AUH is a mitochondrial methylglutaconyl-CoA hydratase of the crotonase superfamily. It catalyzes the reversible hydration of 3-methylglutaconyl-CoA to 3-hydroxy-3-methylglutaryl-CoA during leucine degradation. The protein forms a hexamer and also binds AU-rich RNA sequences through a positively charged surface. In human cells, AUH associates with mitochondrial RNA and ribosomes; altered AUH abundance perturbs mitochondrial protein synthesis. The physiological compartment and RNA targets of the classical AU-rich transcript-binding activity remain unresolved. A secondary itaconyl-CoA hydratase activity has been attributed to AUH in the mitochondrial C5-dicarboxylate pathway. Loss of its leucine-pathway activity causes 3-methylglutaconic aciduria type 1.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | ACCEPT | Summary: The AUH-specific phylogenetic mitochondrial assignment agrees with human localization and precursor features. Reason: The mitochondrial IBA agrees with the source transit peptide, curated localization and AUH-specific PAINT node PTN000234999. No narrower ancestral compartment is inferred. |
| GO:0004300 enoyl-CoA hydratase activity | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Human AUH has measurable weak enoyl-CoA hydratase activity, supporting this inherited secondary activity. Reason: The original human experiments establish weak enoyl-CoA hydratase activity, and the IBD at PTN000234999 includes Q13825 as legitimate experimental grounding. This is a real secondary measured activity; neither its weakness nor target self-inclusion establishes overannotation. The more efficient methylglutaconyl-CoA reaction remains the principal metabolic core. |
| GO:0004490 methylglutaconyl-CoA hydratase activity | IBA GO_REF:0000033 | ACCEPT | Summary: The AUH-specific phylogenetic assignment captures its experimentally established principal hydratase reaction. Reason: The AUH-specific IBD at PTN000234999 is consistent with direct human substrate assays and the leucine-pathway function. The target contributes legitimate experimental evidence to the phylogenetic assertion. |
| GO:0006635 fatty acid beta-oxidation | IBA GO_REF:0000033 | UNDECIDED | Summary: Fatty-acid beta-oxidation is assigned at a distinct ancestral node whose relevance to the AUH lineage remains unresolved. Reason: The cached PAINT IBD places fatty-acid beta-oxidation at PTN000941828. The tree and MSA have not been assessed, and no AUH-specific loss or divergence has been established. Leucine-pathway specialization alone does not falsify ancestral placement, so this process assignment remains unresolved. This PTN differs from PTN000234999, which carries the AUH-specific mitochondrial and hydratase assertions. The different ancestral placement identifies the question to investigate; donor count or lack of target self-inclusion does not establish an erroneous propagation. |
| GO:0003723 RNA binding | IEA GO_REF:0000117 | ACCEPT | Summary: Biochemical and structural evidence establishes RNA binding, while its complete physiological substrate range remains unresolved. Reason: RNA binding is a demonstrated second molecular function of AUH. The structural and mutational study identifies an RNA-contacting surface, while the complete physiological substrate range is unresolved. Retain the broad assertion rather than treating the demonstrated AU-rich 3'-UTR interaction as an exhaustive description of all RNA binding. Human mitochondrial RNA copurification is consistent with additional associations, but does not by itself establish direct contacts with each mitochondrial RNA. This decision does not rely on the presence of a duplicate annotation or assert a new substrate-specific function. Supporting Evidence: PMID:11738050 AUH binds to RNA |
| GO:0003824 catalytic activity | IEA GO_REF:0000002 | MODIFY | Summary: Human substrate assays refine the broad catalytic prediction to methylglutaconyl-CoA hydratase activity. Reason: The general catalytic assertion is biologically sound but lacks the experimentally established substrate specificity. Refine it to the principal human hydratase activity; breadth alone is not excessive biological specificity. Proposed replacements: methylglutaconyl-CoA hydratase activity Supporting Evidence: PMID:12434311 AUH has high 3-methylglutaconyl-CoA hydratase activity |
| GO:0004300 enoyl-CoA hydratase activity | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: The electronic enoyl-CoA assignment agrees with a real, weak secondary activity of recombinant AUH. Reason: The electronic enoyl-CoA activity agrees with the low activity measured in recombinant human AUH. Keep the measured secondary catalysis distinct from its more efficient leucine-pathway chemistry; do not call it an unverified ancestor of the methylglutaconyl term. |
| GO:0004490 methylglutaconyl-CoA hydratase activity | IEA GO_REF:0000120 | ACCEPT | Summary: The EC/Rhea inference matches the reversible hydratase reaction used in leucine degradation. Reason: The EC/Rhea mapping describes the experimentally characterized reversible methylglutaconyl-CoA hydration reaction. Physiological leucine degradation uses the hydration direction, without denying reversibility. |
| GO:0005739 mitochondrion | IEA GO_REF:0000120 | ACCEPT | Summary: The electronic mitochondrial localization agrees with human localization evidence and precursor features. Reason: The electronic mitochondrial assignment agrees with the transit peptide and multiple independent curated localization routes. Retain the supported compartment without expanding the source experiment. |
| GO:0009083 branched-chain amino acid catabolic process | IEA GO_REF:0000117 | MODIFY | Summary: The broad branched-chain catabolic prediction can be specified as the leucine pathway directly served by AUH. Reason: AUH directly catalyzes a leucine-catabolic step. The broader branched-chain amino-acid label can be refined to the substrate pathway established for this enzyme, without implying equivalent valine or isoleucine roles. Proposed replacements: L-leucine catabolic process |
| GO:0050011 itaconyl-CoA hydratase activity | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: The itaconyl-CoA mapping represents a reported secondary reaction rather than the principal leucine-pathway activity. Reason: The EC/Rhea itaconyl-CoA hydration assignment follows author-attributed secondary AUH activity. Keep this conditional metabolic role, distinguishing the TAS-derived support from the paper's direct CLYBL and MUT experiments. |
| GO:0170035 obsolete L-amino acid catabolic process | IEA GO_REF:0000117 | MODIFY | Summary: The obsolete amino-acid catabolism assertion can be retained biologically as the specific leucine-catabolic process. Reason: The official AmiGO record confirms that this source term was obsoleted as an unnecessary grouping term. Its underlying amino-acid-catabolic meaning is consistent with AUH biology. Preserve the original identifier and refine the review to the directly established leucine-catabolic process. Proposed replacements: L-leucine catabolic process |
| GO:0006552 L-leucine catabolic process | IEA GO_REF:0000041 | ACCEPT | Summary: The UniPathway assertion places AUH in the leucine-catabolic step it catalyzes. Reason: The UniPathway assignment captures the pathway step catalyzed by AUH and agrees with direct biochemical and variant evidence. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9914271 | ACCEPT | Summary: Reactome places AUH in the matrix, independently supported by human-cell mitochondrial subfractionation. Reason: The curated mutant reaction places AUH in the mitochondrial matrix. Human-cell subfractionation in PMID:24598254 independently supports matrix localization with inner-membrane association; this does not establish integral membrane topology. Preserve the original Reactome TAS attribution. |
| GO:0050011 itaconyl-CoA hydratase activity | TAS PMID:29056341 The Human Knockout Gene CLYBL Connects Itaconate to Vitamin ... | KEEP AS NON CORE | Summary: The cited pathway paper attributes itaconyl-CoA hydration to AUH through earlier enzymology. Reason: PMID29056341 explicitly attributes itaconyl-CoA hydration to AUH through historical enzymology. Retain its TAS evidence level and secondary-role interpretation; do not turn the attribution into an independent purified-human-AUH assay. Supporting Evidence: PMID:29056341 reaction catalyzed by methylglutaconyl-CoA hydratase (AUH) |
| GO:0110052 toxic metabolite repair | TAS PMID:29056341 The Human Knockout Gene CLYBL Connects Itaconate to Vitamin ... | KEEP AS NON CORE | Summary: AUH is assigned a catalytic step in a metabolite-detoxification model whose physiological flux remains uncertain. Reason: The proposed detoxification pathway assigns AUH a catalytic hydration step, also represented in the existing production GO-CAM. This is actual enzyme participation rather than mere necessity, but macrophage flux and quantitative physiological contribution remain unresolved in the cited paper. Supporting Evidence: PMID:29056341 reaction catalyzed by methylglutaconyl-CoA hydratase (AUH) |
| GO:0006552 L-leucine catabolic process | IMP PMID:16640564 Biochemical characterization of human 3-methylglutaconyl-CoA... | ACCEPT | Summary: Loss of activity in a disease-associated human AUH variant supports its role in leucine degradation. Reason: The human biochemical study links the disease-associated A240V variant to markedly reduced hydratase activity in the leucine pathway. Its normal abstract supports the curated process assertion; no newly inspected full Methods claim is made. Supporting Evidence: PMID:16640564 only 9% of the wild-type 3-MG-CoA hydratase activity. |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: The curated mitochondrial proteomics annotation agrees with independent AUH localization, although its target-specific table entry remains unchecked. Reason: The curated HTP mitochondrial assignment agrees with independent localization. The MitoCoP abstract establishes the study's human proteome scope, while the AUH-specific supplementary row has not been independently inspected; absence from prose is not grounds for rejecting the annotation. The supporting excerpt below supplies independent localization evidence from PMID:24598254; it is not presented as verification of the original proteomics row. Supporting Evidence: PMID:24598254 AUH is most abundant in the matrix |
| GO:0004490 methylglutaconyl-CoA hydratase activity | IDA PMID:16640564 Biochemical characterization of human 3-methylglutaconyl-CoA... | ACCEPT | Summary: Purified human AUH preferentially turns over methylglutaconyl-CoA in direct substrate assays. Reason: The purified human gene product shows its best measured activity on methylglutaconyl-CoA, with substrate kinetics reported in the normal abstract. This directly supports the principal molecular function. Supporting Evidence: PMID:16640564 The best substrates were (E)-3-MG-CoA |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-70785 | ACCEPT | Summary: The normal Reactome reaction and independent human-cell subfractionation support matrix localization. Reason: The curated normal leucine-catabolic reaction places AUH in the mitochondrial matrix, consistent with human-cell mitochondrial subfractionation in PMID:24598254. This is a localization assertion and does not depend on treating every mitochondrial function as matrix-specific. Supporting Evidence: PMID:24598254 AUH is most abundant in the matrix |
| GO:0003730 mRNA 3'-UTR binding | IDA PMID:7892223 AUH, a gene encoding an AU-specific RNA binding protein with... | ACCEPT | Summary: Purified and recombinant AUH bind AU-rich transcript sequences used to establish the 3'-UTR-binding annotation. Reason: Affinity purification and recombinant binding assays establish AU-rich transcript 3'-UTR binding. Retain the molecular interaction as a second function without asserting a separate folded domain, a demonstrated in-vivo transcript-decay process or identical activity of both isoforms. Supporting Evidence: PMID:7892223 specifically to AU-rich transcripts |
| GO:0004300 enoyl-CoA hydratase activity | IDA PMID:7892223 AUH, a gene encoding an AU-specific RNA binding protein with... | KEEP AS NON CORE | Summary: Recombinant AUH exhibits low but real enoyl-CoA hydratase activity alongside its RNA-binding activity. Reason: The original recombinant assay found low enoyl-CoA hydratase activity. This is a real measured side activity, not an incorrect annotation merely because a different substrate is preferred physiologically. Retain the original IDA provenance. Supporting Evidence: PMID:7892223 showed a low degree of the enzymatic activity |
| GO:0005739 mitochondrion | ISS GO_REF:0000024 | ACCEPT | Summary: The rat-ortholog localization transfer is consistent with human mitochondrial localization evidence. Reason: The rat-ortholog ISS mitochondrial transfer agrees with the human precursor features and independent localization routes. Preserve the original donor without relabeling the experiment as human IDA. |
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Download this section (compressed HTML)Q: Does the classical AU-rich transcript-binding activity operate in the mitochondrial matrix, or does a cytosolic or precursor pool mediate that interaction? Direct localization and substrate-specific binding tests are needed to distinguish these possibilities.
Q: Which RNA contacts of AUH are direct in mitochondria, and how does its RNA-binding surface contribute to the effects of AUH abundance and catalytic activity on mitochondrial translation?
Q: How much itaconyl-CoA hydration flux depends on AUH in human macrophages under endogenous itaconate production?
Q: Does the fatty-acid beta-oxidation IBD at PTN000941828 apply to the AUH lineage, and is there direct evidence for retained activity or functional divergence relevant to that process?
Q: How does the 140–168 deletion in Q13825-2 affect folding, enzyme activity and RNA binding?
Experiment: Compare direct RNA binding, mitochondrial translation and metabolite flux after matched expression of human AUH variants that separately perturb the RNA-contact surface and hydratase active site; measure protein abundance, import and folding before attributing changes to a specific activity.
Experiment: Measure AUH-dependent itaconyl-CoA and citramalyl-CoA flux in human macrophages under endogenous itaconate production, with purified-enzyme assays establishing substrate activity separately.
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