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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0006572 L-tyrosine catabolic process | IBA GO_REF:0000033 | ACCEPT | 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. 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. Supporting Evidence: PMID:9305902 HT1 is due to mutations in the fumarylacetoacetate hydrolase gene Fah, encoding the last enzyme in the tyrosine catabolic pathway. |
| GO:0004334 fumarylacetoacetase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically inferred fumarylacetoacetase (EC 3.7.1.2) activity. This is the core molecular function of FAH. 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. Supporting Evidence: PMID:1998338 having enzymatic activity as shown by the hydrolysis of the natural substrate fumarylacetoacetate |
| GO:0006559 L-phenylalanine catabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically inferred involvement in L-phenylalanine catabolism. Phenylalanine is catabolized via conversion to tyrosine, so FAH is the terminal step of both pathways. 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. Supporting Evidence: PMID:1998338 having enzymatic activity as shown by the hydrolysis of the natural substrate fumarylacetoacetate |
| GO:1902000 homogentisate catabolic process | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetically inferred involvement in homogentisate catabolism. Homogentisate is a tyrosine-pathway intermediate several steps upstream of FAH's substrate. 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. |
| GO:0003824 catalytic activity | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: InterPro2GO electronic annotation to the root molecular-function catalytic term. 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. |
| GO:0004334 fumarylacetoacetase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic annotation (combined IEA pipeline, keyed to RHEA:10244 / EC 3.7.1.2) to the core fumarylacetoacetase activity term. 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. |
| GO:0009072 aromatic amino acid metabolic process | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro2GO electronic annotation to the broad aromatic amino acid metabolic process grouping term. 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. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MARK AS OVER ANNOTATED | Summary: Bare protein binding from a high-throughput binary interactome (Y2H) screen; interactors include TCF4 and keratin-associated proteins. 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). |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: Bare protein binding from the HuRI binary reference interactome (Y2H); interactors include ADAMTSL4, CHRDL2, KRTAP13-3, PLEKHF2, SERTAD1. 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. |
| GO:0006572 L-tyrosine catabolic process | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl-Compara ortholog-transfer IEA of tyrosine catabolic process from the mouse ortholog (P35505). 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. |
| GO:0006559 L-phenylalanine catabolic process | IEA GO_REF:0000041 | ACCEPT | Summary: UniPathway-derived electronic annotation to L-phenylalanine catabolic process (UniPathway UPA00139). 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. |
| GO:0070062 extracellular exosome | HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres... | KEEP AS NON CORE | Summary: High-throughput mass-spectrometry detection of FAH in prostatic-secretion (urinary) exosome preparations. 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. Supporting Evidence: PMID:23533145 In pooled EPS-urine exosome samples, ~900 proteins were detected. |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | KEEP AS NON CORE | Summary: High-throughput mass-spectrometry detection of FAH in human urinary exosome proteome. 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. Supporting Evidence: PMID:19056867 the analysis identified 1132 proteins unambiguously |
| GO:0005829 cytosol | TAS Reactome:R-HSA-71181 | ACCEPT | Summary: Traceable assertion (Reactome) that FAH acts in the cytosol, where the final step of tyrosine degradation occurs. 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. Supporting Evidence: Reactome:R-HSA-71181 This is the final step of tyrosine degradation. |
| GO:0004334 fumarylacetoacetase activity | TAS PMID:1998338 Cloning and expression of the cDNA encoding human fumarylace... | ACCEPT | Summary: Traceable assertion of fumarylacetoacetase activity from the human FAH cDNA cloning and expression study, which demonstrated hydrolysis of the natural substrate. Reason: Expression of the human FAH cDNA yielded a protein with fumarylacetoacetase enzymatic activity, directly supporting the core molecular function annotation. Supporting Evidence: PMID:1998338 having enzymatic activity as shown by the hydrolysis of the natural substrate fumarylacetoacetate |
| GO:0006572 L-tyrosine catabolic process | TAS PMID:9305902 Complete rescue of lethal albino c14CoS mice by null mutatio... | ACCEPT | 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. 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. Supporting Evidence: PMID:9305902 HT1 is due to mutations in the fumarylacetoacetate hydrolase gene Fah, encoding the last enzyme in the tyrosine catabolic pathway. |
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