id: Q13825
gene_symbol: AUH
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  AUH is a mitochondrial-matrix enzyme of the enoyl-CoA hydratase/isomerase
  (crotonase) superfamily that assembles as a homohexamer. Its principal
  catalytic role is 3-methylglutaconyl-CoA hydratase activity (EC 4.2.1.18):
  it catalyzes the fifth step of the L-leucine degradation pathway, the
  reversible hydration of (E)-3-methylglutaconyl-CoA to (S)-3-hydroxy-3-
  methylglutaryl-CoA (HMG-CoA), with the hydration direction favored
  physiologically; the product HMG-CoA is then cleaved to acetyl-CoA and
  acetoacetate. AUH is the major human 3-methylglutaconyl-CoA hydratase, and
  loss of its activity causes the autosomal-recessive inborn error of leucine
  metabolism 3-methylglutaconic aciduria type I (MGCA1). The protein is
  synthesized as a precursor with an N-terminal mitochondrial transit peptide
  that is cleaved on import. AUH is also a genuinely bifunctional (moonlighting)
  protein: it was originally identified as an AU-rich element (ARE) RNA-binding
  protein that binds specifically to AU-rich sequences in the 3' untranslated
  regions of short-lived mRNAs (e.g. cytokine and proto-oncogene transcripts
  such as IL-3, GM-CSF, c-fos and c-myc), a function localized to a distinct
  region of the polypeptide separate from the catalytic site. In addition to its
  leucine-pathway role, the crotonase fold gives AUH broad in vitro activity on
  related short acyl-CoA substrates and an inferred itaconyl-CoA hydratase
  activity that may contribute to detoxification of macrophage-derived itaconate
  via the C5-dicarboxylate catabolism pathway.
alternative_products:
- name: '1'
  id: Q13825-1
- name: '2'
  id: Q13825-2
  sequence_note: VSP_008336
existing_annotations:
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Phylogenetic (IBA) assignment of mitochondrial localization. AUH is a
      well-established mitochondrial-matrix enzyme with an N-terminal transit
      peptide; this is correct though less specific than the matrix annotation.
    action: ACCEPT
    reason: >-
      Localization is consistent across orthologs and experimental data.
      Correct, but see the mitochondrial matrix (GO:0005759) annotation for the
      more precise compartment.
    supported_by:
    - reference_id: file:human/AUH/AUH-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Mitochondrion"
- term:
    id: GO:0004300
    label: enoyl-CoA hydratase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Family-level (crotonase / enoyl-CoA hydratase) molecular function assigned
      by phylogeny. AUH does have measurable enoyl-CoA hydratase activity, but
      its physiological, specific activity is 3-methylglutaconyl-CoA hydratase.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      This is the superfamily-level activity; the historically observed enoyl-CoA
      hydratase activity of AUH is weak relative to its physiological
      3-methylglutaconyl-CoA hydratase activity (GO:0004490). Retained as a
      correct but less-precise family annotation rather than as a core function.
    propagation_review:
      root_cause: TERM_SCOPING_PROBLEM
      failure_modes:
      - GRANULARITY_MISMATCH
    supported_by:
    - reference_id: PMID:7892223
      supporting_text: >-
        Sequence analysis revealed an unexpected homology to enoyl-CoA hydratase
        (EC 4.2.1.17), and the recombinant protein showed a low degree of the
        enzymatic activity.
- term:
    id: GO:0004490
    label: methylglutaconyl-CoA hydratase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetic assignment of the core, specific molecular function of AUH:
      3-methylglutaconyl-CoA hydratase activity in leucine degradation.
    action: ACCEPT
    reason: >-
      This is the physiological catalytic function of AUH, concordant with direct
      biochemical (IDA) and disease evidence. Represents a core function.
    supported_by:
    - reference_id: PMID:16640564
      supporting_text: >-
        giving strong evidence that the AUH gene encodes for the major human
        3-MG-CoA hydratase in leucine degradation.
- term:
    id: GO:0006635
    label: fatty acid beta-oxidation
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetic assignment of a fatty-acid beta-oxidation role, propagated at
      the crotonase-superfamily level. AUH's physiological role is leucine
      catabolism, not fatty-acid beta-oxidation.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      AUH belongs to the enoyl-CoA hydratase/isomerase superfamily, many members
      of which act in fatty-acid beta-oxidation, so the IBA is propagated from
      FAO-acting relatives (the with/from includes P30084 ECHS1-type orthologs).
      The characterized physiological role of AUH is the leucine-degradation step
      3-methylglutaconyl-CoA -> HMG-CoA, and there is no evidence AUH performs the
      enoyl-CoA hydratase step of mitochondrial fatty-acid beta-oxidation in vivo.
      This is a family-level over-propagation rather than a demonstrably wrong
      inference, so it is flagged rather than removed.
    propagation_review:
      root_cause: PROPAGATION_BAD
      failure_modes:
      - FUNCTIONAL_DIVERGENCE
    supported_by:
    - reference_id: file:human/AUH/AUH-uniprot.txt
      supporting_text: >-
        Catalyzes the fifth step in the leucine degradation pathway, the
        reversible hydration of 3-methylglutaconyl-CoA (3-MG-CoA) to 3-
        hydroxy-3-methylglutaryl-CoA (HMG-CoA)
- term:
    id: GO:0003723
    label: RNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: enables
  review:
    summary: >-
      Electronic (ARBA) assignment of RNA binding. This is the parent of the more
      specific, experimentally supported mRNA 3'-UTR (AU-rich element) binding of
      AUH.
    action: ACCEPT
    reason: >-
      AUH is a bona fide RNA-binding protein (originally identified as an
      AU-specific RNA-binding protein). The electronic RNA-binding term is correct
      though less specific than GO:0003730 (mRNA 3'-UTR binding).
    supported_by:
    - reference_id: PMID:7892223
      supporting_text: >-
        In vitro, the recombinant protein bound specifically to AU-rich
        transcripts
- term:
    id: GO:0003824
    label: catalytic activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      Root-level catalytic-activity term assigned electronically from an InterPro
      crotonase domain. Uninformative given the specific hydratase annotations.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      GO:0003824 is the most general molecular-function catalytic term and adds no
      information beyond the specific methylglutaconyl-CoA hydratase activity
      (GO:0004490). Retained but flagged as an over-general InterPro-to-GO mapping.
    supported_by:
    - reference_id: file:human/AUH/AUH-uniprot.txt
      supporting_text: "CDD; cd06558; crotonase-like; 1."
- term:
    id: GO:0004300
    label: enoyl-CoA hydratase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: enables
  review:
    summary: >-
      Electronic (ARBA) assignment of the family-level enoyl-CoA hydratase
      activity; duplicate in aspect of the IBA enoyl-CoA hydratase annotation.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Correct at the superfamily level but less precise than the physiological
      3-methylglutaconyl-CoA hydratase activity; flagged as a family-level
      over-annotation for the same reasons as the IBA enoyl-CoA hydratase term.
    supported_by:
    - reference_id: PMID:7892223
      supporting_text: >-
        Sequence analysis revealed an unexpected homology to enoyl-CoA hydratase
        (EC 4.2.1.17), and the recombinant protein showed a low degree of the
        enzymatic activity.
- term:
    id: GO:0004490
    label: methylglutaconyl-CoA hydratase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Electronic assignment (RHEA:21536 / EC 4.2.1.18) of the core specific
      molecular function, mirroring the experimental IDA and IBA annotations.
    action: ACCEPT
    reason: >-
      Correctly captures the physiological 3-methylglutaconyl-CoA hydratase
      activity (EC 4.2.1.18) and matches the UniProt catalytic-activity record.
    supported_by:
    - reference_id: file:human/AUH/AUH-uniprot.txt
      supporting_text: >-
        Reaction=(3S)-3-hydroxy-3-methylglutaryl-CoA = 3-methyl-(2E)-
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: >-
      Electronic assignment of mitochondrial localization (UniProt SubCell
      SL-0173). Correct.
    action: ACCEPT
    reason: >-
      Consistent with the transit peptide, experimental proteomics, and Reactome;
      the mitochondrial matrix annotation (GO:0005759) is the more specific form.
    supported_by:
    - reference_id: file:human/AUH/AUH-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Mitochondrion"
- term:
    id: GO:0009083
    label: branched-chain amino acid catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: >-
      Electronic (ARBA) assignment of branched-chain amino acid catabolism, the
      parent process of leucine (a branched-chain amino acid) degradation.
    action: ACCEPT
    reason: >-
      Leucine is a branched-chain amino acid, so AUH's leucine-degradation role is
      correctly a branched-chain amino acid catabolic process. Correct but less
      specific than L-leucine catabolic process (GO:0006552).
    supported_by:
    - reference_id: file:human/AUH/AUH-uniprot.txt
      supporting_text: >-
        Catalyzes the fifth step in the leucine degradation pathway
- term:
    id: GO:0050011
    label: itaconyl-CoA hydratase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Electronic assignment (RHEA:13785 / EC 4.2.1.56) of itaconyl-CoA hydratase
      activity, a secondary crotonase-family activity attributed to AUH in
      itaconate detoxification.
    action: KEEP_AS_NON_CORE
    reason: >-
      AUH is reported to catalyze the reversible hydration between itaconyl-CoA and
      citramalyl-CoA in the C5-dicarboxylate pathway. This is a genuine but
      secondary/context-dependent activity (evidence is inferential, ECO:0000303),
      not the core physiological function; kept as non-core.
    supported_by:
    - reference_id: PMID:29056341
      supporting_text: >-
        itaconyl-CoA and citramalyl-CoA via the previously reported reversible
        hydration
- term:
    id: GO:0170035
    label: obsolete L-amino acid catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: >-
      Electronic (ARBA) assignment to a GO term that is now obsolete.
    action: REMOVE
    reason: >-
      GO:0170035 is an obsolete term (verified via QuickGO: isObsolete=true).
      Obsolete electronic annotations should not be retained; the substantive
      biology (leucine/branched-chain amino acid catabolism) is captured by
      GO:0006552 and GO:0009083.
    supported_by:
    - reference_id: file:human/AUH/AUH-uniprot.txt
      supporting_text: >-
        Catalyzes the fifth step in the leucine degradation pathway
- term:
    id: GO:0006552
    label: L-leucine catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000041
  qualifier: involved_in
  review:
    summary: >-
      UniPathway-derived electronic assignment of L-leucine catabolism, the core
      biological process for AUH.
    action: ACCEPT
    reason: >-
      Matches the experimentally supported (IMP) leucine-catabolism role and the
      UniProt pathway record (L-leucine degradation, step 3/3 to HMG-CoA). Core
      biological process.
    supported_by:
    - reference_id: file:human/AUH/AUH-uniprot.txt
      supporting_text: >-
        PATHWAY: Amino-acid degradation; L-leucine degradation
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9914271
  qualifier: located_in
  review:
    summary: >-
      Reactome-asserted mitochondrial matrix localization, the specific
      subcompartment where the soluble leucine-degradation enzymes act.
    action: ACCEPT
    reason: >-
      AUH is a soluble matrix enzyme (imported via a cleaved transit peptide);
      the matrix is the correct, specific compartment and represents the core
      location.
    supported_by:
    - reference_id: file:human/AUH/AUH-uniprot.txt
      supporting_text: >-
        TRANSIT         1..67
- term:
    id: GO:0050011
    label: itaconyl-CoA hydratase activity
  evidence_type: TAS
  original_reference_id: PMID:29056341
  qualifier: enables
  review:
    summary: >-
      Author-stated (TAS) itaconyl-CoA hydratase activity: AUH catalyzes the
      reversible hydration converting itaconyl-CoA to citramalyl-CoA in the
      C5-dicarboxylate / itaconate-detoxification pathway.
    action: KEEP_AS_NON_CORE
    reason: >-
      The itaconate paper attributes the itaconyl-CoA <-> citramalyl-CoA hydration
      to methylglutaconyl-CoA hydratase (AUH). This is a real but secondary
      activity of the crotonase fold, distinct from the core leucine-pathway role;
      kept as non-core.
    supported_by:
    - reference_id: PMID:29056341
      supporting_text: >-
        reaction catalyzed by methylglutaconyl-CoA hydratase (AUH)
- term:
    id: GO:0110052
    label: toxic metabolite repair
  evidence_type: TAS
  original_reference_id: PMID:29056341
  qualifier: involved_in
  review:
    summary: >-
      Author-stated (TAS) involvement in toxic-metabolite repair: the
      C5-dicarboxylate pathway (in which AUH's itaconyl-CoA hydratase activity
      participates) detoxifies macrophage-derived itaconate, a B12-poisoning
      metabolite.
    action: KEEP_AS_NON_CORE
    reason: >-
      This process annotation is tied to AUH's secondary itaconyl-CoA hydratase
      activity in itaconate detoxification, not to its core leucine-degradation
      role; retained as non-core.
    supported_by:
    - reference_id: PMID:29056341
      supporting_text: >-
        itaconate, an anti-microbial metabolite
- term:
    id: GO:0006552
    label: L-leucine catabolic process
  evidence_type: IMP
  original_reference_id: PMID:16640564
  qualifier: involved_in
  review:
    summary: >-
      Experimental (IMP) evidence that AUH functions in L-leucine catabolism:
      the disease-associated A240V variant produces an enzyme with only ~9% of
      wild-type 3-methylglutaconyl-CoA hydratase activity, linking loss of AUH
      function to a leucine-degradation defect (MGCA1).
    action: ACCEPT
    reason: >-
      Direct genotype-phenotype and enzymatic evidence place AUH in the leucine
      degradation pathway; this is a core biological process. The curator had the
      full text linking the MGCA1 mutation to reduced hydratase activity.
    supported_by:
    - reference_id: PMID:16640564
      supporting_text: >-
        MGA1 is caused by reduced or absent 3-methylglutaconyl-coenzyme A
        (3-MG-CoA) hydratase activity within the leucine degradation pathway.
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  qualifier: located_in
  review:
    summary: >-
      High-throughput proteomics (HTP) detection of AUH in the human
      mitochondrial proteome.
    action: ACCEPT
    reason: >-
      Consistent with all other localization evidence (transit peptide, Reactome,
      IBA/IEA). Mitochondrial localization is well established; matrix (GO:0005759)
      is the more specific compartment.
    supported_by:
    - reference_id: file:human/AUH/AUH-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Mitochondrion"
- term:
    id: GO:0004490
    label: methylglutaconyl-CoA hydratase activity
  evidence_type: IDA
  original_reference_id: PMID:16640564
  qualifier: enables
  review:
    summary: >-
      Direct biochemical assay (IDA) of purified AUH gene product demonstrating
      3-methylglutaconyl-CoA hydratase activity with (E)-3-MG-CoA as the best
      substrate. This is the strongest evidence for the core molecular function.
    action: ACCEPT
    reason: >-
      Purified recombinant AUH shows robust hydratase activity on (E)-3-MG-CoA
      (Vmax 3.9 U/mg, Km 8.3 uM), establishing it as the major human
      3-methylglutaconyl-CoA hydratase. Core molecular function.
    supported_by:
    - reference_id: PMID:16640564
      supporting_text: >-
        The best substrates were (E)-3-MG-CoA (V(max) = 3.9 U.mg(-1),
        K(m) = 8.3 microM, k(cat) = 5.1 s(-1))
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-70785
  qualifier: located_in
  review:
    summary: >-
      Reactome-asserted mitochondrial matrix localization associated with the
      3-methylglutaconyl-CoA hydration reaction.
    action: ACCEPT
    reason: >-
      Duplicate-in-aspect of the other matrix annotation; correct and specific
      compartment for this soluble matrix enzyme.
    supported_by:
    - reference_id: file:human/AUH/AUH-uniprot.txt
      supporting_text: >-
        TRANSIT         1..67
- term:
    id: GO:0003730
    label: mRNA 3'-UTR binding
  evidence_type: IDA
  original_reference_id: PMID:7892223
  qualifier: enables
  review:
    summary: >-
      Direct experimental evidence (IDA) that AUH binds AU-rich elements in mRNA
      3' untranslated regions: it was affinity-purified on an AUUUA matrix and the
      recombinant protein bound specifically to AU-rich 3'UTR transcripts
      (IL-3, GM-CSF, c-fos, c-myc). This is the moonlighting RNA-binding function.
    action: ACCEPT
    reason: >-
      Establishes AUH's second, genuine molecular function as an AU-rich element
      (ARE) RNA-binding protein, on a domain distinct from the catalytic site.
      Represents a core molecular function separate from the hydratase activity.
    supported_by:
    - reference_id: PMID:7892223
      supporting_text: >-
        AU-rich elements within the 3' untranslated region of transcripts of
        lymphokines and some protooncogenes serve as signal for rapid mRNA
        degradation.
    - reference_id: PMID:7892223
      supporting_text: >-
        In vitro, the recombinant protein bound specifically to AU-rich
        transcripts, including those for interleukin 3, granulocyte/macrophage
        colony-stimulating factor, c-fos, and c-myc.
- term:
    id: GO:0004300
    label: enoyl-CoA hydratase activity
  evidence_type: IDA
  original_reference_id: PMID:7892223
  qualifier: enables
  review:
    summary: >-
      Direct assay (IDA) showing that recombinant AUH has enoyl-CoA hydratase
      activity, though only a low degree. Historically this was the first
      demonstration of the catalytic (crotonase-family) activity of AUH.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The observed enoyl-CoA hydratase activity is the family-level activity and
      is weak; the physiologically relevant, specific activity is
      3-methylglutaconyl-CoA hydratase (GO:0004490). Retained as a correct but
      less-precise molecular-function annotation rather than a core function.
    supported_by:
    - reference_id: PMID:7892223
      supporting_text: >-
        the recombinant protein showed a low degree of the enzymatic activity
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: >-
      Sequence-similarity (ISS) transfer of mitochondrial localization from the
      rat ortholog (Q62651). Correct.
    action: ACCEPT
    reason: >-
      Concordant with transit peptide, proteomics, Reactome and phylogenetic
      evidence for mitochondrial localization.
    supported_by:
    - reference_id: file:human/AUH/AUH-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Mitochondrion"
core_functions:
- description: >-
    3-methylglutaconyl-CoA hydratase catalyzing the fifth step of L-leucine
    degradation in the mitochondrial matrix: the reversible hydration of
    (E)-3-methylglutaconyl-CoA to (S)-3-hydroxy-3-methylglutaryl-CoA (HMG-CoA).
  molecular_function:
    id: GO:0004490
    label: methylglutaconyl-CoA hydratase activity
  directly_involved_in:
  - id: GO:0006552
    label: L-leucine catabolic process
  locations:
  - id: GO:0005759
    label: mitochondrial matrix
  supported_by:
  - reference_id: PMID:16640564
    supporting_text: >-
      The best substrates were (E)-3-MG-CoA (V(max) = 3.9 U.mg(-1),
      K(m) = 8.3 microM, k(cat) = 5.1 s(-1))
  - reference_id: PMID:16640564
    supporting_text: >-
      giving strong evidence that the AUH gene encodes for the major human
      3-MG-CoA hydratase in leucine degradation.
- description: >-
    AU-rich element (ARE) RNA-binding protein that binds specifically to AU-rich
    sequences in the 3' untranslated regions of short-lived mRNAs (e.g. cytokine
    and proto-oncogene transcripts), a moonlighting function on a domain distinct
    from the catalytic site.
  molecular_function:
    id: GO:0003730
    label: mRNA 3'-UTR binding
  supported_by:
  - reference_id: PMID:7892223
    supporting_text: >-
      In vitro, the recombinant protein bound specifically to AU-rich
      transcripts, including those for interleukin 3, granulocyte/macrophage
      colony-stimulating factor, c-fos, and c-myc.
  - reference_id: PMID:7892223
    supporting_text: >-
      suggesting that hydratase and AU-binding functions are located on distinct
      domains within a single polypeptide.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000041
  title: Gene Ontology annotation based on UniPathway vocabulary mapping
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:16640564
  title: Biochemical characterization of human 3-methylglutaconyl-CoA hydratase and
    its role in leucine metabolism.
  findings:
  - statement: >-
      Purified recombinant AUH is the major human 3-methylglutaconyl-CoA hydratase,
      with (E)-3-methylglutaconyl-CoA and (E)-glutaconyl-CoA as its best substrates,
      acting in the leucine degradation pathway.
    supporting_text: >-
      giving strong evidence that the AUH gene encodes for the major human
      3-MG-CoA hydratase in leucine degradation.
  - statement: >-
      The MGCA1-associated A240V missense variant retains only ~9% of wild-type
      3-MG-CoA hydratase activity.
    supporting_text: >-
      leading to the amino acid exchange A240V, produces an enzyme with only 9% of
      the wild-type 3-MG-CoA hydratase activity.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified; abstract-only cache (full_text_available: false). Directly
      establishes AUH as the physiological 3-methylglutaconyl-CoA hydratase and its
      role in leucine catabolism; supports the IDA and IMP annotations.
- id: PMID:29056341
  title: The Human Knockout Gene CLYBL Connects Itaconate to Vitamin B(12).
  findings:
  - statement: >-
      Itaconate can be converted to itaconyl-CoA and citramalyl-CoA via a
      reversible hydration reaction catalyzed by methylglutaconyl-CoA hydratase
      (AUH), placing AUH in the C5-dicarboxylate / itaconate detoxification pathway.
    supporting_text: >-
      reaction catalyzed by methylglutaconyl-CoA hydratase (AUH)
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Full text available and grep-verified. The paper is primarily about CLYBL
      (citramalyl-CoA lyase) but explicitly attributes the itaconyl-CoA to
      citramalyl-CoA hydration to AUH; supports the secondary (non-core)
      itaconyl-CoA hydratase and toxic-metabolite-repair annotations.
- id: PMID:34800366
  title: Quantitative high-confidence human mitochondrial proteome and its dynamics
    in cellular context.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      High-throughput mitochondrial proteome dataset supporting mitochondrial
      localization (HTP). AUH is not present in the cached prose (dataset in
      supplementary tables); localization corroborated by UniProt and Reactome.
- id: PMID:7892223
  title: AUH, a gene encoding an AU-specific RNA binding protein with intrinsic enoyl-CoA
    hydratase activity.
  findings:
  - statement: >-
      AUH was identified by affinity purification on an AUUUA matrix as a protein
      that binds specifically to AU-rich 3'UTR transcripts of lymphokines and
      proto-oncogenes (IL-3, GM-CSF, c-fos, c-myc).
    supporting_text: >-
      In vitro, the recombinant protein bound specifically to AU-rich transcripts,
      including those for interleukin 3, granulocyte/macrophage colony-stimulating
      factor, c-fos, and c-myc.
  - statement: >-
      AUH has intrinsic (low) enoyl-CoA hydratase activity, and the hydratase and
      AU-binding functions reside on distinct domains within a single polypeptide.
    supporting_text: >-
      suggesting that hydratase and AU-binding functions are located on distinct
      domains within a single polypeptide.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified; abstract-only cache. Foundational paper establishing the
      moonlighting ARE-RNA-binding function of AUH alongside its crotonase-family
      enzymatic activity.
- id: Reactome:R-HSA-70785
  title: beta-methylglutaconyl-CoA + H2O <=> beta-hydroxy-beta-methylglutaryl-CoA
  findings: []
- id: Reactome:R-HSA-9914271
  title: AUH mutants don't synthesize 3-hydroxy-methylglutaryl-CoA
  findings: []
proposed_new_terms: []
suggested_questions:
- question: >-
    Is the AU-rich element (ARE) RNA-binding activity of AUH functional in the
    mitochondrial matrix, or does a cytosolic/precursor pool of AUH mediate mRNA
    regulation? How is the moonlighting RNA-binding role coordinated with the
    matrix-localized enzymatic role?
- question: >-
    Does AUH contribute physiologically to itaconate detoxification (itaconyl-CoA
    hydratase activity) in human macrophages in vivo, and is this activity relevant
    to the clinical phenotype of MGCA1 patients?
suggested_experiments:
- description: >-
    Quantify AUH-dependent ARE-mediated mRNA turnover in cells depleted of AUH
    versus rescued with hydratase-dead or RNA-binding-dead (K105/K109/K113) mutants,
    to dissect the moonlighting RNA-binding function from catalysis.
- description: >-
    Assay itaconyl-CoA hydratase activity of purified human AUH and measure
    citramalyl-CoA flux in AUH-knockout macrophages challenged with itaconate to
    test the proposed role in C5-dicarboxylate / itaconate detoxification.