id: ARBA00067001
description: Assigns EC 1.2.1.75 in the recommended name (displayed as "malonyl CoA
  reductase (malonate semialdehyde-forming)") to archaeal proteins matching CATH FunFam
  3.40.50.720:FF:000411. The FunFam contains both malonyl-CoA reductases and their
  aspartate-semialdehyde dehydrogenase paralogs, and the rule has no condition that
  separates them.
status: COMPLETE
rule_type: ARBA
rule:
  rule_id: ARBA00067001
  condition_sets:
  - number: 1
    conditions:
    - condition_type: FUNFAM
      value: 3.40.50.720:FF:000411
      curie: CATH.FunFam:3.40.50.720:FF:000411
      label: Aspartate-semialdehyde dehydrogenase
      negated: false
    - condition_type: TAXON
      value: Archaea
      curie: NCBITaxon:2157
      label: Archaea
      negated: false
    notes: 'Single condition set: CATH FunFam 3.40.50.720:FF:000411 (named "Aspartate-semialdehyde
      dehydrogenase") AND taxon Archaea. In Sulfolobales the FunFam covers both paralogs
      of the aspartate-semialdehyde dehydrogenase family: the malonyl-CoA reductase
      (MCR) of the 3-hydroxypropionate/4-hydroxybutyrate CO2-fixation cycle and the
      true aspartate-semialdehyde dehydrogenase (ASD) of aspartate-family amino acid
      synthesis.'
  go_annotations: []
  protein_name_annotations:
  - name_type: RECOMMENDED
    ec_numbers:
    - 1.2.1.75
  catalytic_activity_annotations: []
  reviewed_protein_count: 0
  unreviewed_protein_count: 38
  created_date: '2025-03-21'
  modified_date: '2025-03-21'
  retrieved_date: '2026-11-10'
  source_condition_set_count: 1
  entries:
  - id: 3.40.50.720:FF:000411
    type: FUNFAM
    label: Aspartate-semialdehyde dehydrogenase
    appears_in_condition_sets:
    - 1
review_summary: 'The rule is right for about half of the proteins it annotates. Of
  38 rule-annotated archaeal entries (UniProt, 2026-10-15), 17 match the MCR-type
  CDD models and are malonyl-CoA reductases, 17 match the archaeal/fungal ASD-type
  models and are aspartate-semialdehyde dehydrogenases, and 4 match neither. In each
  genome both paralogs receive the malonyl-CoA reductase annotation. Gene reviews
  in this repository document both sides: Msed_0709 (the real M. sedula MCR, curated
  in Swiss-Prot and not rule-annotated) and Msed_1700 (its ASD paralog, misannotated
  by this rule).'
action: MODIFY
action_rationale: 'The single condition (FunFam plus Archaea) does not separate the
  neofunctionalized MCR from the ancestral ASD. The CDD subfamily models separate
  them cleanly in all 34 classified entries, so adding them as conditions fixes the
  rule without losing any MCR. NCBIfam TIGR00978 cannot be used: every MCR and ASD
  in this set carries it.'
suggested_modifications:
- Implemented as the curated replacement rule rules/curated/CR-0004.yaml (FunFam AND MCR-type CDD model AND Archaea)
- Require an MCR-type CDD model (cd23940 ASADH_C_MCR or cd24150 ASADH_MCR_N) in the
  condition set
- Alternatively add the archaeal/fungal ASD-type CDD models (cd18130, cd02315) as
  negative conditions
- Re-check the 4 entries with neither model (A0A8D5U5J5, A0AAT9GNW8, A0AAX4L5L8, Q4J6D4)
  after the change
- ARBA00052213 (catalytic activity RHEA:26446) has the identical condition set and
  should be fixed in the same way
parsimony:
  assessment: ACCEPTABLE
  notes: The rule is minimal (one domain condition plus taxon). The problem is that
    it is not specific enough, which ParsimonyEnum does not capture; see annotation_assessments.
literature_support:
  assessment: MODERATE
  notes: The MCR activity is well established for the MCR-type members (purified M.
    sedula and S. tokodaii enzymes). The literature also establishes that Sulfolobales
    carry a separate asd paralog in the aspartate-family gene cluster, which this
    rule annotates as MCR.
  supported_by:
  - reference_id: PMID:23325803
    supporting_text: The two paralogous MCR and ASD enzymes show ∼40% amino acid sequence
      identity in the same organism, and their genes mcr and asd have different chromosomal
      locations.
  - reference_id: PMID:23325803
    supporting_text: The asd gene clusters together with threonine synthase, aspartokinase,
      and ornithine carbamoyltransferase, among other genes, which is in line with
      its role in the biosynthesis of amino acids of the aspartate family.
condition_overlap:
  assessment: NONE
  notes: Only one domain condition, so there is no overlap to assess.
  supported_by: []
taxonomic_scope:
  assessment: APPROPRIATE
  notes: 'Restricting to Archaea is reasonable: the crenarchaeal MCR is unrelated
    to the Chloroflexus enzyme. The error is in the domain condition, not the taxon.'
  supported_by: []
annotation_assessments:
- annotation_kind: EC_NUMBER
  value: EC:1.2.1.75
  label: EC 1.2.1.75 in the recommended name (displayed as "malonyl CoA reductase
    (malonate semialdehyde-forming)")
  assessment: PARTIALLY_CORRECT
  matched_protein_count: 38
  incorrect_protein_count: 17
  correct_examples:
  - A0A031LU45
  - A0A1W6JXP6
  - A0A2U9IBW6
  - A0A2U9IQ94
  - A0A4D8S1H1
  - A0A510DRG8
  - A0A650CK04
  - A0A650CYF4
  - A0A6A9QEN3
  - A0A6A9QJK8
  - A0A6N0NWX1
  - A0A8F5BTZ9
  - A0AAQ4CTM4
  - F0NCD9
  - F4BA03
  - Q97WN3
  - W7KXV3
  incorrect_examples:
  - A0A2U9IP35
  - A0A4D8S3J4
  - A0A510DUH8
  - A0A650CGS8
  - A0A650CNP6
  - A0A6A9QII6
  - A0A8D5U8A4
  - A0A8F5BX26
  - A0AAQ4CPM1
  - A0AAT9GTT2
  - A0AAX4L0T0
  - A4YHF3
  - F0NEZ2
  - Q4J8Z0
  - Q971Y6
  - Q97ZL8
  - W7KWJ9
  gene_reviews:
  - genes/METS5/Msed_1700/Msed_1700-ai-review.yaml
  - genes/METS5/Msed_0709/Msed_0709-ai-review.yaml
  discriminating_features:
  - CDD:cd23940
  - CDD:cd24150
  - CDD:cd18130
  - CDD:cd02315
  notes: Incorrect count = entries matching only the ASD-type CDD models (classify_rule_matches.py).
    The 4 entries with no CDD model are counted neither correct nor incorrect; each
    comes from a species whose other entry is ASD-type, so they are probably MCRs.
    The two reviewed MCRs (A4YEN2, Q96YK1) carry curated, not rule, annotation.
  supported_by:
  - reference_id: file:rules/arba/ARBA00067001/RESULTS.md
    supporting_text: 'Every species with an ASD-type entry also has a second entry
      that is MCR-type or

      unclassified, so in effect the rules name both paralogs of each genome "malonyl-CoA

      reductase".'
  - reference_id: file:rules/arba/ARBA00067001/RESULTS.md
    supporting_text: 'NCBIfam TIGR00978 (asd_EA) is present on all 19 MCR-type and
      all 17 ASD-type entries, so

      it cannot separate them. The CDD models do, with no entry matching both.'
confidence: 0.5
references:
- id: PMID:23325803
  title: Structural basis for a bispecific NADP+ and CoA binding site in an archaeal
    malonyl-coenzyme A reductase.
  findings:
  - statement: Archaeal MCR evolved by duplication of the aspartate-semialdehyde dehydrogenase
      gene; the two paralogs coexist in Sulfolobales genomes at different loci, with
      asd in the aspartate-family amino acid cluster.
- id: file:rules/arba/ARBA00067001/RESULTS.md
  title: 'ARBA00067001 / ARBA00052213: which proteins do they annotate?'
  findings:
  - statement: 17 of 38 rule-annotated archaeal entries are ASD-type by CDD models;
      TIGR00978 does not separate the paralogs.
supported_by:
- reference_id: file:rules/arba/ARBA00067001/RESULTS.md
  supporting_text: 'Every species with an ASD-type entry also has a second entry that
    is MCR-type or

    unclassified, so in effect the rules name both paralogs of each genome "malonyl-CoA

    reductase".'