FH (fumarate hydratase, fumarase; EC 4.2.1.2) is a class II, iron-independent enzyme that forms a homotetramer and catalyses the reversible conversion of fumarate and L-malate. The mitochondrial product supplies the fumarate-to-malate step of the tricarboxylic acid cycle; a shorter natural product lacks the N-terminal targeting sequence and supports extramitochondrial fumarate metabolism. Cytosolic FH controls fumarate abundance and its coupling to arginine and urea-cycle metabolism. In FH-deficient renal models, excess fumarate drives reversed argininosuccinate lyase flux and abnormal argininosuccinate accumulation. After DNA damage, nuclear FH is phosphorylated by DNA-PK at Thr236 and binds histone H2A.Z at double-strand breaks. Local fumarate production inhibits KDM2B-mediated H3K36 demethylation, supporting repair-factor accumulation and nonhomologous end joining. FH is also a tumour suppressor: inherited heterozygous loss-of-function variants predispose to hereditary leiomyomatosis and renal cell cancer following somatic inactivation of the remaining allele. Fumarate accumulation can inhibit 2-oxoglutarate-dependent dioxygenases and succinate protein cysteines. Biallelic defects cause fumarase deficiency, a severe metabolic encephalopathy.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000050 urea cycle | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl Compara transfer of urea cycle from mouse Fh1 (P97807). Reason: Retain the curated mouse-to-human inference as a peripheral metabolic coupling. In PMID:23643539, cytosol-restricted human FH expressed in mouse renal models and human UOK262 cells lowers fumarate and argininosuccinate abnormalities (Figures 2-4); isotope tracing identifies reversed ASL flux in FH deficiency. FH performs fumarate/malate chemistry that controls this coupling, whereas ASL performs the arginine/argininosuccinate conversion. These experiments do not demonstrate that FH is an ornithine-cycle enzyme or establish dominant normal-tissue flux. The engineered FHcyt construct is not assigned to a natural isoform by name alone. Supporting Evidence: PMID:27554470 Cytosolic FH acts in the urea cycle (19), principally in liver and kidney (20) but not in adipose tissue. PMID:24280230 Argininosuccinate was found to be produced from arginine and fumarate by the reverse activity of the urea cycle enzyme argininosuccinate lyase (ASL), making these cells auxotrophic for arginine. file:human/FH/FH-source-evidence.md |
| GO:0000050 urea cycle | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Curator ISS transfer of urea cycle from mouse Fh1 (P97807). Reason: Retain the curated mouse-to-human inference as a peripheral metabolic coupling. In PMID:23643539, cytosol-restricted human FH expressed in mouse renal models and human UOK262 cells lowers fumarate and argininosuccinate abnormalities (Figures 2-4); isotope tracing identifies reversed ASL flux in FH deficiency. FH performs fumarate/malate chemistry that controls this coupling, whereas ASL performs the arginine/argininosuccinate conversion. These experiments do not demonstrate that FH is an ornithine-cycle enzyme or establish dominant normal-tissue flux. The engineered FHcyt construct is not assigned to a natural isoform by name alone. Supporting Evidence: PMID:27554470 Cytosolic FH acts in the urea cycle (19), principally in liver and kidney (20) but not in adipose tissue. PMID:24280230 Argininosuccinate was found to be produced from arginine and fumarate by the reverse activity of the urea cycle enzyme argininosuccinate lyase (ASL), making these cells auxotrophic for arginine. file:human/FH/FH-source-evidence.md |
| GO:0003824 catalytic activity | IEA GO_REF:0000002 | MODIFY | Summary: InterPro2GO mapping to the root catalytic activity term. Reason: Correct but uninformative; FH has a well-established specific activity (EC 4.2.1.2, fumarate hydratase activity), which should replace the root term. Proposed replacements: fumarate hydratase activity Supporting Evidence: PMID:30761759 Fumarate hydratases (FHs, fumarases) catalyze the reversible conversion of fumarate into l-malate. |
| GO:0004333 fumarate hydratase activity | IBA GO_REF:0000033 | ACCEPT | Summary: IBA from PANTHER node PTN000154499 (class II fumarase family; donors include human FH, mouse Fh1, rat Fh, yeast FUM1, Arabidopsis FUM1/FUM2, E. coli FumC). Reason: FH catalyses reversible fumarate/L-malate interconversion. The preserved PTHR11444 PAINT slice records a positive IBD at PTN000154499 for this activity, including human experimental input; target self-inclusion is not circularity. Direct recombinant human kinetics in PMID:29456767 support the catalytic claim independently. A308T and H318Y strongly reduce, rather than uniformly abolish, measured activity. The comparative mitochondrial study supplies family context, not an independent reconstruction of this PAINT placement. Supporting Evidence: PMID:30761759 Fumarate hydratases (FHs, fumarases) catalyze the reversible conversion of fumarate into l-malate. PMID:42822426 LECA mitochondria also contained multiple pairs of non-homologous enzymes with similar activities, such as class I and class II FHs, CDP-type and PLD-type CLSs, and the ClpXP and ClpYQ proteases |
| GO:0004333 fumarate hydratase activity | IDA PMID:30761759 Structural, biochemical and biophysical characterization of ... | ACCEPT | Summary: Recombinant human FH kinetics and crystal structure. Reason: FH catalyses the reversible stereospecific hydration of fumarate to L-malate (EC 4.2.1.2); this is the defining activity of the gene product, supported by direct kinetics on recombinant human FH and by disease variants that severely reduce activity. Supporting Evidence: PMID:30761759 Fumarate hydratases (FHs, fumarases) catalyze the reversible conversion of fumarate into l-malate. PMID:30761759 human FH (HsFH) was characterized by using enzyme kinetics |
| GO:0004333 fumarate hydratase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Combined automated (EC/InterPro/UniRule) assignment of fumarate hydratase activity. Reason: FH catalyses the reversible stereospecific hydration of fumarate to L-malate (EC 4.2.1.2); this is the defining activity of the gene product, supported by direct kinetics on recombinant human FH and by disease variants that severely reduce activity. Supporting Evidence: PMID:30761759 Fumarate hydratases (FHs, fumarases) catalyze the reversible conversion of fumarate into l-malate. |
| GO:0004333 fumarate hydratase activity | IMP PMID:29456767 Biochemical Characterization of Two Clinically-Relevant Huma... | ACCEPT | Summary: Human FH activity depends on tetramer assembly; A308T and H318Y have severe kinetic and oligomerization defects. Reason: PMID:29456767 Figures 5-6 and Table 1 measure recombinant human FH kinetics and oligomerization. The variants show more than 900-fold lower turnover and predominantly dimeric populations, with small tetrameric fractions. The Results also distinguish recombinant A308T activity from the approximately 20% activity reported in patient fibroblasts. This directly supports fumarase activity and its assembly requirement without treating all variant measurements as absolute zero. Supporting Evidence: PMID:29456767 Fumarase, a significant enzyme of energy metabolism, catalyzes the reversible hydration of fumarate to L-malate. PMID:29456767 We conclude that A308T and H318Y render human fumarase enzymatically inactive via defective oligomerization. |
| GO:0004333 fumarate hydratase activity | ISS GO_REF:0000024 | ACCEPT | Summary: ISS transfer of fumarate hydratase activity. Reason: FH catalyses the reversible stereospecific hydration of fumarate to L-malate (EC 4.2.1.2); this is the defining activity of the gene product, supported by direct kinetics on recombinant human FH and by disease variants that severely reduce activity. Supporting Evidence: PMID:30761759 Fumarate hydratases (FHs, fumarases) catalyze the reversible conversion of fumarate into l-malate. |
| GO:0004333 fumarate hydratase activity | ISS GO_REF:0000024 | ACCEPT | Summary: ISS transfer of fumarate hydratase activity. Reason: FH catalyses the reversible stereospecific hydration of fumarate to L-malate (EC 4.2.1.2); this is the defining activity of the gene product, supported by direct kinetics on recombinant human FH and by disease variants that severely reduce activity. Supporting Evidence: PMID:30761759 Fumarate hydratases (FHs, fumarases) catalyze the reversible conversion of fumarate into l-malate. |
| GO:0004333 fumarate hydratase activity | TAS PMID:3828494 Nucleotide sequence of a cDNA coding for mitochondrial fumar... | ACCEPT | Summary: Original human liver cDNA cloning identifying mitochondrial fumarase, with strong identity to B. subtilis and E. coli FumC (class II) fumarases. Reason: FH catalyses the reversible stereospecific hydration of fumarate to L-malate (EC 4.2.1.2); this is the defining activity of the gene product, supported by direct kinetics on recombinant human FH and by disease variants that severely reduce activity. Supporting Evidence: PMID:3828494 This protein, with the exception of an N-terminal methionine, was identified as mitochondrial fumarase. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MODIFY | Summary: FH binds the serine/threonine protein kinase PIM1 in the human binary-interaction map. Reason: The exact FH/P11309 pair is represented by three positive IntAct records from PMID:25416956, covering array, prey-pooling and validated two-hybrid methods. Official UniProt identifies P11309 as PIM1, a protein kinase; GO:0019901 describes binding that partner class. This refines the measured interaction without assigning kinase activity, phosphorylation of FH, or an endogenous regulatory mechanism to FH. Proposed replacements: protein kinase binding |
| GO:0005515 protein binding | IPI PMID:26237645 Local generation of fumarate promotes DNA repair through inh... | MODIFY | Summary: Interaction with histone variant H2A.Z (H2AZ1, P0C0S5) at DNA double-strand breaks. Reason: Jiang et al. show that DNA-PK-phosphorylated FH binds H2A.Z directly (purified proteins in vitro; binding lost with the H2A.Z NKLLG alphaC-helix swap) and that this interaction recruits FH to DSB chromatin. This is a specific, functionally characterised histone interaction, so histone binding is the informative replacement for protein binding. Proposed replacements: histone binding Supporting Evidence: PMID:26237645 ionizing radiation induces DNA-PK-dependent phosphorylation of nuclear fumarase at Thr 236, which leads to an interaction between fumarase and the histone variant H2A.Z at DNA double-strand break (DSB) regions. PMID:26237645 the purified H2A.Z (NKLLG) mutant lost its binding to purified FH in vitro file:human/FH/FH-source-evidence.md |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Positive binary-interaction evidence links FH to O14787-2. Reason: The exact FH/O14787-2 pair has positive IntAct records from PMID:32296183, including two-hybrid screening and validation methods. These support the existing interaction; the related assay records are not counted as independent functional replications. No informative FH molecular role beyond the measured binding is established by this bounded source read. Retain supported generic binding as non-core under the explicit campaign instruction, without inferring the partner's function or a natural FH product specificity. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Positive binary-interaction evidence links FH to O15160. Reason: The exact FH/O15160 pair has positive IntAct records from PMID:32296183, including two-hybrid screening and validation methods. These support the existing interaction; the related assay records are not counted as independent functional replications. No informative FH molecular role beyond the measured binding is established by this bounded source read. Retain supported generic binding as non-core under the explicit campaign instruction, without inferring the partner's function or a natural FH product specificity. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Positive binary-interaction evidence links FH to P21673. Reason: The exact FH/P21673 pair has positive IntAct records from PMID:32296183, including two-hybrid screening and validation methods. These support the existing interaction; the related assay records are not counted as independent functional replications. No informative FH molecular role beyond the measured binding is established by this bounded source read. Retain supported generic binding as non-core under the explicit campaign instruction, without inferring the partner's function or a natural FH product specificity. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MODIFY | Summary: FH binds lamin-B2 in the human binary-interaction map. Reason: The exact FH/Q03252 pair has three positive IntAct records from PMID:32296183. Official UniProt identifies Q03252 as lamin-B2, matching the lamin partner class in GO:0005521. The refinement describes the interaction, not a demonstrated FH role in nuclear-lamina assembly. The three records describe related screening/validation methods, not three independent biological replications. Proposed replacements: lamin binding |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Positive binary-interaction evidence links FH to Q14129. Reason: The exact FH/Q14129 pair has positive IntAct records from PMID:32296183, including two-hybrid screening and validation methods. These support the existing interaction; the related assay records are not counted as independent functional replications. No informative FH molecular role beyond the measured binding is established by this bounded source read. Retain supported generic binding as non-core under the explicit campaign instruction, without inferring the partner's function or a natural FH product specificity. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Positive binary-interaction evidence links FH to Q2TAC2-2. Reason: The exact FH/Q2TAC2-2 pair has positive IntAct records from PMID:32296183, including two-hybrid screening and validation methods. These support the existing interaction; the related assay records are not counted as independent functional replications. No informative FH molecular role beyond the measured binding is established by this bounded source read. Retain supported generic binding as non-core under the explicit campaign instruction, without inferring the partner's function or a natural FH product specificity. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Positive binary-interaction evidence links FH to Q68D86. Reason: The exact FH/Q68D86 pair has positive IntAct records from PMID:32296183, including two-hybrid screening and validation methods. These support the existing interaction; the related assay records are not counted as independent functional replications. No informative FH molecular role beyond the measured binding is established by this bounded source read. Retain supported generic binding as non-core under the explicit campaign instruction, without inferring the partner's function or a natural FH product specificity. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Positive binary-interaction evidence links FH to Q6DKK2. Reason: The exact FH/Q6DKK2 pair has positive IntAct records from PMID:32296183, including two-hybrid screening and validation methods. These support the existing interaction; the related assay records are not counted as independent functional replications. No informative FH molecular role beyond the measured binding is established by this bounded source read. Retain supported generic binding as non-core under the explicit campaign instruction, without inferring the partner's function or a natural FH product specificity. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Positive binary-interaction evidence links FH to Q8WZ60. Reason: The exact FH/Q8WZ60 pair has positive IntAct records from PMID:32296183, including two-hybrid screening and validation methods. These support the existing interaction; the related assay records are not counted as independent functional replications. No informative FH molecular role beyond the measured binding is established by this bounded source read. Retain supported generic binding as non-core under the explicit campaign instruction, without inferring the partner's function or a natural FH product specificity. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Positive binary-interaction evidence links FH to Q9H6J7-2. Reason: The exact FH/Q9H6J7-2 pair has positive IntAct records from PMID:32296183, including two-hybrid screening and validation methods. These support the existing interaction; the related assay records are not counted as independent functional replications. No informative FH molecular role beyond the measured binding is established by this bounded source read. Retain supported generic binding as non-core under the explicit campaign instruction, without inferring the partner's function or a natural FH product specificity. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Positive binary-interaction evidence links FH to Q9NQT4. Reason: The exact FH/Q9NQT4 pair has positive IntAct records from PMID:32296183, including two-hybrid screening and validation methods. These support the existing interaction; the related assay records are not counted as independent functional replications. No informative FH molecular role beyond the measured binding is established by this bounded source read. Retain supported generic binding as non-core under the explicit campaign instruction, without inferring the partner's function or a natural FH product specificity. |
| GO:0005515 protein binding | IPI PMID:39251607 Systematic identification of post-transcriptional regulatory... | KEEP AS NON CORE | Summary: FH and EXOSC5 have BioID proximity evidence and independent binary-interaction support. Reason: The exact PMID:39251607 IntAct record EBI-56902538 uses proximity-dependent biotin identification (MI:1314; interaction type proximity), not yeast two-hybrid, and alone does not establish direct binding. The identical FH/EXOSC5 pair has positive binary-interaction records in PMID:32296183. Retain the supported generic interaction as non-core under the campaign policy, without attributing an RNA-exosome regulatory activity to FH. The 2024 correction is affiliation-only. |
| GO:0005634 nucleus | EXP PMID:20231875 Fumarase: a mitochondrial metabolic enzyme and a cytosolic/n... | ACCEPT | Summary: Immunofluorescence and fractionation in human HeLa/HCT116 cells show FH entering the nucleus after DNA damage. Reason: Yogev et al. assayed human cells directly: FH is mitochondrial and cytosolic at rest and accumulates in the nucleus within minutes of IR or HU treatment, with a dose-dependent increase in nuclear FH by fractionation. Nuclear FH is a minor, damage-induced localization pool. These experiments do not establish that this pool derives exclusively from natural product P07954-2. Supporting Evidence: PMID:20231875 Surprisingly, after both HU or IR treatments, FH is also localized in the nucleus, showing increasing nuclear levels over time. PMID:20231875 We show that the cytosolic fumarase is a member of the DNA damage response that is recruited from the cytosol to the nucleus upon DNA damage induction. |
| GO:0005634 nucleus | EXP PMID:26237645 Local generation of fumarate promotes DNA repair through inh... | ACCEPT | Summary: Fractionation in U2OS cells shows nuclear and chromatin-associated FH enhanced by IR. Reason: Supports damage-induced nuclear FH, recruited to DSB chromatin through DNA-PK phosphorylation at Thr236 and binding to H2A.Z. Supporting Evidence: PMID:26237645 Cell fractionation analyses showed that nuclear FH was much less in amount than cytosolic FH, and IR enhanced both nuclear and chromatin-associated FH PMID:26237645 ionizing radiation induces DNA-PK-dependent phosphorylation of nuclear fumarase at Thr 236, which leads to an interaction between fumarase and the histone variant H2A.Z at DNA double-strand break (DSB) regions. |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular location mapping (cytoplasmic isoform: nucleus). Reason: Consistent with experimental evidence from PMID:20231875 and PMID:26237645. Supporting Evidence: PMID:20231875 Surprisingly, after both HU or IR treatments, FH is also localized in the nucleus, showing increasing nuclear levels over time. |
| GO:0005694 chromosome | EXP PMID:26237645 Local generation of fumarate promotes DNA repair through inh... | MODIFY | Summary: Chromatin-associated FH is recruited adjacent to experimentally induced DNA double-strand breaks. Reason: PMID:26237645 reports FH chromatin association and ChIP at DNA adjacent to the defined break; GO:0035861 refines the same source assertion rather than adding a separate location claim. The experimental FH(N) deletion of residues 1-21 is not equated with the natural P07954-2 deletion of residues 1-43. Correction PMID:29632342 concerns duplicated images in Figure 2d, not the ChIP or catalytic assays; corrected figure pixels were not independently inspected. Proposed replacements: site of double-strand break Supporting Evidence: PMID:26237645 A chromatin immunoprecipitation (ChIP) assay with antibodies against H2A.Z and FH showed that both H2A.Z and FH bound to the DNA adjacent to the I-SceI cutting site PMID:26237645 Cell fractionation analyses showed that nuclear FH was much less in amount than cytosolic FH, and IR enhanced both nuclear and chromatin-associated FH file:human/FH/FH-source-evidence.md |
| GO:0005694 chromosome | IEA GO_REF:0000044 | TOO GENERAL | Summary: Broad curated chromosome localization is covered by the source-supported DSB-site refinement. Reason: The imported UniProt chromosome mapping is biologically compatible with the same PMID:26237645 damage-associated chromatin evidence. GO:0035861 is_a GO:0090734, which is part_of GO:0005694. Retain this source object and evidence, while the more precise location is represented by the MODIFY on the experimental chromosome row; no distinct broader chromosome function is asserted here. Supporting Evidence: PMID:26237645 A chromatin immunoprecipitation (ChIP) assay with antibodies against H2A.Z and FH showed that both H2A.Z and FH bound to the DNA adjacent to the I-SceI cutting site file:human/FH/FH-source-evidence.md |
| GO:0005737 cytoplasm | TAS PMID:8200987 Mutation of the fumarase gene in two siblings with progressi... | ACCEPT | Summary: Cytosolic fumarase isoenzyme activity in patient tissues. Reason: A cytosolic FH pool exists, generated by alternative transcription initiation that removes the mitochondrial targeting sequence (PMID:27037871). Cytoplasm is correct; cytosol (annotated separately) is more precise. Supporting Evidence: PMID:8200987 affecting the cytosolic and the mitochondrial fumarase isoenzymes to the same degree PMID:27037871 the FH gene encodes two gene products, one containing and one lacking the mitochondrial targeting sequence |
| GO:0005739 mitochondrion | EXP PMID:27037871 Human Fumarate Hydratase Is Dual Localized by an Alternative... | ACCEPT | Summary: Human cells: FH dual localisation by alternative transcription initiation; the MTS-containing product is mitochondrial. Reason: The longer FH isoform carries an N-terminal mitochondrial targeting sequence and is imported into the matrix, where it acts in the TCA cycle. Mitochondrial localisation is the principal location of FH. Supporting Evidence: PMID:27037871 the FH gene encodes two gene products, one containing and one lacking the mitochondrial targeting sequence PMID:27037871 Fumarate hydratase (FH, fumarase), is a tricarboxylic acid cycle enzyme localized in the mitochondrial matrix. |
| GO:0005739 mitochondrion | HDA PMID:20833797 Phosphoproteome analysis of functional mitochondria isolated... | ACCEPT | Summary: FH detected in a phosphoproteome of isolated human skeletal muscle mitochondria. Reason: The longer FH isoform carries an N-terminal mitochondrial targeting sequence and is imported into the matrix, where it acts in the TCA cycle. Mitochondrial localisation is the principal location of FH. Supporting Evidence: PMID:20833797 We performed a phosphoproteomics study of functional mitochondria isolated from human muscle biopsies PMID:20833797 Many of the mitochondrial phosphoproteins are involved in oxidative phosphorylation, tricarboxylic acid cycle, and lipid metabolism |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: FH in the high-confidence human mitochondrial proteome (MitoCoP). Reason: The longer FH isoform carries an N-terminal mitochondrial targeting sequence and is imported into the matrix, where it acts in the TCA cycle. Mitochondrial localisation is the principal location of FH. Supporting Evidence: PMID:27037871 Fumarate hydratase (FH, fumarase), is a tricarboxylic acid cycle enzyme localized in the mitochondrial matrix. |
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | ACCEPT | Summary: IBA for mitochondrion (PTN000154501). Reason: The longer FH isoform carries an N-terminal mitochondrial targeting sequence and is imported into the matrix, where it acts in the TCA cycle. Retain the curator's mitochondrial IBA from PTN000154501, consistent with direct human FH localization evidence. This review does not independently reconstruct the family tree or claim to have verified the ancestral node placement. Supporting Evidence: PMID:27037871 Fumarate hydratase (FH, fumarase), is a tricarboxylic acid cycle enzyme localized in the mitochondrial matrix. |
| GO:0005739 mitochondrion | IDA GO_REF:0000052 | ACCEPT | Summary: Human Protein Atlas immunofluorescence. Reason: The longer FH isoform carries an N-terminal mitochondrial targeting sequence and is imported into the matrix, where it acts in the TCA cycle. Mitochondrial localisation is the principal location of FH. Supporting Evidence: PMID:27037871 Fumarate hydratase (FH, fumarase), is a tricarboxylic acid cycle enzyme localized in the mitochondrial matrix. |
| GO:0005739 mitochondrion | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular location mapping (mitochondrial isoform). Reason: The longer FH isoform carries an N-terminal mitochondrial targeting sequence and is imported into the matrix, where it acts in the TCA cycle. Mitochondrial localisation is the principal location of FH. Supporting Evidence: PMID:27037871 Fumarate hydratase (FH, fumarase), is a tricarboxylic acid cycle enzyme localized in the mitochondrial matrix. |
| GO:0005739 mitochondrion | TAS PMID:8200987 Mutation of the fumarase gene in two siblings with progressi... | ACCEPT | Summary: Mitochondrial fumarase isoenzyme activity in patient tissues. Reason: The longer FH isoform carries an N-terminal mitochondrial targeting sequence and is imported into the matrix, where it acts in the TCA cycle. Mitochondrial localisation is the principal location of FH. Supporting Evidence: PMID:8200987 affecting the cytosolic and the mitochondrial fumarase isoenzymes to the same degree PMID:27037871 Fumarate hydratase (FH, fumarase), is a tricarboxylic acid cycle enzyme localized in the mitochondrial matrix. |
| GO:0005759 mitochondrial matrix | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara transfer (is_active_in mitochondrial matrix). Reason: Mitochondrial FH is a soluble matrix enzyme of the TCA cycle; matrix is the most precise location for the core function. Supporting Evidence: PMID:27037871 Fumarate hydratase (FH, fumarase), is a tricarboxylic acid cycle enzyme localized in the mitochondrial matrix. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-70982 | ACCEPT | Summary: Reactome: FH tetramer hydrates fumarate to L-malate (matrix). Reason: Mitochondrial FH is a soluble matrix enzyme of the TCA cycle; matrix is the most precise location for the core function. Supporting Evidence: PMID:27037871 Fumarate hydratase (FH, fumarase), is a tricarboxylic acid cycle enzyme localized in the mitochondrial matrix. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9838035 | ACCEPT | Summary: Reactome: FH as a substrate of the matrix proteases LONP1/CLPXP. Reason: Mitochondrial FH is a soluble matrix enzyme of the TCA cycle; matrix is the most precise location for the core function. The Reactome events concern FH turnover, not FH function, but the location they assert is correct. Supporting Evidence: PMID:27037871 Fumarate hydratase (FH, fumarase), is a tricarboxylic acid cycle enzyme localized in the mitochondrial matrix. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9838081 | ACCEPT | Summary: Reactome: FH as a substrate of the matrix proteases LONP1/CLPXP. Reason: Mitochondrial FH is a soluble matrix enzyme of the TCA cycle; matrix is the most precise location for the core function. The Reactome events concern FH turnover, not FH function, but the location they assert is correct. Supporting Evidence: PMID:27037871 Fumarate hydratase (FH, fumarase), is a tricarboxylic acid cycle enzyme localized in the mitochondrial matrix. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9838093 | ACCEPT | Summary: Reactome: FH as a substrate of the matrix proteases LONP1/CLPXP. Reason: Mitochondrial FH is a soluble matrix enzyme of the TCA cycle; matrix is the most precise location for the core function. The Reactome events concern FH turnover, not FH function, but the location they assert is correct. Supporting Evidence: PMID:27037871 Fumarate hydratase (FH, fumarase), is a tricarboxylic acid cycle enzyme localized in the mitochondrial matrix. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9838289 | ACCEPT | Summary: Reactome: FH as a substrate of the matrix proteases LONP1/CLPXP. Reason: Mitochondrial FH is a soluble matrix enzyme of the TCA cycle; matrix is the most precise location for the core function. The Reactome events concern FH turnover, not FH function, but the location they assert is correct. Supporting Evidence: PMID:27037871 Fumarate hydratase (FH, fumarase), is a tricarboxylic acid cycle enzyme localized in the mitochondrial matrix. |
| GO:0005829 cytosol | IDA PMID:20231875 Fumarase: a mitochondrial metabolic enzyme and a cytosolic/n... | ACCEPT | Summary: Immunofluorescence in human HeLa cells shows FH in mitochondria and cytosol. Reason: Human-cell staining directly supports a cytosolic FH pool; Jiang et al. also found cytosolic FH far more abundant than nuclear FH. Pool localization does not by itself assign every molecule to a particular natural product or establish that the damage-induced nuclear pool derives exclusively from P07954-2. Supporting Evidence: PMID:20231875 under normal conditions the FH staining pattern reflects its localization mainly to mitochondria and the cytosol. PMID:26237645 Cell fractionation analyses showed that nuclear FH was much less in amount than cytosolic FH, and IR enhanced both nuclear and chromatin-associated FH |
| GO:0005829 cytosol | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular location mapping (cytoplasmic isoform: cytosol). Reason: Consistent with experimental data. Supporting Evidence: PMID:20231875 under normal conditions the FH staining pattern reflects its localization mainly to mitochondria and the cytosol. PMID:27037871 the FH gene encodes two gene products, one containing and one lacking the mitochondrial targeting sequence |
| GO:0006099 tricarboxylic acid cycle | IBA GO_REF:0000033 | ACCEPT | Summary: IBA for tricarboxylic acid cycle. Reason: FH catalyses the fumarate to L-malate step of the TCA cycle in the mitochondrial matrix; loss causes fumarase deficiency, an inborn error of the TCA cycle, and HLRCC tumours with fumarate accumulation. Supporting Evidence: PMID:27037871 Fumarate hydratase (FH, fumarase), is a tricarboxylic acid cycle enzyme localized in the mitochondrial matrix. PMID:8200987 We report an inborn error of the tricarboxylic acid cycle, fumarase deficiency, in two siblings born to first cousin parents. |
| GO:0006099 tricarboxylic acid cycle | IEA GO_REF:0000120 | ACCEPT | Summary: Combined automated assignment of tricarboxylic acid cycle. Reason: FH catalyses the fumarate to L-malate step of the TCA cycle in the mitochondrial matrix; loss causes fumarase deficiency, an inborn error of the TCA cycle, and HLRCC tumours with fumarate accumulation. Supporting Evidence: PMID:11865300 that this gene encodes fumarate hydratase, an enzyme of the tricarboxylic acid cycle. PMID:8200987 We report an inborn error of the tricarboxylic acid cycle, fumarase deficiency, in two siblings born to first cousin parents. |
| GO:0006106 fumarate metabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: IBA for fumarate metabolic process. Reason: FH is the main enzyme interconverting fumarate and malate in both mitochondria and cytosol. Fumarate metabolic process is correct, though the TCA cycle and fumarate hydratase activity describe the role more precisely. Supporting Evidence: PMID:30761759 Fumarate hydratases (FHs, fumarases) catalyze the reversible conversion of fumarate into l-malate. |
| GO:0006106 fumarate metabolic process | IDA PMID:30761759 Structural, biochemical and biophysical characterization of ... | ACCEPT | Summary: Recombinant human FH kinetics with fumarate and malate. Reason: FH is the main enzyme interconverting fumarate and malate in both mitochondria and cytosol. Fumarate metabolic process is correct, though the TCA cycle and fumarate hydratase activity describe the role more precisely. Supporting Evidence: PMID:30761759 Fumarate hydratases (FHs, fumarases) catalyze the reversible conversion of fumarate into l-malate. |
| GO:0006106 fumarate metabolic process | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO assignment of fumarate metabolic process. Reason: FH is the main enzyme interconverting fumarate and malate in both mitochondria and cytosol. Fumarate metabolic process is correct, though the TCA cycle and fumarate hydratase activity describe the role more precisely. Supporting Evidence: PMID:30761759 Fumarate hydratases (FHs, fumarases) catalyze the reversible conversion of fumarate into l-malate. |
| GO:0006106 fumarate metabolic process | TAS PMID:8200987 Mutation of the fumarase gene in two siblings with progressi... | ACCEPT | Summary: Fumarase deficiency patients show high urinary fumarate. Reason: FH is the main enzyme interconverting fumarate and malate in both mitochondria and cytosol. Fumarate metabolic process is correct, though the TCA cycle and fumarate hydratase activity describe the role more precisely. Supporting Evidence: PMID:8200987 affecting the cytosolic and the mitochondrial fumarase isoenzymes to the same degree |
| GO:0006108 malate metabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: IBA for malate metabolic process. Reason: FH produces L-malate from fumarate (and the reverse); malate metabolic process is a correct, if general, process for the enzyme. Supporting Evidence: PMID:30761759 Fumarate hydratases (FHs, fumarases) catalyze the reversible conversion of fumarate into l-malate. |
| GO:0006108 malate metabolic process | IDA PMID:30761759 Structural, biochemical and biophysical characterization of ... | ACCEPT | Summary: Recombinant human FH kinetics with L-malate as substrate. Reason: FH produces L-malate from fumarate (and the reverse); malate metabolic process is a correct, if general, process for the enzyme. Supporting Evidence: PMID:30761759 Fumarate hydratases (FHs, fumarases) catalyze the reversible conversion of fumarate into l-malate. |
| GO:0006525 arginine metabolic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl Compara transfer of arginine metabolic process from mouse Fh1. Reason: The actual mouse donor annotation is IMP from PMID:23643539. FH performs the fumarate/malate reaction within a metabolically coupled arginine pathway: isotope tracing links excess fumarate to reversed ASL flux, and cytosolic human FH re-expression in mouse renal models and human UOK262 cells reduces fumarate/argininosuccinate abnormalities (Figures 2-4). This is catalytic control of a pathway metabolite, rather than an inference from disease necessity alone. GO:0006525 covers reactions and pathways involving arginine; it does not require every participating enzyme to use arginine itself as a substrate. ASL performs the arginine/argininosuccinate conversion, while FH controls the coupled fumarate pool. Retain the existing broad curated inference as non-core with disease-model and orthology limits; normal human tissue flux and a specific natural-product assignment are not established by the engineered rescue constructs. PMID:24280230 independently supports reversed ASL adaptation after FH loss. Supporting Evidence: PMID:24280230 Argininosuccinate was found to be produced from arginine and fumarate by the reverse activity of the urea cycle enzyme argininosuccinate lyase (ASL), making these cells auxotrophic for arginine. file:human/FH/FH-source-evidence.md |
| GO:0006525 arginine metabolic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Curator ISS transfer of arginine metabolic process from mouse Fh1. Reason: The actual mouse donor annotation is IMP from PMID:23643539. FH performs the fumarate/malate reaction within a metabolically coupled arginine pathway: isotope tracing links excess fumarate to reversed ASL flux, and cytosolic human FH re-expression in mouse renal models and human UOK262 cells reduces fumarate/argininosuccinate abnormalities (Figures 2-4). This is catalytic control of a pathway metabolite, rather than an inference from disease necessity alone. GO:0006525 covers reactions and pathways involving arginine; it does not require every participating enzyme to use arginine itself as a substrate. ASL performs the arginine/argininosuccinate conversion, while FH controls the coupled fumarate pool. Retain the existing broad curated inference as non-core with disease-model and orthology limits; normal human tissue flux and a specific natural-product assignment are not established by the engineered rescue constructs. PMID:24280230 independently supports reversed ASL adaptation after FH loss. Supporting Evidence: PMID:24280230 Argininosuccinate was found to be produced from arginine and fumarate by the reverse activity of the urea cycle enzyme argininosuccinate lyase (ASL), making these cells auxotrophic for arginine. file:human/FH/FH-source-evidence.md |
| GO:0016829 lyase activity | IEA GO_REF:0000002 | TOO GENERAL | Summary: The broad lyase assignment is entailed by the retained fumarate hydratase activity. Reason: Official typed ancestry is GO:0004333 is_a GO:0016836 is_a GO:0016835 is_a GO:0016829. The specific fumarate hydratase activity is retained with direct human biochemical evidence. The generic InterPro lyase assertion is correct but adds no distinct activity. Supporting Evidence: PMID:30761759 Fumarate hydratases (FHs, fumarases) catalyze the reversible conversion of fumarate into l-malate. file:human/FH/FH-source-evidence.md |
| GO:0070062 extracellular exosome | HDA PMID:20458337 MHC class II-associated proteins in B-cell exosomes and pote... | UNDECIDED | Summary: The original B-cell exosome proteome assertion remains unresolved at the FH target-table level. Reason: The available PMID:20458337 record describes the 539-protein B-cell exosome proteome, but the exact FH/P07954 supplementary target entry has not been recovered in this audit. The original curator's localization claim is therefore not overruled. No nonspecific carriage, contamination, or absence of an extracellular role has been demonstrated; an extracellular-vesicle location also does not require a known vesicle-specific function. Supporting Evidence: PMID:20458337 we first analyzed the total proteome of highly purified B cell-derived exosomes using sensitive and accurate mass spectrometry (MS), and identified 539 proteins file:human/FH/FH-source-evidence.md |
| GO:0120162 positive regulation of cold-induced thermogenesis | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl Compara transfer from mouse Fh1. Reason: PMID:27554470 directly documents impaired cold-challenge temperature maintenance, reduced BAT UCP1 transcript and undetectable UCP1 protein in adipose-specific Fh1-knockout mice (Figure 4E-H). The Discussion and Figure 8 place this phenotype within severe adipose mitochondrial dysfunction and ATP depletion, with impaired nonshivering thermogenesis and compensatory shivering. These results establish a metabolic requirement for thermogenic capacity but do not separate an FH regulatory step from the general bioenergetic capacity required for the response. Mark the positive-regulation assertion over-annotated without disputing the phenotype or the original mouse evidence. The concern is not that regulation must involve a temperature sensor or transcription factor; it is that the reported experiments do not resolve regulation from metabolic requirement. The respiratory-inhibitor comparison concerns triglyceride synthesis in white adipocytes, not an experimental demonstration that every TCA perturbation has the same cold phenotype. Supporting Evidence: PMID:27554470 In BAT, AFHKO mice show a marked decrease of UCP1 expression, hypertrophic brown adipocytes, and defective thermogenesis. file:human/FH/FH-source-evidence.md |
| GO:0120162 positive regulation of cold-induced thermogenesis | ISS PMID:27554470 Adipose-Specific Deficiency of Fumarate Hydratase in Mice Pr... | MARK AS OVER ANNOTATED | Summary: ISS from mouse adipose-specific Fh1 knockout (PMID:27554470). Reason: PMID:27554470 directly documents impaired cold-challenge temperature maintenance, reduced BAT UCP1 transcript and undetectable UCP1 protein in adipose-specific Fh1-knockout mice (Figure 4E-H). The Discussion and Figure 8 place this phenotype within severe adipose mitochondrial dysfunction and ATP depletion, with impaired nonshivering thermogenesis and compensatory shivering. These results establish a metabolic requirement for thermogenic capacity but do not separate an FH regulatory step from the general bioenergetic capacity required for the response. Mark the positive-regulation assertion over-annotated without disputing the phenotype or the original mouse evidence. The concern is not that regulation must involve a temperature sensor or transcription factor; it is that the reported experiments do not resolve regulation from metabolic requirement. The respiratory-inhibitor comparison concerns triglyceride synthesis in white adipocytes, not an experimental demonstration that every TCA perturbation has the same cold phenotype. Supporting Evidence: PMID:27554470 In BAT, AFHKO mice show a marked decrease of UCP1 expression, hypertrophic brown adipocytes, and defective thermogenesis. file:human/FH/FH-source-evidence.md |
| GO:2001034 positive regulation of double-strand break repair via nonhomologous end joining | IMP PMID:26237645 Local generation of fumarate promotes DNA repair through inh... | NEW | Summary: Nuclear FH promotes NHEJ by producing fumarate locally at DSBs, which inhibits KDM2B, raises H3K36me2 and promotes Ku70/DNA-PK accumulation. Reason: Retain this authored proposal on target-specific mechanistic evidence, not because other pathway participants have annotations. In PMID:26237645 human-cell experiments, recruitment-defective but catalytically active FH and catalytically inactive but recruited FH separate local catalysis from localization; fumarate/KDM2B interventions connect that catalysis to H3K36me2, repair-factor accumulation and NHEJ. FH supplies the locally produced regulatory metabolite and therefore performs work in the regulation process; it is neither a passive substrate nor the ligase. Current QuickGO has no corresponding FH process row, and the existing paper is already curated for interaction/location; this proposal explicitly adds a reviewed mechanistic interpretation. SETMAR provides a qualified positive catalytic/chromatin comparator, while ACLY and KDM2B absences are not treated as proof of an overlooked annotation. Correction PMID:29632342 replaces duplicated Figure 2d images; no corrected pixels or Figshare repetitions were independently assessed. The artificial FH(N) deletion of residues 1-21 construct is not assigned to natural P07954-2 deletion of residues 1-43. Supporting Evidence: PMID:26237645 These results indicate that FH-produced fumarate promotes NHEJ-dependent DNA repair by inhibiting KDM2B-mediated demethylation at DSB regions. PMID:26237645 In contrast, the catalytically inactive FH (N) R233H mutant, which was phosphorylated and recruited to chromatin PMID:20231875 We show that the cytosolic fumarase is a member of the DNA damage response that is recruited from the cytosol to the nucleus upon DNA damage induction. file:human/FH/FH-source-evidence.md |
| GO:0035861 site of double-strand break | IDA PMID:26237645 Local generation of fumarate promotes DNA repair through inh... | NEW | Summary: Historically authored DSB-site proposal retained as a retired duplicate of the refined experimental chromosome assertion. Reason: The localization is supported, but this authored NEW duplicates a stricter refinement of imported PMID:26237645 chromosome row 27. The typed path is GO:0035861 is_a GO:0090734 part_of GO:0005694. Retire this authored row instead of deleting its inherited quotation associations or implying the biology is false; its active coverage moves to the row 27 MODIFY. Original source metadata, action NEW as historical provenance, and supported_by entries remain preserved. Supporting Evidence: PMID:26237645 A chromatin immunoprecipitation (ChIP) assay with antibodies against H2A.Z and FH showed that both H2A.Z and FH bound to the DNA adjacent to the I-SceI cutting site PMID:26237645 ionizing radiation induces DNA-PK-dependent phosphorylation of nuclear fumarase at Thr 236, which leads to an interaction between fumarase and the histone variant H2A.Z at DNA double-strand break (DSB) regions. |
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Download this section (compressed HTML)Q: How does cytosolic FH-dependent fumarate turnover couple to arginine and urea-cycle flux in normal human tissues, compared with the reversed-ASL adaptation established in FH-deficient renal models?
Suggested experts: GO metabolism editors
Q: Is the nuclear DNA-repair role carried exclusively by the cytosolic (MTS-lacking) isoform in vivo, and does physiological nuclear FH abundance suffice to change local fumarate concentrations at DSBs?
Q: Should FH tumour suppression in HLRCC be represented in GO? It largely reflects fumarate oncometabolite effects (dioxygenase inhibition, protein succination) that follow loss of FH activity, not a distinct FH activity.
Experiment: Tether catalytically dead versus wild-type FH to an inducible DSB (e.g. via a LacI/dCas9 fusion) in FH-null cells, and measure local fumarate (biosensor), H3K36me2 ChIP and NHEJ reporter efficiency.
Hypothesis: Nuclear FH supports NHEJ through its local catalytic product rather than through scaffolding at H2A.Z.
Type: genetic interaction / reporter assay
Experiment: Use isoform-specific promoter or start-site editing in hepatocyte models to abolish the cytosolic or mitochondrial product, then trace 15N-ammonia/13C-aspartate flux through argininosuccinate and fumarate.
Hypothesis: The cytosolic FH isoform alone accounts for urea-cycle coupling in hepatocytes.
Type: metabolic flux analysis
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