id: Q9UDR5
gene_symbol: AASS
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  AASS (alpha-aminoadipic semialdehyde synthase; alias LKR/SDH) is a mitochondrial
  bifunctional enzyme that catalyzes the first two committed steps of the main
  (saccharopine) pathway of L-lysine degradation in the mitochondrial matrix. Its
  N-terminal domain carries lysine-ketoglutarate reductase (LKR, EC 1.5.1.8) activity,
  which condenses L-lysine with 2-oxoglutarate to form L-saccharopine using NADPH; its
  C-terminal domain carries saccharopine dehydrogenase (SDH, EC 1.5.1.9) activity, which
  oxidizes L-saccharopine to L-2-aminoadipate-6-semialdehyde (alpha-aminoadipic
  semialdehyde) and L-glutamate, reducing NAD+. The two domains are homologous to the
  yeast Lys1 and Lys9 enzymes, and the protein forms a homotetramer. AASS is expressed
  broadly with highest levels in liver and is induced by starvation. Loss of AASS activity
  causes autosomal recessive hyperlysinemia type 1 and saccharopinuria, metabolic
  conditions that are generally benign; AASS is also secondarily impaired in
  mitochondrial NADP(H) deficiency (DECRD, due to NADK2 mutation).
existing_annotations:
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Phylogenetic (IBA) placement in cytoplasm. AASS is a mitochondrial-matrix protein;
      "cytoplasm" is a correct but very broad ancestor localization that is superseded by
      the specific mitochondrial matrix annotation.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The precise, well-supported localization is the mitochondrial matrix (Reactome TAS,
      Ensembl IEA from mouse, UniProt SUBCELL; experimentally confirmed as mitochondrial by
      PMID:463877). The generic IBA "cytoplasm" call is uninformative relative to the matrix
      annotation and should not be treated as a core localization.
    propagation_review:
      root_cause: NO_FAILURE_NON_CORE
      failure_modes:
      - GRANULARITY_MISMATCH
    supported_by:
    - reference_id: PMID:463877
      supporting_text: >-
        In all instances there was a deficiency in lysine-ketoglutarate reductase,
        saccharopine dehydrogenase, and saccharopine oxidoreductase activities.
- term:
    id: GO:0019477
    label: L-lysine catabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      AASS catalyzes the first two steps of the saccharopine pathway of lysine degradation,
      the major route of L-lysine catabolism in humans. This is a core biological process
      for the gene and is independently supported by IMP evidence (PMID:10775527).
    action: ACCEPT
    reason: >-
      The phylogenetic assignment matches the experimentally established function: AASS
      converts L-lysine to alpha-aminoadipic semialdehyde, the committed entry into lysine
      catabolism.
    supported_by:
    - reference_id: PMID:10775527
      supporting_text: >-
        we propose that AASS catalyzes the first two steps of the major lysine-degradation
        pathway in human cells and that inactivating mutations in the AASS gene are a cause
        of hyperlysinemia.
- term:
    id: GO:0004753
    label: saccharopine dehydrogenase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Grouping (parent) term for saccharopine dehydrogenase activity, assigned by
      phylogenetic inference. AASS possesses the specific NAD+, L-glutamate-forming SDH
      activity (GO:0047131); this broader term is a valid but less specific representation.
    action: ACCEPT
    reason: >-
      Correct at the family level. The C-terminal domain of AASS is the saccharopine
      dehydrogenase moiety, homologous to yeast Lys9. Retained as a valid grouping;
      the specific glutamate-forming activity (GO:0047131) captures the core function.
    supported_by:
    - reference_id: PMID:10775527
      supporting_text: >-
        an apparently bifunctional protein, with the N-terminal half similar to that of
        yeast LYS1 and with the C-terminal half similar to that of yeast LYS9.
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Electronic assignment to mitochondrion from UniProt Subcellular Location keyword
      mapping. Consistent with the experimentally verified mitochondrial localization and
      the N-terminal mitochondrial transit peptide.
    action: ACCEPT
    reason: >-
      AASS carries a mitochondrial transit peptide (residues 1-27) and is experimentally
      localized to mitochondria (PMID:463877); mitochondrion is correct, though the matrix
      annotation is more specific.
    supported_by:
    - reference_id: PMID:463877
      supporting_text: >-
        saccharopine oxidoreductase was partially purified from human liver and
        characterized.
- term:
    id: GO:0047130
    label: saccharopine dehydrogenase (NADP+, L-lysine-forming) activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Electronic assignment (ARBA/RHEA/EC mapping) of the lysine-ketoglutarate reductase
      (LKR, EC 1.5.1.8) activity, the first catalytic step of AASS. This is a core molecular
      function, corroborated by EXP (PMID:463877) and IMP (PMID:10775527) annotations.
    action: ACCEPT
    reason: >-
      Correct. This term (RHEA:19373, EC 1.5.1.8) is the NADPH-dependent condensation of
      L-lysine and 2-oxoglutarate to saccharopine catalyzed by the N-terminal LKR domain.
    supported_by:
    - reference_id: PMID:10775527
      supporting_text: >-
        The first two steps in the mammalian lysine-degradation pathway are catalyzed by
        lysine-ketoglutarate reductase and saccharopine dehydrogenase, respectively,
        resulting in the conversion of lysine to alpha-aminoadipic semialdehyde.
    - reference_id: file:human/AASS/AASS-uniprot.txt
      supporting_text: >-
        Bifunctional enzyme that catalyzes the first two steps in
- term:
    id: GO:0047131
    label: saccharopine dehydrogenase (NAD+, L-glutamate-forming) activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Electronic assignment (ARBA/RHEA/EC mapping) of the saccharopine dehydrogenase (SDH,
      EC 1.5.1.9) activity, the second catalytic step of AASS. This is a core molecular
      function, corroborated by EXP (PMID:463877) and IMP (PMID:10775527) annotations.
    action: ACCEPT
    reason: >-
      Correct. This term (RHEA:24520, EC 1.5.1.9) is the NAD+-dependent oxidation of
      saccharopine to alpha-aminoadipic semialdehyde and L-glutamate catalyzed by the
      C-terminal SDH domain.
    supported_by:
    - reference_id: PMID:10775527
      supporting_text: >-
        The first two steps in the mammalian lysine-degradation pathway are catalyzed by
        lysine-ketoglutarate reductase and saccharopine dehydrogenase, respectively,
        resulting in the conversion of lysine to alpha-aminoadipic semialdehyde.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: is_active_in
  review:
    summary: >-
      Automatic transfer (Ensembl Compara) from the mouse ortholog (Q99K67) placing AASS in
      the mitochondrial matrix, the compartment where the saccharopine pathway operates.
    action: ACCEPT
    reason: >-
      Mitochondrial matrix is the correct, specific compartment for this soluble matrix
      enzyme, consistent with the transit peptide and experimental mitochondrial
      localization (PMID:463877). This is the core localization.
    supported_by:
    - reference_id: PMID:10567240
      supporting_text: >-
        the bifunctional enzyme is likely to be a mitochondrial protein.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-70938
  qualifier: located_in
  review:
    summary: >-
      Reactome (TAS) localization of the LKR reaction (lysine + alpha-ketoglutarate + NADPH
      => saccharopine) to the mitochondrial matrix. Consistent with the core localization.
    action: ACCEPT
    reason: >-
      The LKR step of AASS occurs in the mitochondrial matrix; Reactome curates this
      reaction there. Correct.
    supported_by:
    - reference_id: PMID:10567240
      supporting_text: >-
        the bifunctional enzyme is likely to be a mitochondrial protein.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-70940
  qualifier: located_in
  review:
    summary: >-
      Reactome (TAS) localization of the SDH reaction (saccharopine + NAD+ => alpha-aminoadipic
      semialdehyde + glutamate) to the mitochondrial matrix. Consistent with the core
      localization.
    action: ACCEPT
    reason: >-
      The SDH step of AASS occurs in the mitochondrial matrix; Reactome curates this
      reaction there. Correct.
    supported_by:
    - reference_id: PMID:10567240
      supporting_text: >-
        the bifunctional enzyme is likely to be a mitochondrial protein.
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: EXP
  original_reference_id: PMID:463877
  qualifier: located_in
  review:
    summary: >-
      Experimental localization of AASS activities to mitochondria, from enzyme studies of
      the lysine-degrading activities partially purified from human liver.
    action: ACCEPT
    reason: >-
      Directly supported experimental annotation of mitochondrial localization; consistent
      with all other localization evidence.
    supported_by:
    - reference_id: PMID:463877
      supporting_text: >-
        saccharopine oxidoreductase was partially purified from human liver and
        characterized.
- term:
    id: GO:0047130
    label: saccharopine dehydrogenase (NADP+, L-lysine-forming) activity
  evidence_type: EXP
  original_reference_id: PMID:463877
  qualifier: enables
  review:
    summary: >-
      Experimental demonstration of lysine-ketoglutarate reductase (LKR) activity in human
      cells/liver; deficiency of this activity is characteristic of familial hyperlysinemia.
      Core molecular function.
    action: ACCEPT
    reason: >-
      LKR activity was directly assayed and shown deficient in hyperlysinemia patients,
      establishing this NADP+/L-lysine-forming (EC 1.5.1.8) activity for the human enzyme.
    supported_by:
    - reference_id: PMID:463877
      supporting_text: >-
        In all instances there was a deficiency in lysine-ketoglutarate reductase,
        saccharopine dehydrogenase, and saccharopine oxidoreductase activities.
- term:
    id: GO:0047131
    label: saccharopine dehydrogenase (NAD+, L-glutamate-forming) activity
  evidence_type: EXP
  original_reference_id: PMID:463877
  qualifier: enables
  review:
    summary: >-
      Experimental demonstration of saccharopine dehydrogenase (SDH) activity in human
      cells/liver; deficiency of this activity is characteristic of familial hyperlysinemia.
      Core molecular function.
    action: ACCEPT
    reason: >-
      SDH activity was directly assayed and shown deficient in hyperlysinemia patients,
      establishing this NAD+/L-glutamate-forming (EC 1.5.1.9) activity for the human enzyme.
    supported_by:
    - reference_id: PMID:463877
      supporting_text: >-
        In all instances there was a deficiency in lysine-ketoglutarate reductase,
        saccharopine dehydrogenase, and saccharopine oxidoreductase activities.
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  qualifier: located_in
  review:
    summary: >-
      High-throughput identification of AASS in the high-confidence human mitochondrial
      proteome (MitoCoP). Corroborates the mitochondrial localization.
    action: ACCEPT
    reason: >-
      Consistent proteome-scale evidence supporting mitochondrial localization, in agreement
      with the experimental and computational annotations.
    supported_by:
    - reference_id: PMID:34800366
      supporting_text: >-
        mitochondrial high-confidence proteome of >1,100 proteins (MitoCoP)
- term:
    id: GO:0047130
    label: saccharopine dehydrogenase (NADP+, L-lysine-forming) activity
  evidence_type: IMP
  original_reference_id: PMID:10775527
  qualifier: enables
  review:
    summary: >-
      Loss-of-function evidence: a homozygous frameshift/premature-stop AASS variant in a
      hyperlysinemia patient abolishes the enzyme, supporting the LKR (EC 1.5.1.8) activity
      of AASS. Core molecular function.
    action: ACCEPT
    reason: >-
      Mutational (IMP) evidence links AASS specifically to the LKR activity of the
      lysine-degradation pathway.
    supported_by:
    - reference_id: PMID:10775527
      supporting_text: >-
        we propose that AASS catalyzes the first two steps of the major lysine-degradation
        pathway in human cells and that inactivating mutations in the AASS gene are a cause
        of hyperlysinemia.
- term:
    id: GO:0019477
    label: L-lysine catabolic process
  evidence_type: IMP
  original_reference_id: PMID:10775527
  qualifier: involved_in
  review:
    summary: >-
      Mutational evidence that AASS is required for L-lysine catabolism: inactivating AASS
      variants cause hyperlysinemia (accumulation of lysine). Core biological process.
    action: ACCEPT
    reason: >-
      Directly establishes AASS involvement in the L-lysine catabolic process via a
      loss-of-function patient allele.
    supported_by:
    - reference_id: PMID:10775527
      supporting_text: >-
        we propose that AASS catalyzes the first two steps of the major lysine-degradation
        pathway in human cells and that inactivating mutations in the AASS gene are a cause
        of hyperlysinemia.
- term:
    id: GO:0047131
    label: saccharopine dehydrogenase (NAD+, L-glutamate-forming) activity
  evidence_type: IMP
  original_reference_id: PMID:10775527
  qualifier: enables
  review:
    summary: >-
      Loss-of-function evidence: an inactivating AASS variant in a hyperlysinemia patient
      supports the SDH (EC 1.5.1.9) activity of AASS. Core molecular function.
    action: ACCEPT
    reason: >-
      Mutational (IMP) evidence links AASS to the saccharopine dehydrogenase activity of the
      lysine-degradation pathway; both AASS activities are lost in the patient.
    supported_by:
    - reference_id: PMID:10775527
      supporting_text: >-
        we propose that AASS catalyzes the first two steps of the major lysine-degradation
        pathway in human cells and that inactivating mutations in the AASS gene are a cause
        of hyperlysinemia.
- term:
    id: GO:0000122
    label: negative regulation of transcription by RNA polymerase II
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      ISS transfer from the Drosophila ortholog dLKR/SDH (UniProtKB:Q9VLX0), which was
      reported to have a nuclear/transcriptional moonlighting role in fly. No experimental
      support in human, and the assignment conflicts with the established mitochondrial-matrix
      metabolic localization of the human enzyme.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      This is a species-specific moonlighting function reported for the Drosophila protein,
      transferred by sequence similarity from a single non-mammalian ortholog. Human AASS
      is a mitochondrial-matrix enzyme with no evidence for transcriptional regulation; the
      transferred nuclear role is not validated for human and is not a core function.
      Per curation policy this ISS transfer is marked as over-annotated rather than removed.
    propagation_review:
      root_cause: PROPAGATION_BAD
      failure_modes:
      - FUNCTIONAL_DIVERGENCE
      source_entities:
      - source_id: UniProtKB:Q9VLX0
        source_label: Drosophila melanogaster LKR/SDH (dLKR/SDH)
        source_status: SUPPORTS_SOURCE_BUT_NOT_TARGET
        comment: >-
          Nuclear/transcriptional moonlighting reported for the fly enzyme; not conserved
          or validated for human AASS.
- term:
    id: GO:0003714
    label: transcription corepressor activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: >-
      ISS transfer from the Drosophila ortholog (UniProtKB:Q9VLX0) of a transcription
      corepressor moonlighting activity. Not supported for human AASS and inconsistent with
      its mitochondrial-matrix localization; also a "binding/regulatory" MF that is not the
      gene's core catalytic function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The corepressor role was described for the fly enzyme and transferred by similarity;
      there is no human experimental evidence, and a mitochondrial-matrix oxidoreductase is
      not expected to act as a nuclear transcription corepressor. Marked over-annotated.
    propagation_review:
      root_cause: PROPAGATION_BAD
      failure_modes:
      - FUNCTIONAL_DIVERGENCE
      source_entities:
      - source_id: UniProtKB:Q9VLX0
        source_label: Drosophila melanogaster LKR/SDH (dLKR/SDH)
        source_status: SUPPORTS_SOURCE_BUT_NOT_TARGET
        comment: >-
          Corepressor moonlighting activity reported for the fly enzyme; not validated for
          human AASS.
- term:
    id: GO:0004754
    label: saccharopine dehydrogenase (NAD+, L-lysine-forming) activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: >-
      ISS transfer (from Drosophila Q9VLX0) of the L-lysine-forming (biosynthetic, yeast
      Lys1-type) direction of saccharopine dehydrogenase. This is the reverse (anabolic)
      reaction; the human enzyme runs the catabolic activities (LKR GO:0047130 and
      glutamate-forming SDH GO:0047131), not lysine biosynthesis.
    action: MODIFY
    reason: >-
      Mammals do not synthesize lysine via saccharopine; AASS is catabolic. The correct
      catalytic activities are the NADP+, L-lysine-forming reductase (GO:0047130) and the
      NAD+, L-glutamate-forming dehydrogenase (GO:0047131). The lysine-forming SDH direction
      (GO:0004754) is the wrong physiological direction for the human enzyme.
    proposed_replacement_terms:
    - id: GO:0047131
      label: saccharopine dehydrogenase (NAD+, L-glutamate-forming) activity
    supported_by:
    - reference_id: file:human/AASS/AASS-uniprot.txt
      supporting_text: >-
        the lysine ketoglutarate reductase and saccharopine dehydrogenase
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: >-
      ISS transfer of cytosolic localization from the Drosophila ortholog (UniProtKB:Q9VLX0),
      likely associated with the reported fly moonlighting role. Contradicts the
      mitochondrial-matrix localization of human AASS.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Human AASS has an N-terminal mitochondrial transit peptide and is experimentally
      localized to the mitochondrial matrix; a cytosolic localization transferred from a fly
      ortholog is not supported and conflicts with the core compartment. Marked over-annotated.
    propagation_review:
      root_cause: PROPAGATION_BAD
      failure_modes:
      - COMPARTMENT_OR_COMPLEX_MISMATCH
      source_entities:
      - source_id: UniProtKB:Q9VLX0
        source_label: Drosophila melanogaster LKR/SDH (dLKR/SDH)
        source_status: SUPPORTS_SOURCE_BUT_NOT_TARGET
        comment: >-
          Human AASS has a mitochondrial transit peptide and matrix localization; cytosolic
          transfer is unsafe.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: >-
      ISS transfer of nuclear localization from the Drosophila ortholog (UniProtKB:Q9VLX0),
      linked to the fly transcriptional moonlighting role. No human evidence; conflicts with
      the established mitochondrial-matrix localization.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Nuclear localization is part of the Drosophila-specific moonlighting function and is
      not validated for the human mitochondrial-matrix enzyme. Marked over-annotated.
    propagation_review:
      root_cause: PROPAGATION_BAD
      failure_modes:
      - COMPARTMENT_OR_COMPLEX_MISMATCH
      source_entities:
      - source_id: UniProtKB:Q9VLX0
        source_label: Drosophila melanogaster LKR/SDH (dLKR/SDH)
        source_status: SUPPORTS_SOURCE_BUT_NOT_TARGET
        comment: >-
          Nuclear localization is part of the fly moonlighting role; not validated for the
          human mitochondrial-matrix enzyme.
- term:
    id: GO:0042393
    label: histone binding
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: >-
      ISS transfer of histone binding from the Drosophila ortholog (UniProtKB:Q9VLX0),
      associated with the reported fly chromatin/transcription moonlighting role. Not
      supported for human AASS.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Histone binding was inferred from the fly moonlighting function and transferred by
      similarity; there is no human experimental support, and it is inconsistent with the
      mitochondrial-matrix metabolic role. Marked over-annotated.
    propagation_review:
      root_cause: PROPAGATION_BAD
      failure_modes:
      - FUNCTIONAL_DIVERGENCE
      source_entities:
      - source_id: UniProtKB:Q9VLX0
        source_label: Drosophila melanogaster LKR/SDH (dLKR/SDH)
        source_status: SUPPORTS_SOURCE_BUT_NOT_TARGET
        comment: >-
          Histone binding tied to the fly chromatin moonlighting role; not validated for
          human AASS.
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: TAS
  original_reference_id: PMID:10567240
  qualifier: located_in
  review:
    summary: >-
      Author statement (TAS) that the bifunctional LKR/SDH enzyme is a mitochondrial protein,
      based on sequence analysis of the mammalian (mouse) enzyme. Consistent with the human
      mitochondrial localization.
    action: ACCEPT
    reason: >-
      Corroborates mitochondrial localization; the paper characterizes the mammalian
      bifunctional LKR/SDH and infers a mitochondrial targeting sequence.
    supported_by:
    - reference_id: PMID:10567240
      supporting_text: >-
        the bifunctional enzyme is likely to be a mitochondrial protein.
core_functions:
- description: >-
    Lysine-ketoglutarate reductase (LKR) activity: the N-terminal domain condenses
    L-lysine with 2-oxoglutarate to form L-saccharopine, using NADPH, as the first
    committed step of the saccharopine pathway of L-lysine degradation in the
    mitochondrial matrix.
  molecular_function:
    id: GO:0047130
    label: saccharopine dehydrogenase (NADP+, L-lysine-forming) activity
  directly_involved_in:
  - id: GO:0019477
    label: L-lysine catabolic process
  locations:
  - id: GO:0005759
    label: mitochondrial matrix
  supported_by:
  - reference_id: PMID:463877
    supporting_text: >-
      In all instances there was a deficiency in lysine-ketoglutarate reductase,
      saccharopine dehydrogenase, and saccharopine oxidoreductase activities.
  - reference_id: PMID:10775527
    supporting_text: >-
      The first two steps in the mammalian lysine-degradation pathway are catalyzed by
      lysine-ketoglutarate reductase and saccharopine dehydrogenase, respectively,
      resulting in the conversion of lysine to alpha-aminoadipic semialdehyde.
- description: >-
    Saccharopine dehydrogenase (SDH) activity: the C-terminal domain oxidizes
    L-saccharopine to L-2-aminoadipate-6-semialdehyde (alpha-aminoadipic semialdehyde)
    and L-glutamate, reducing NAD+, as the second step of the saccharopine pathway of
    L-lysine degradation in the mitochondrial matrix.
  molecular_function:
    id: GO:0047131
    label: saccharopine dehydrogenase (NAD+, L-glutamate-forming) activity
  directly_involved_in:
  - id: GO:0019477
    label: L-lysine catabolic process
  locations:
  - id: GO:0005759
    label: mitochondrial matrix
  supported_by:
  - reference_id: PMID:463877
    supporting_text: >-
      In all instances there was a deficiency in lysine-ketoglutarate reductase,
      saccharopine dehydrogenase, and saccharopine oxidoreductase activities.
  - reference_id: PMID:10775527
    supporting_text: >-
      The first two steps in the mammalian lysine-degradation pathway are catalyzed by
      lysine-ketoglutarate reductase and saccharopine dehydrogenase, respectively,
      resulting in the conversion of lysine to alpha-aminoadipic semialdehyde.
references:
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      ISS pipeline reference. The transferred nuclear/transcriptional and lysine-forming
      annotations derive from the Drosophila ortholog (UniProtKB:Q9VLX0) and are not
      supported for human AASS.
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      PAN-GO/IBA pipeline; correctly recovers the core saccharopine-pathway function and
      lysine catabolic process.
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: SubCell keyword mapping to mitochondrion; consistent with experimental data.
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Ensembl Compara transfer from mouse Q99K67; correctly places AASS in the mitochondrial matrix.
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      ARBA/RHEA/EC mapping recovering both catalytic activities (EC 1.5.1.8 and 1.5.1.9);
      consistent with UniProt and experimental annotations.
- id: PMID:10567240
  title: 'Lysine degradation through the saccharopine pathway in mammals: involvement
    of both bifunctional and monofunctional lysine-degrading enzymes in mouse.'
  findings:
  - statement: >-
      Characterizes a mammalian (mouse) bifunctional lysine-oxoglutarate
      reductase/saccharopine dehydrogenase and infers mitochondrial localization; also
      reports starvation induction.
    reference_section_type: ABSTRACT
    supporting_text: >-
      the bifunctional enzyme is likely to be a mitochondrial protein.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Establishes the mammalian bifunctional LKR/SDH and its mitochondrial
      localization and starvation induction (ortholog of human AASS).
- id: PMID:10775527
  title: Identification of the alpha-aminoadipic semialdehyde synthase gene, which
    is defective in familial hyperlysinemia.
  findings:
  - statement: >-
      Identifies human AASS as a bifunctional enzyme (N-terminal LKR ~ yeast LYS1,
      C-terminal SDH ~ yeast LYS9) catalyzing the first two steps of lysine degradation;
      inactivating mutations cause hyperlysinemia.
    reference_section_type: ABSTRACT
    supporting_text: >-
      we propose that AASS catalyzes the first two steps of the major lysine-degradation
      pathway in human cells and that inactivating mutations in the AASS gene are a cause
      of hyperlysinemia.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Defining reference for the human gene, its bifunctional domain
      organization, and the disease link (HYPLYS1).
- id: PMID:34800366
  title: Quantitative high-confidence human mitochondrial proteome and its dynamics
    in cellular context.
  findings:
  - statement: AASS is a member of the high-confidence human mitochondrial proteome (MitoCoP).
    reference_section_type: ABSTRACT
    supporting_text: >-
      mitochondrial high-confidence proteome of >1,100 proteins (MitoCoP)
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified proteomics dataset; supports mitochondrial localization at proteome
      scale (HTP evidence).
- id: PMID:463877
  title: 'Familial hyperlysinemia: enzyme studies, diagnostic methods, comments on
    terminology.'
  findings:
  - statement: >-
      Enzyme studies in hyperlysinemia patients show combined deficiency of
      lysine-ketoglutarate reductase and saccharopine dehydrogenase; the activities
      co-purify from human liver and localize to the same protein.
    reference_section_type: ABSTRACT
    supporting_text: >-
      In all instances there was a deficiency in lysine-ketoglutarate reductase,
      saccharopine dehydrogenase, and saccharopine oxidoreductase activities.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Experimental basis for both AASS enzyme activities and for the
      type I / saccharopinuria distinction.
- id: Reactome:R-HSA-70938
  title: lysine + alpha-ketoglutarate +NADPH + H+ => saccharopine + NADP+ + H2O
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Reactome reaction for the LKR step; localized to the mitochondrial matrix.
- id: Reactome:R-HSA-70940
  title: saccharopine + NAD+ + H2O => alpha-aminoadipic semialdehyde + glutamate +
    NADH + H+
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Reactome reaction for the SDH step; localized to the mitochondrial matrix.
proposed_new_terms: []
suggested_questions:
- question: >-
    Does human AASS have any validated moonlighting function outside the mitochondrion (e.g.
    a nuclear/transcriptional role analogous to that reported for the Drosophila ortholog),
    or is such a role restricted to insects?
suggested_experiments:
- description: >-
    Test whether endogenous AASS is detectable in the nucleus of human cells and whether it
    associates with chromatin or represses transcription, to determine if the Drosophila-derived
    transcriptional moonlighting annotations are conserved in humans.