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. file:interpro/panther/PTHR43069/PTHR43069-paint.tsv PTHR43069 PTN002453799 GO:0006572 P IBD false |
| 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 file:interpro/panther/PTHR43069/PTHR43069-paint.tsv PTHR43069 PTN002453799 GO:0004334 F IBD false |
| 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 file:interpro/panther/PTHR43069/PTHR43069-paint.tsv PTHR43069 PTN002453799 GO:0006559 P IBD false |
| GO:1902000 homogentisate catabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically inferred involvement in homogentisate catabolism. Homogentisate is ring-cleaved by HGD to maleylacetoacetate, isomerized by GSTZ1 to 4-fumarylacetoacetate, and FAH hydrolyzes that to fumarate and acetoacetate, completing homogentisate breakdown. Reason: A catabolic process term covers every step from the named substrate to its end products, so FAH, which catalyzes the final hydrolytic step of the homogentisate branch, does part of the work of homogentisate catabolism. This is the same logic by which FAH is accepted for L-tyrosine catabolic process (where it acts five steps after tyrosine), and GO:1902000 is in fact the narrowest pathway term describing FAH's step. The PAINT IBD node PTN002453799 is seeded by the experimentally characterized Arabidopsis FAH, and the bacterial ortholog HmgB is experimentally placed in the homogentisate central pathway (PMID:15262943). Accepted as core; an earlier draft had this as non-core, which was inconsistent with accepting the tyrosine-catabolic terms. Supporting Evidence: file:interpro/panther/PTHR43069/PTHR43069-paint.tsv PTHR43069 PTN002453799 GO:1902000 P IBD false Reactome:R-HSA-71181 Fumarylacetoacetase catalyzes the hydrolysis of 4-fumarylacetoacetate (4FAA) to form fumarate and acetoacetate. |
| GO:0003824 catalytic activity | IEA GO_REF:0000002 | MODIFY | Summary: InterPro2GO electronic annotation to the root molecular-function catalytic term. Reason: GO:0003824 is the top-level catalytic activity term. It is true of FAH but far less specific than the evidence supports; the specific activity (fumarylacetoacetase, GO:0004334, a descendant of catalytic activity) is experimentally supported and already annotated to the gene, so the term is refined to it. Proposed replacements: fumarylacetoacetase activity Supporting Evidence: PMID:1998338 having enzymatic activity as shown by the hydrolysis of the natural substrate fumarylacetoacetate |
| 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 | MODIFY | 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, but it is less specific than the evidence supports. Both L-tyrosine catabolic process (GO:0006572) and L-phenylalanine catabolic process (GO:0006559) are is_a descendants (via aromatic amino acid catabolic process) and are already annotated to FAH, so the term is refined to both. Proposed replacements: L-tyrosine catabolic process L-phenylalanine catabolic 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. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: Bare protein binding from a high-throughput binary interactome (Y2H) screen; interactors include TCF4 and keratin-associated proteins. Reason: Bare protein binding from a genome-scale binary interactome map (Y2H). The GOA rows for this reference cover five partners (WITH/FROM P15884 TCF4, P26371 KRTAP5-9, P60410 KRTAP10-8, Q53GC0 SERTAD1, Q6UY14-3 ADAMTSL4), none of which has a known functional relationship to a cytosolic tyrosine-catabolic hydrolase, and the screen reports no activity that could support a more informative molecular-function term. Per the protein-binding policy the generic GO:0005515 annotation is removed as uninformative; removal does not assert that the reported interactions are false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Bare protein binding from the HuRI binary reference interactome (Y2H); interactors in GOA are CHRDL2, KRTAP13-3 and PLEKHF2. Reason: As with PMID:25416956, this is a bare protein binding annotation from a systematic binary interactome screen (Y2H). The GOA rows for this reference cover three partners (WITH/FROM Q3SY46 KRTAP13-3, Q6WN34-2 CHRDL2, Q9H8W4 PLEKHF2) with no functional relationship to FAH's enzymatic role, and no informative molecular-function term is supported. Removed per the protein-binding policy as uninformative; removal does not assert that the interactions are false. |
| 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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