id: P16930
gene_symbol: FAH
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  FAH encodes fumarylacetoacetase (fumarylacetoacetate hydrolase, EC 3.7.1.2), the enzyme
  that catalyzes the fifth and final step of the cytosolic L-tyrosine and L-phenylalanine
  catabolic pathway: the hydrolysis of 4-fumarylacetoacetate to fumarate plus acetoacetate.
  It is a homodimer, with each subunit using a bound Ca(2+) and Mg(2+) ion as catalytic
  cofactors, and is expressed mainly in liver and kidney with lower levels in other tissues.
  By clearing 4-fumarylacetoacetate, FAH prevents accumulation of this reactive intermediate
  and the upstream metabolite maleylacetoacetate, feeding fumarate into the citric acid cycle
  and acetoacetate into ketone-body/lipid metabolism. Loss-of-function variants cause
  hepatorenal tyrosinemia type I (TYRSN1), the most severe tyrosinemia, in which accumulated
  fumarylacetoacetate, maleylacetoacetate, and the derived toxin succinylacetone drive
  hepatocyte apoptosis, cirrhosis, hepatocellular carcinoma risk, and renal tubular
  dysfunction.
alternative_products:
- name: '1'
  id: P16930-1
- name: '2'
  id: P16930-2
  sequence_note: VSP_055491
existing_annotations:
- term:
    id: GO:0006572
    label: L-tyrosine catabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetically inferred involvement of FAH in L-tyrosine catabolism. FAH is the
      terminal (fifth) enzyme of the tyrosine degradation pathway, and this is a core
      biological-process annotation.
    action: ACCEPT
    reason: >-
      FAH catalyzes the last step of tyrosine catabolism, hydrolyzing 4-fumarylacetoacetate
      to fumarate and acetoacetate; this is well supported experimentally and is the defining
      role of the gene. The IBA is consistent with the whole FAH family and with the direct
      human evidence.
    supported_by:
    - reference_id: PMID:9305902
      supporting_text: >-
        HT1 is due to mutations in the fumarylacetoacetate hydrolase gene Fah, encoding the
        last enzyme in the tyrosine catabolic pathway.
- term:
    id: GO:0004334
    label: fumarylacetoacetase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetically inferred fumarylacetoacetase (EC 3.7.1.2) activity. This is the
      core molecular function of FAH.
    action: ACCEPT
    reason: >-
      Direct enzymatic activity is documented for human FAH and the term matches the
      catalyzed reaction exactly (4-fumarylacetoacetate + H2O = acetoacetate + fumarate + H+).
      The IBA is at the correct level of specificity.
    supported_by:
    - reference_id: PMID:1998338
      supporting_text: >-
        having enzymatic activity as shown by the hydrolysis of the natural substrate
        fumarylacetoacetate
- term:
    id: GO:0006559
    label: L-phenylalanine catabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetically inferred involvement in L-phenylalanine catabolism. Phenylalanine is
      catabolized via conversion to tyrosine, so FAH is the terminal step of both pathways.
    action: ACCEPT
    reason: >-
      UniProt places FAH as the final step (step 6/6) of L-phenylalanine degradation to
      acetoacetate and fumarate (UniPathway UPA00139). The annotation is correct, though the
      phenylalanine framing is one metabolic conversion removed from FAH's direct substrate;
      the more direct role is captured by L-tyrosine catabolic process.
    supported_by:
    - reference_id: PMID:1998338
      supporting_text: >-
        having enzymatic activity as shown by the hydrolysis of the natural substrate
        fumarylacetoacetate
- term:
    id: GO:1902000
    label: homogentisate catabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetically inferred involvement in homogentisate catabolism. Homogentisate is a
      tyrosine-pathway intermediate several steps upstream of FAH's substrate.
    action: KEEP_AS_NON_CORE
    reason: >-
      FAH acts on 4-fumarylacetoacetate, three enzymatic steps downstream of homogentisate
      (which is ring-cleaved by HGD to maleylacetoacetate). This IBA reflects a pathway-level
      grouping propagated across the FAH family rather than a direct role of FAH in
      homogentisate breakdown. It is not wrong at the whole-pathway level but is broader than
      FAH's actual biochemical step, so it is retained as non-core.
- term:
    id: GO:0003824
    label: catalytic activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      InterPro2GO electronic annotation to the root molecular-function catalytic term.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      GO:0003824 is the top-level catalytic activity term and is uninformative for FAH, whose
      specific activity (fumarylacetoacetase, GO:0004334) is already annotated with stronger
      evidence. It is not incorrect, but it is an over-general mapping superseded by the
      specific EC 3.7.1.2 term.
- term:
    id: GO:0004334
    label: fumarylacetoacetase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Electronic annotation (combined IEA pipeline, keyed to RHEA:10244 / EC 3.7.1.2) to the
      core fumarylacetoacetase activity term.
    action: ACCEPT
    reason: >-
      This IEA maps FAH to its correct catalyzed reaction via RHEA:10244 and EC 3.7.1.2, in
      agreement with the IBA and TAS annotations to the same term. Redundant but correct.
- term:
    id: GO:0009072
    label: aromatic amino acid metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      InterPro2GO electronic annotation to the broad aromatic amino acid metabolic process
      grouping term.
    action: KEEP_AS_NON_CORE
    reason: >-
      Tyrosine and phenylalanine are aromatic amino acids, so FAH's catabolic role legitimately
      falls under this grouping term. However it is more general than the specific tyrosine and
      phenylalanine catabolic process annotations that better describe FAH, so it is retained
      as non-core.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: >-
      Bare protein binding from a high-throughput binary interactome (Y2H) screen; interactors
      include TCF4 and keratin-associated proteins.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      This is an uninformative bare protein binding annotation from a genome-scale binary
      interactome map (the human interactome network / HuRI project). The reported partners
      (e.g. TCF4, keratin-associated proteins) have no plausible functional relationship to a
      cytosolic tyrosine-catabolic hydrolase and are typical high-throughput Y2H hits. Per
      curation guidelines this bare protein binding conveys no specific molecular function; it
      is retained but flagged as an over-annotation (not removed, as it is an experimental IPI).
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      Bare protein binding from the HuRI binary reference interactome (Y2H); interactors
      include ADAMTSL4, CHRDL2, KRTAP13-3, PLEKHF2, SERTAD1.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      As with PMID:25416956, this is an uninformative bare protein binding annotation from a
      systematic binary interactome screen. The partners are unrelated to FAH's enzymatic
      function and are consistent with high-throughput screening artifacts. Retained but flagged
      as an over-annotation (not removed, as it is an experimental IPI) per the guideline
      discouraging bare protein binding.
- term:
    id: GO:0006572
    label: L-tyrosine catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Ensembl-Compara ortholog-transfer IEA of tyrosine catabolic process from the mouse
      ortholog (P35505).
    action: ACCEPT
    reason: >-
      This transfers a correct annotation (L-tyrosine catabolic process) from the mouse
      ortholog Fah. It is redundant with the IBA and TAS annotations to the same term and is
      at the appropriate level of specificity, so it is accepted despite being an
      ortholog-transfer inference.
- term:
    id: GO:0006559
    label: L-phenylalanine catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000041
  qualifier: involved_in
  review:
    summary: >-
      UniPathway-derived electronic annotation to L-phenylalanine catabolic process
      (UniPathway UPA00139).
    action: ACCEPT
    reason: >-
      UniProt records FAH as step 6/6 of L-phenylalanine degradation to acetoacetate and
      fumarate (UPA00139/UER00341). This IEA correctly reflects that pathway placement and is
      consistent with the IBA to the same term.
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:23533145
  qualifier: located_in
  review:
    summary: >-
      High-throughput mass-spectrometry detection of FAH in prostatic-secretion (urinary)
      exosome preparations.
    action: KEEP_AS_NON_CORE
    reason: >-
      FAH was cataloged among ~900 proteins in a shotgun proteomic survey of urinary exosomes.
      This is a bulk proteomics detection rather than a functional localization; FAH is
      fundamentally a cytosolic liver/kidney enzyme. The annotation is retained as a non-core
      secondary location observation.
    supported_by:
    - reference_id: PMID:23533145
      supporting_text: >-
        In pooled EPS-urine exosome samples, ~900 proteins were detected.
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19056867
  qualifier: located_in
  review:
    summary: >-
      High-throughput mass-spectrometry detection of FAH in human urinary exosome proteome.
    action: KEEP_AS_NON_CORE
    reason: >-
      FAH was among 1132 proteins identified in a large-scale proteomic profile of human
      urinary exosomes. As with PMID:23533145, this is a proteomic catalog detection, not a
      functional site of action; kept as non-core relative to the core cytosolic localization.
    supported_by:
    - reference_id: PMID:19056867
      supporting_text: >-
        the analysis identified 1132 proteins unambiguously
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-71181
  qualifier: located_in
  review:
    summary: >-
      Traceable assertion (Reactome) that FAH acts in the cytosol, where the final step of
      tyrosine degradation occurs.
    action: ACCEPT
    reason: >-
      FAH is a cytosolic enzyme catalyzing the terminal cytosolic step of tyrosine/phenylalanine
      catabolism. This is the core subcellular localization and is well established.
    supported_by:
    - reference_id: Reactome:R-HSA-71181
      supporting_text: This is the final step of tyrosine degradation.
- term:
    id: GO:0004334
    label: fumarylacetoacetase activity
  evidence_type: TAS
  original_reference_id: PMID:1998338
  qualifier: enables
  review:
    summary: >-
      Traceable assertion of fumarylacetoacetase activity from the human FAH cDNA cloning and
      expression study, which demonstrated hydrolysis of the natural substrate.
    action: ACCEPT
    reason: >-
      Expression of the human FAH cDNA yielded a protein with fumarylacetoacetase enzymatic
      activity, directly supporting the core molecular function annotation.
    supported_by:
    - reference_id: PMID:1998338
      supporting_text: >-
        having enzymatic activity as shown by the hydrolysis of the natural substrate
        fumarylacetoacetate
- term:
    id: GO:0006572
    label: L-tyrosine catabolic process
  evidence_type: TAS
  original_reference_id: PMID:9305902
  qualifier: involved_in
  review:
    summary: >-
      Traceable assertion that FAH is the last enzyme of the tyrosine catabolic pathway,
      based on the Fah-deficient mouse model of tyrosinemia type 1.
    action: ACCEPT
    reason: >-
      This annotation is directly supported: FAH encodes the last enzyme in tyrosine
      catabolism, and its loss causes accumulation of toxic pathway intermediates. Core
      biological process.
    supported_by:
    - reference_id: PMID:9305902
      supporting_text: >-
        HT1 is due to mutations in the fumarylacetoacetate hydrolase gene Fah, encoding the
        last enzyme in the tyrosine catabolic pathway.
core_functions:
- description: >-
    Fumarylacetoacetase catalyzing the terminal step of cytosolic tyrosine/phenylalanine
    catabolism: hydrolysis of 4-fumarylacetoacetate to fumarate and acetoacetate.
  molecular_function:
    id: GO:0004334
    label: fumarylacetoacetase activity
  directly_involved_in:
  - id: GO:0006572
    label: L-tyrosine catabolic process
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:1998338
    supporting_text: >-
      having enzymatic activity as shown by the hydrolysis of the natural substrate
      fumarylacetoacetate
  - reference_id: PMID:9305902
    supporting_text: >-
      HT1 is due to mutations in the fumarylacetoacetate hydrolase gene Fah, encoding the
      last enzyme in the tyrosine catabolic pathway.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  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:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs
    using Ensembl Compara
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:19056867
  title: Large-scale proteomics and phosphoproteomics of urinary exosomes.
  findings:
  - statement: >-
      FAH was among 1132 proteins identified in a large-scale proteomic profile of human
      urinary exosomes; a bulk proteomics detection rather than a functional localization.
    supporting_text: >-
      the analysis identified 1132 proteins unambiguously
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Abstract-verified. Supports HDA extracellular-exosome detection of FAH but is a
      proteomic catalog, not evidence of functional localization for a cytosolic enzyme.
- id: PMID:1998338
  title: 'Cloning and expression of the cDNA encoding human fumarylacetoacetate hydrolase,
    the enzyme deficient in hereditary tyrosinemia: assignment of the gene to chromosome
    15.'
  findings:
  - statement: >-
      Human FAH cDNA expressed in mammalian cells produces an enzymatically active protein
      that hydrolyzes the natural substrate fumarylacetoacetate; the in vivo dimer is a
      homodimer.
    supporting_text: >-
      having enzymatic activity as shown by the hydrolysis of the natural substrate
      fumarylacetoacetate
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Abstract-verified; establishes human FAH catalyzes the fumarylacetoacetate hydrolysis
      reaction (core MF) and maps the gene to chromosome 15q23-q25.
- id: PMID:23533145
  title: In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions
    in urine.
  findings:
  - statement: >-
      FAH was cataloged among ~900 proteins in a shotgun proteomic survey of prostatic-secretion
      (urinary) exosomes.
    supporting_text: >-
      In pooled EPS-urine exosome samples, ~900 proteins were detected.
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Abstract-verified. Bulk exosome proteomics; supports HDA extracellular-exosome
      detection but not a core functional localization.
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings:
  - statement: >-
      Genome-scale binary interactome (Y2H) map reporting FAH interactions with partners
      unrelated to its enzymatic function.
    supporting_text: A proteome-scale map of the human interactome network.
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Correctly cited high-throughput binary interactome screen. Yields only uninformative
      bare protein binding with functionally unrelated partners; annotation recommended for
      removal.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings:
  - statement: >-
      HuRI binary reference interactome (Y2H) reporting FAH interactions with functionally
      unrelated partners (e.g. ADAMTSL4, CHRDL2, KRTAPs, PLEKHF2, SERTAD1).
    supporting_text: A reference map of the human binary protein interactome.
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Correctly cited systematic binary interactome map; only supports bare protein binding
      with unrelated partners, recommended for removal.
- id: PMID:9305902
  title: Complete rescue of lethal albino c14CoS mice by null mutation of 4-hydroxyphenylpyruvate
    dioxygenase and induction of apoptosis of hepatocytes in these mice by in vivo retrieval
    of the tyrosine catabolic pathway.
  findings:
  - statement: >-
      Fah encodes the last enzyme of the tyrosine catabolic pathway; its loss causes
      accumulation of fumarylacetoacetate, maleylacetoacetate, and succinylacetone that
      trigger hepatocyte apoptosis, the mouse model of tyrosinemia type 1.
    supporting_text: >-
      HT1 is due to mutations in the fumarylacetoacetate hydrolase gene Fah, encoding the
      last enzyme in the tyrosine catabolic pathway.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Abstract-verified. Establishes FAH's pathway position (terminal tyrosine-catabolic
      enzyme) and the toxic-metabolite/apoptosis mechanism of tyrosinemia type 1.
- id: Reactome:R-HSA-71181
  title: FAH cleaves 4FAA
  findings:
  - statement: >-
      Reactome reaction: FAH (a cytosolic homodimer using Ca2+ and Mg2+ cofactors) catalyzes
      the final step of tyrosine degradation, hydrolyzing 4-fumarylacetoacetate to fumarate
      and acetoacetate.
    supporting_text: This is the final step of tyrosine degradation.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Cached Reactome entry describing the FAH-catalyzed terminal reaction and cytosolic
      localization; consistent with UniProt catalytic/cofactor/subunit annotations.