ARBA00026249 thioredoxin-disulfide reductase (NADPH) activity (GO:0004791)

View original ARBA rule on UniProt

Type: ARBA
Status: COMPLETE
Action: ACCEPT
Confidence: 0.75

Description

ARBA rule assigning GO:0004791 thioredoxin-disulfide reductase (NADPH) activity through three condition sets: three thioredoxin reductase InterPro signatures together, a thioredoxin reductase FunFam in Eukaryota, and a second thioredoxin reductase FunFam in Glires.

Analysis Summary

Condition-set counts describe the sets recorded in this review, which may omit the full rule.

3
Domain Pairs Analyzed
3
Recorded condition sets
3
Subset Relationships
0
Redundant Annotations

No domain overlap table is shown: the cached overlap analysis for this version of the review is not available. Run just analyze-rule ARBA00026249 and re-render to add it.

Review Summary

All three live condition sets were examined. Set 1 rests on IPR005982 (Thioredoxin reductase), which InterPro2GO already maps to GO:0004791. The FunFams of sets 2 and 3 each hold 18 Swiss-Prot proteins, all annotated to GO:0004791. The annotation is correct for what the rule matches. Most of the rule duplicates InterPro2GO: sets 1 and 3 add nothing to the IPR005982 and IPR006338 mappings, and set 2 adds 136 UniProtKB proteins that carry neither signature.

Action Rationale

Every condition set is supported: by a curated InterPro2GO mapping for set 1, and by complete agreement with Swiss-Prot annotation for the FunFams of sets 2 and 3. Overlap with InterPro2GO makes the rule largely redundant, which is not a fault in its annotations.

GO Annotations

GO:0004791 - thioredoxin-disulfide reductase (NADPH) activity
Aspect: MF

Annotation Assessments

CORRECT GO_TERM GO:0004791 - thioredoxin-disulfide reductase (NADPH) activity
Matched proteins: ; incorrect:

rules/arba/_interpro2go.txt: IPR005982 Thioredoxin reductase > GO:0004791; IPR006338 Thioredoxin/glutathione reductase selenoprotein > GO:0004791. Recorded Swiss-Prot counts: FunFam 3.50.50.60:FF:000064, 18 proteins, 18 with GO:0004791; FunFam 3.50.50.60:FF:000190, 18 proteins, 18 with GO:0004791. UniProtKB counts (2026-11-09): set 2 conjunction 2641, of which 136 lack both IPR005982 and IPR006338.

Rule Definition

Condition Sets

Condition Set 1

3 condition(s)
Notes:

IPR005982 maps to GO:0004791 in InterPro2GO, so every protein this set matches already receives the term from that mapping. In Swiss-Prot all 65 proteins with IPR005982 also have the other two signatures.

Pairwise Overlap Analysis

Condition A Condition B Count A Count B Intersection Jaccard A in B B in A Interpretation
IPR005982 IPR008255 65 84 65 0.774 1.000 0.774 SUBSET
IPR005982 IPR023753 65 869 65 0.075 1.000 0.075 SUBSET
IPR008255 IPR023753 84 869 84 0.097 1.000 0.097 SUBSET

Condition Set 2

2 condition(s)
Notes:

In Swiss-Prot the FunFam holds 18 proteins, all with IPR005982 and all annotated to GO:0004791. In all of UniProtKB the set matches 2641 proteins, of which 136 have neither IPR005982 nor IPR006338.

Condition Set 3

2 condition(s)
Notes:

In Swiss-Prot the FunFam holds 18 proteins, all with IPR006338 (which maps to GO:0004791 in InterPro2GO) and all annotated to GO:0004791. No Glires protein with this FunFam lacks both IPR005982 and IPR006338.

Assessments

STRONG

Thioredoxin reductase is a structurally and mechanistically characterised enzyme family.

Supporting Evidence:

  • PMID:11481439: electron transfer from NADPH to the disulfide of the substrate is possible without large conformational changes
MINOR

In Swiss-Prot the FunFams of sets 2 and 3 share no protein with each other; all 18 proteins of the set 2 FunFam also carry IPR005982, the signature of set 1, and none of the set 3 FunFam does.

APPROPRIATE

GO:0004791 names the reaction itself and is the term InterPro2GO assigns to the same families.

References (2)

Raw YAML

View Source YAML 
id: ARBA00026249
description: >-
  ARBA rule assigning GO:0004791 thioredoxin-disulfide reductase (NADPH) activity through three condition
  sets: three thioredoxin reductase InterPro signatures together, a thioredoxin reductase FunFam in
  Eukaryota, and a second thioredoxin reductase FunFam in Glires.
status: COMPLETE
rule_type: ARBA
rule:
  rule_id: ARBA00026249
  condition_sets:
  - number: 1
    conditions:
    - condition_type: INTERPRO
      value: IPR005982
      curie: InterPro:IPR005982
      label: Thioredoxin reductase
      negated: false
    - condition_type: INTERPRO
      value: IPR008255
      curie: InterPro:IPR008255
      label: Pyridine nucleotide-disulphide oxidoreductase, class-II, active site
      negated: false
    - condition_type: INTERPRO
      value: IPR023753
      curie: InterPro:IPR023753
      label: FAD/NAD(P)-binding domain
      negated: false
    notes: >-
      IPR005982 maps to GO:0004791 in InterPro2GO, so every protein this set matches already receives
      the term from that mapping. In Swiss-Prot all 65 proteins with IPR005982 also have the other
      two signatures.
    pairwise_overlap:
    - condition_a: IPR005982
      condition_b: IPR008255
      protein_database: SWISSPROT
      count_a: 65
      count_b: 84
      intersection_count: 65
      a_minus_b_count: 0
      b_minus_a_count: 19
      jaccard_similarity: 0.7738095238095238
      containment_a_in_b: 1.0
      containment_b_in_a: 0.7738095238095238
      interpretation: SUBSET
    - condition_a: IPR005982
      condition_b: IPR023753
      protein_database: SWISSPROT
      count_a: 65
      count_b: 869
      intersection_count: 65
      a_minus_b_count: 0
      b_minus_a_count: 804
      jaccard_similarity: 0.07479861910241657
      containment_a_in_b: 1.0
      containment_b_in_a: 0.07479861910241657
      interpretation: SUBSET
    - condition_a: IPR008255
      condition_b: IPR023753
      protein_database: SWISSPROT
      count_a: 84
      count_b: 869
      intersection_count: 84
      a_minus_b_count: 0
      b_minus_a_count: 785
      jaccard_similarity: 0.09666283084004602
      containment_a_in_b: 1.0
      containment_b_in_a: 0.09666283084004602
      interpretation: SUBSET
  - number: 2
    conditions:
    - condition_type: FUNFAM
      value: 3.50.50.60:FF:000064
      curie: CATH.FunFam:3.50.50.60:FF:000064
      label: Thioredoxin reductase
      negated: false
    - condition_type: TAXON
      value: Eukaryota
      label: Eukaryota
      negated: false
    notes: >-
      In Swiss-Prot the FunFam holds 18 proteins, all with IPR005982 and all annotated to GO:0004791.
      In all of UniProtKB the set matches 2641 proteins, of which 136 have neither IPR005982 nor IPR006338.
  - number: 3
    conditions:
    - condition_type: FUNFAM
      value: 3.50.50.60:FF:000190
      curie: CATH.FunFam:3.50.50.60:FF:000190
      label: Thioredoxin reductase
      negated: false
    - condition_type: TAXON
      value: Glires
      label: Glires
      negated: false
    notes: >-
      In Swiss-Prot the FunFam holds 18 proteins, all with IPR006338 (which maps to GO:0004791 in
      InterPro2GO) and all annotated to GO:0004791. No Glires protein with this FunFam lacks both
      IPR005982 and IPR006338.
  go_annotations:
  - go_id: GO:0004791
    go_label: thioredoxin-disulfide reductase (NADPH) activity
    aspect: MF
  entries:
  - id: 3.50.50.60:FF:000064
    type: FUNFAM
    label: Thioredoxin reductase
    appears_in_condition_sets:
    - 2
    protein_count: 18
    related_entries:
    - relationship: PREDICTS
      target_id: IPR005982
      containment: 0.277
      jaccard_similarity: 0.277
      intersection_count: 18
      exclusive_count: 47
    - relationship: PREDICTS
      target_id: IPR008255
      containment: 0.214
      jaccard_similarity: 0.214
      intersection_count: 18
      exclusive_count: 66
    - relationship: PREDICTS
      target_id: IPR023753
      containment: 0.021
      jaccard_similarity: 0.021
      intersection_count: 18
      exclusive_count: 851
    - relationship: EQUIV
      target_id: 3.30.390.30:FF:000004
      containment: 0.0
      jaccard_similarity: 0.0
      intersection_count: 0
      exclusive_count: 18
    - relationship: EQUIV
      target_id: 3.50.50.60:FF:000190
      containment: 0.0
      jaccard_similarity: 0.0
      intersection_count: 0
      exclusive_count: 18
    - relationship: EQUIV
      target_id: IPR006338
      containment: 0.0
      jaccard_similarity: 0.0
      intersection_count: 0
      exclusive_count: 18
    - relationship: EQUIV
      target_id: IPR045870
      containment: 0.0
      jaccard_similarity: 0.0
      intersection_count: 0
      exclusive_count: 18
    - relationship: PREDICTS
      target_id: GO:0004791
      containment: 1.0
      jaccard_similarity: 0.13
      intersection_count: 18
      exclusive_count: 0
  - id: 3.50.50.60:FF:000190
    type: FUNFAM
    label: Thioredoxin reductase
    appears_in_condition_sets:
    - 3
    protein_count: 18
    related_entries:
    - relationship: EQUIV
      target_id: IPR005982
      containment: 0.0
      jaccard_similarity: 0.0
      intersection_count: 0
      exclusive_count: 18
    - relationship: EQUIV
      target_id: IPR008255
      containment: 0.0
      jaccard_similarity: 0.0
      intersection_count: 0
      exclusive_count: 18
    - relationship: PREDICTS
      target_id: IPR023753
      containment: 0.021
      jaccard_similarity: 0.021
      intersection_count: 18
      exclusive_count: 851
    - relationship: EQUIV
      target_id: 3.50.50.60:FF:000064
      containment: 0.0
      jaccard_similarity: 0.0
      intersection_count: 0
      exclusive_count: 18
    - relationship: PREDICTED_BY
      target_id: 3.30.390.30:FF:000004
      containment: 0.889
      jaccard_similarity: 0.842
      intersection_count: 16
      exclusive_count: 2
    - relationship: PREDICTS
      target_id: IPR006338
      containment: 1.0
      jaccard_similarity: 0.947
      intersection_count: 18
      exclusive_count: 0
    - relationship: EQUIV
      target_id: IPR045870
      containment: 0.0
      jaccard_similarity: 0.0
      intersection_count: 0
      exclusive_count: 18
    - relationship: PREDICTS
      target_id: GO:0004791
      containment: 1.0
      jaccard_similarity: 0.13
      intersection_count: 18
      exclusive_count: 0
  - id: IPR005982
    type: INTERPRO
    label: Thioredoxin reductase
    appears_in_condition_sets:
    - 1
    protein_count: 65
    related_entries:
    - relationship: PREDICTS
      target_id: IPR008255
      containment: 1.0
      jaccard_similarity: 0.774
      intersection_count: 65
      exclusive_count: 0
    - relationship: PREDICTS
      target_id: IPR023753
      containment: 1.0
      jaccard_similarity: 0.075
      intersection_count: 65
      exclusive_count: 0
    - relationship: PREDICTED_BY
      target_id: 3.50.50.60:FF:000064
      containment: 1.0
      jaccard_similarity: 0.277
      intersection_count: 18
      exclusive_count: 0
    - relationship: EQUIV
      target_id: 3.30.390.30:FF:000004
      containment: 0.0
      jaccard_similarity: 0.0
      intersection_count: 0
      exclusive_count: 65
    - relationship: EQUIV
      target_id: 3.50.50.60:FF:000190
      containment: 0.0
      jaccard_similarity: 0.0
      intersection_count: 0
      exclusive_count: 65
    - relationship: EQUIV
      target_id: IPR006338
      containment: 0.0
      jaccard_similarity: 0.0
      intersection_count: 0
      exclusive_count: 65
    - relationship: EQUIV
      target_id: IPR045870
      containment: 0.0
      jaccard_similarity: 0.0
      intersection_count: 0
      exclusive_count: 65
    - relationship: PREDICTS
      target_id: GO:0004791
      containment: 1.0
      jaccard_similarity: 0.471
      intersection_count: 65
      exclusive_count: 0
  - id: IPR006338
    type: INTERPRO
    source: ipr2go
    protein_count: 19
    asserted_predicted_go_terms:
    - GO:0004791
    related_entries:
    - relationship: EQUIV
      target_id: IPR005982
      containment: 0.0
      jaccard_similarity: 0.0
      intersection_count: 0
      exclusive_count: 19
    - relationship: EQUIV
      target_id: IPR008255
      containment: 0.0
      jaccard_similarity: 0.0
      intersection_count: 0
      exclusive_count: 19
    - relationship: PREDICTS
      target_id: IPR023753
      containment: 0.022
      jaccard_similarity: 0.022
      intersection_count: 19
      exclusive_count: 850
    - relationship: EQUIV
      target_id: 3.50.50.60:FF:000064
      containment: 0.0
      jaccard_similarity: 0.0
      intersection_count: 0
      exclusive_count: 19
    - relationship: PREDICTED_BY
      target_id: 3.30.390.30:FF:000004
      containment: 0.895
      jaccard_similarity: 0.895
      intersection_count: 17
      exclusive_count: 2
    - relationship: PREDICTED_BY
      target_id: 3.50.50.60:FF:000190
      containment: 0.947
      jaccard_similarity: 0.947
      intersection_count: 18
      exclusive_count: 1
    - relationship: EQUIV
      target_id: IPR045870
      containment: 0.0
      jaccard_similarity: 0.0
      intersection_count: 0
      exclusive_count: 19
    - relationship: PREDICTS
      target_id: GO:0004791
      containment: 1.0
      jaccard_similarity: 0.138
      intersection_count: 19
      exclusive_count: 0
  - id: IPR008255
    type: INTERPRO
    label: Pyridine nucleotide-disulphide oxidoreductase, class-II, active site
    appears_in_condition_sets:
    - 1
    protein_count: 84
    related_entries:
    - relationship: PREDICTED_BY
      target_id: IPR005982
      containment: 0.774
      jaccard_similarity: 0.774
      intersection_count: 65
      exclusive_count: 19
    - relationship: PREDICTS
      target_id: IPR023753
      containment: 1.0
      jaccard_similarity: 0.097
      intersection_count: 84
      exclusive_count: 0
    - relationship: PREDICTED_BY
      target_id: 3.50.50.60:FF:000064
      containment: 1.0
      jaccard_similarity: 0.214
      intersection_count: 18
      exclusive_count: 0
    - relationship: EQUIV
      target_id: 3.30.390.30:FF:000004
      containment: 0.0
      jaccard_similarity: 0.0
      intersection_count: 0
      exclusive_count: 84
    - relationship: EQUIV
      target_id: 3.50.50.60:FF:000190
      containment: 0.0
      jaccard_similarity: 0.0
      intersection_count: 0
      exclusive_count: 84
    - relationship: EQUIV
      target_id: IPR006338
      containment: 0.0
      jaccard_similarity: 0.0
      intersection_count: 0
      exclusive_count: 84
    - relationship: EQUIV
      target_id: IPR045870
      containment: 0.0
      jaccard_similarity: 0.0
      intersection_count: 0
      exclusive_count: 84
    - relationship: PREDICTS
      target_id: GO:0004791
      containment: 0.857
      jaccard_similarity: 0.48
      intersection_count: 72
      exclusive_count: 12
  - id: IPR023753
    type: INTERPRO
    label: FAD/NAD(P)-binding domain
    appears_in_condition_sets:
    - 1
    protein_count: 869
    related_entries:
    - relationship: PREDICTED_BY
      target_id: IPR005982
      containment: 0.075
      jaccard_similarity: 0.075
      intersection_count: 65
      exclusive_count: 804
    - relationship: PREDICTED_BY
      target_id: IPR008255
      containment: 0.097
      jaccard_similarity: 0.097
      intersection_count: 84
      exclusive_count: 785
    - relationship: PREDICTED_BY
      target_id: 3.50.50.60:FF:000064
      containment: 1.0
      jaccard_similarity: 0.021
      intersection_count: 18
      exclusive_count: 0
    - relationship: PREDICTED_BY
      target_id: 3.30.390.30:FF:000004
      containment: 1.0
      jaccard_similarity: 0.02
      intersection_count: 17
      exclusive_count: 0
    - relationship: PREDICTED_BY
      target_id: 3.50.50.60:FF:000190
      containment: 1.0
      jaccard_similarity: 0.021
      intersection_count: 18
      exclusive_count: 0
    - relationship: PREDICTED_BY
      target_id: IPR006338
      containment: 1.0
      jaccard_similarity: 0.022
      intersection_count: 19
      exclusive_count: 0
    - relationship: EQUIV
      target_id: IPR045870
      containment: 0.0
      jaccard_similarity: 0.0
      intersection_count: 0
      exclusive_count: 869
    - relationship: PREDICTED_BY
      target_id: GO:0004791
      containment: 0.775
      jaccard_similarity: 0.119
      intersection_count: 107
      exclusive_count: 31
  reviewed_protein_count: 0
  unreviewed_protein_count: 0
  created_date: '2021-10-20'
  modified_date: '2026-07-18'
  retrieved_date: '2026-11-09'
  source_condition_set_count: 3
review_summary: >-
  All three live condition sets were examined. Set 1 rests on IPR005982 (Thioredoxin reductase), which
  InterPro2GO already maps to GO:0004791. The FunFams of sets 2 and 3 each hold 18 Swiss-Prot proteins,
  all annotated to GO:0004791. The annotation is correct for what the rule matches. Most of the rule
  duplicates InterPro2GO: sets 1 and 3 add nothing to the IPR005982 and IPR006338 mappings, and set
  2 adds 136 UniProtKB proteins that carry neither signature.
action: ACCEPT
action_rationale: >-
  Every condition set is supported: by a curated InterPro2GO mapping for set 1, and by complete agreement
  with Swiss-Prot annotation for the FunFams of sets 2 and 3. Overlap with InterPro2GO makes the rule
  largely redundant, which is not a fault in its annotations.
suggested_modifications:
- >-
  Before any retirement on grounds of redundancy, check the 136 UniProtKB proteins matched by set
  2 that have neither IPR005982 nor IPR006338; they are the only annotations this rule adds.
literature_support:
  assessment: STRONG
  notes: Thioredoxin reductase is a structurally and mechanistically characterised enzyme family.
  supported_by:
  - reference_id: PMID:11481439
    supporting_text: >-
      electron transfer from NADPH to the disulfide of the substrate is possible without large conformational
      changes
condition_overlap:
  assessment: MINOR
  notes: >-
    In Swiss-Prot the FunFams of sets 2 and 3 share no protein with each other; all 18 proteins of
    the set 2 FunFam also carry IPR005982, the signature of set 1, and none of the set 3 FunFam does.
go_specificity:
  assessment: APPROPRIATE
  notes: >-
    GO:0004791 names the reaction itself and is the term InterPro2GO assigns to the same families.
annotation_assessments:
- annotation_kind: GO_TERM
  value: GO:0004791
  label: thioredoxin-disulfide reductase (NADPH) activity
  assessment: CORRECT
  notes: >-
    rules/arba/_interpro2go.txt: IPR005982 Thioredoxin reductase > GO:0004791; IPR006338 Thioredoxin/glutathione
    reductase selenoprotein > GO:0004791. Recorded Swiss-Prot counts: FunFam 3.50.50.60:FF:000064,
    18 proteins, 18 with GO:0004791; FunFam 3.50.50.60:FF:000190, 18 proteins, 18 with GO:0004791.
    UniProtKB counts (2026-11-09): set 2 conjunction 2641, of which 136 lack both IPR005982 and IPR006338.
confidence: 0.75
references:
- id: PMID:11481439
  title: >-
    Three-dimensional structure of a mammalian thioredoxin reductase: implications for mechanism and
    evolution of a selenocysteine-dependent enzyme
  findings:
  - statement: Crystal structure of rat thioredoxin reductase.
- id: PMID:31367788
  title: 'The thioredoxin system and cancer therapy: a review'
  findings:
  - statement: Review of the thioredoxin system.
supported_by:
- reference_id: PMID:31367788
  supporting_text: >-
    Thioredoxin (Trx), thioredoxin reductase (TrxR), and NADPH are key members of the Trx system that
    is involved in redox regulation and antioxidant defense
corrections:
- date: '2026-11-10'
  withdrawn_claim: >-
    The rule is completely redundant with InterPro2GO and provides zero unique annotations, so it
    should be deprecated.
  correction: >-
    Redundancy was measured in Swiss-Prot only. In UniProtKB, set 2 matches 136 proteins that neither
    InterPro2GO mapping covers. Redundancy is in any case a reason about efficiency, not about correctness,
    and every other assessment of the rule was favourable.
  error_type: SAMPLE_OVERGENERALISED
  evidence:
  - 'UniProtKB query xref funfam-3.50.50.60:FF:000064 AND taxonomy 2759: 2641'
  - 'Same query AND NOT IPR005982 AND NOT IPR006338: 136'
- date: '2026-11-10'
  withdrawn_claim: Condition set 3 is two FunFams restricted to Rattus.
  correction: The live set 3 is one FunFam (3.50.50.60:FF:000190) restricted to Glires.
  error_type: STALE_RULE_VERSION
  evidence:
  - rest.uniprot.org/arba/ARBA00026249, modified 2026-07-18
- date: '2026-11-10'
  withdrawn_claim: >-
    The AND logic of set 1 is redundant because IPR005982 alone is sufficient; elsewhere, the AND
    requirement is a specificity filter that prevents false positives.
  correction: >-
    The two statements contradict each other. What is recorded is only that in Swiss-Prot every IPR005982
    protein also has the other two signatures; in UniProtKB 2154 proteins with IPR005982 lack one
    of them, so the conjunction is narrower than the InterPro2GO mapping.
  error_type: OTHER
  evidence:
  - 'Recorded Swiss-Prot counts: IPR005982 65, all with IPR008255 and IPR023753'
  - 'UniProtKB query IPR005982 AND NOT (IPR008255 AND IPR023753): 2154 of 21693'
- date: '2026-11-10'
  withdrawn_claim: >-
    IPR008255 also covers class-II enzymes such as glutathione reductase and lipoamide dehydrogenase.
  correction: >-
    The 19 Swiss-Prot proteins with IPR008255 but not IPR005982 were not identified; the statement
    is removed. Dihydrolipoamide dehydrogenase belongs to the class I family IPR001100.
  error_type: WRONG_IDENTIFIER_MEANING
  evidence:
  - 'InterPro API: IPR001100 = Pyridine nucleotide-disulphide oxidoreductase, class I'
- date: '2026-11-10'
  withdrawn_claim: >-
    Mechanistic and structural details taken from deep-research files support a strong literature
    assessment.
  correction: >-
    Generated research notes are not literature. The assessment now rests on the cached publications
    only.
  error_type: UNSUPPORTED_SOURCE
  evidence:
  - Previous supported_by cited three ARBA00026249-deep-research-*.md files