5896 where PomBase curators noted that S. pombe
  cannot plausibly have 10-11 spermidine transporters.'
suggested_modifications:
- 'N/A - recommend deprecation rather than modification. A replacement rule would
  need to use domains specific to characterized polyamine transporters (e.g. DHA1
  family signatures matching Tpo1-5 orthologs) rather than generic MFS multidrug
  transporter FunFams.'
parsimony:
  assessment: OVERLY_COMPLEX
  notes: 'The rule combines two functionally unrelated transporter families (MFS
    multidrug and urea transporters) under different taxonomic constraints. While
    MFS transporters as a superfamily include some polyamine transporters, the
    specific FunFam used here is too broad to be diagnostic. The urea transporter
    condition set has no biological justification for predicting spermidine transport.'
literature_support:
  assessment: WEAK
  notes: 'While MFS transporters can transport spermidine -- the S. cerevisiae Tpo1-5
    (DHA1 family) are well-characterized polyamine exporters, and B. subtilis Blt
    is an MFS transporter whose natural function is spermidine efflux -- these
    characterized transporters belong to specific MFS subfamilies, not the generic
    "MFS multidrug transporter, putative" FunFam used in this rule. No literature
    supports the urea active transporter family having polyamine transport activity.
    The rule lacks the specificity needed to distinguish genuine polyamine
    transporters from the broader MFS superfamily.'
  supported_by:
  - reference_id: PMID:9083003
    supporting_text: 'the natural function of the Blt transporter is the efflux of
      spermidine, whereas multiple drugs may be recognized by Blt merely
      opportunistically'
  - reference_id: PMID:15637075
    supporting_text: 'Uptake of spermidine and spermine occurred at alkaline pH
      (pH 8.0), whereas inhibition of spermidine uptake, but not spermine uptake,
      was observed at acidic pH (pH 5.0)'
  - reference_id: PMID:24136413
    supporting_text: 'the polyamine transporter Tpo1 controls spermidine and spermine
      concentrations and mediates induction of antioxidant proteins'
  - reference_id: PMID:11470516
    supporting_text: 'TPO1, a gene previously found to be involved in spermidine
      resistance and vacuolar polyamine transport, is a determinant of multidrug
      transporter since it also mediates growth resistance to cycloheximide and
      quinidine'
  - reference_id: PMID:20159658
    supporting_text: 'There are also five kinds of polyamine excretion proteins
      (TPO1-5), consisting of 12 transmembrane segments'
  - reference_id: github:geneontology/go-annotation#5896
    supporting_text: 'highly unlikely that fission yeast has 10/11 spermidine
      transporters (it does not even have this many hexose transporters). Inferring
      transporter substrates across paralogous families is dangerous practice'
condition_overlap:
  assessment: NONE
  notes: 'The two domain conditions show complete disjointness (Jaccard similarity
    = 0.0), indicating they identify completely different protein sets. This supports
    the assessment that these are functionally distinct families that should not be
    grouped under a single annotation rule predicting spermidine transport.'
go_specificity:
  assessment: MISMATCHED
  notes: 'GO:1903711 (spermidine transmembrane transport) is a specific and appropriate
    GO term in general, but it mismatches the specificity of the condition domains.
    The FunFam 1.20.1250.20:FF:000011 is too broad to reliably predict this specific
    transport function. While some MFS transporters do transport spermidine (Tpo1-5),
    the FunFam captures many MFS proteins that are multidrug efflux pumps with
    no polyamine specificity. The urea active transporter FunFam has no known
    connection to spermidine transport.'
  supported_by:
  - reference_id: github:geneontology/go-annotation#5896
    supporting_text: 'highly unlikely that fission yeast has 10/11 spermidine
      transporters (it does not even have this many hexose transporters)'
  - reference_id: PMID:9083003
    supporting_text: 'the natural function of the Blt transporter is the efflux
      of spermidine, whereas multiple drugs may be recognized by Blt merely
      opportunistically'
taxonomic_scope:
  assessment: UNNECESSARY
  notes: 'The taxonomic restrictions (Taphrinomycotina for MFS multidrug, all Fungi
    for urea transporters) appear arbitrary. If these FunFams truly predicted
    spermidine transport, the function would be expected across broader taxonomic
    groups. The differential taxonomic restrictions for the two condition sets
    suggest ad hoc rule construction rather than biologically grounded predictions.'
confidence: 0.15
references:
- id: PMID:9083003
  title: 'Efflux of the natural polyamine spermidine facilitated by the Bacillus
    subtilis multidrug transporter Blt'
  findings:
  - statement: 'Blt is an MFS multidrug transporter whose natural physiological
      function is spermidine efflux. It forms an operon with bltD (spermine/spermidine
      acetyltransferase). Multiple drugs are recognized merely opportunistically.'
- id: PMID:15637075
  title: 'Characteristics of the polyamine transporter TPO1 and regulation of its
    activity and cellular localization by phosphorylation'
  findings:
  - statement: 'S. cerevisiae TPO1 is an MFS transporter located on the plasma
      membrane that mediates spermidine and spermine transport in a pH-dependent
      manner.'
- id: PMID:24136413
  title: 'Tpo1-mediated spermine and spermidine export controls cell cycle delay
    and times antioxidant protein expression during the oxidative stress response'
  findings:
  - statement: 'Tpo1 controls spermidine and spermine concentrations during oxidative
      stress and mediates induction of antioxidant proteins in S. cerevisiae.'
- id: PMID:11470516
  title: 'Novel target genes of the yeast regulator Pdr1p: a contribution of the
    TPO1 gene in resistance to quinidine and other drugs'
  findings:
  - statement: 'TPO1 is a DHA1 subfamily MFS transporter involved in both vacuolar
      polyamine transport and multidrug resistance in S. cerevisiae.'
- id: PMID:20159658
  title: 'Characteristics of cellular polyamine transport in prokaryotes and
    eukaryotes'
  findings:
  - statement: 'Comprehensive review showing S. cerevisiae has five polyamine
      excretion proteins (TPO1-5), all MFS transporters with 12 transmembrane
      segments belonging to the DHA1 family.'
- id: PMID:25135753
  title: 'Purifying selection against gene conversions between the polyamine
    transport (TPO) genes of Saccharomyces species'
  findings:
  - statement: 'Saccharomyces species have five TPO genes (TPO1-5) coding for
      polyamine transport proteins. Gene conversions occur only between TPO2 and
      TPO3, which are closely related paralogs.'
- id: github:geneontology/go-annotation#5896
  title: 'ARBA00089391/ARBA00089395 likely not all spermine/spermidine transporters'
  findings:
  - statement: 'PomBase curators noted that S. pombe cannot plausibly have 10-11
      spermidine transporters (more than hexose transporters), indicating the rule
      generates false positive annotations.'
  - statement: 'Inferring transporter substrates across paralogous families is
      described as dangerous practice.'
supported_by:
- reference_id: PMID:20159658
  supporting_text: 'There are also five kinds of polyamine excretion proteins
    (TPO1-5), consisting of 12 transmembrane segments'
- reference_id: github:geneontology/go-annotation#5896
  supporting_text: 'Rule generates biologically implausible annotation counts for
    S. pombe spermidine transporters'