ID FUMH_HUMAN Reviewed; 510 AA. AC P07954; B1ANK7; DT 01-AUG-1988, integrated into UniProtKB/Swiss-Prot. DT 01-OCT-1996, sequence version 3. DT 27-MAR-2024, entry version 248. DE RecName: Full=Fumarate hydratase, mitochondrial {ECO:0000303|PubMed:21445611, ECO:0000303|PubMed:27037871}; DE Short=Fumarase {ECO:0000303|PubMed:27037871, ECO:0000303|PubMed:3828494, ECO:0000303|Ref.2}; DE Short=HsFH {ECO:0000303|PubMed:24419633}; DE EC=4.2.1.2 {ECO:0000269|PubMed:30761759}; DE Flags: Precursor; GN Name=FH {ECO:0000303|PubMed:27037871, ECO:0000312|HGNC:HGNC:3700}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA]. RC TISSUE=Brain; RA Gellera C., Baratta S., Cavadini P., Invernizzi F., Lamantea E., RA Didonato S., Taroni F.; RL Submitted (MAY-1996) to the EMBL/GenBank/DDBJ databases. RN [2] RP NUCLEOTIDE SEQUENCE [MRNA]. RA Bourgeron T., Parfait B., Chretien D., Rotig A., Munnich A., Rustin P.; RT "Complete cDNA sequence of the human fumarase."; RL Submitted (FEB-1996) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., RA Phelan M., Farmer A.; RT "Cloning of human full-length CDSs in BD Creator(TM) system donor vector."; RL Submitted (AUG-2003) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Brain; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Brain, and Uterus; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [7] RP NUCLEOTIDE SEQUENCE [MRNA] OF 44-510. RC TISSUE=Liver; RX PubMed=3828494; DOI=10.1007/bf01116247; RA Kinsella B.T., Doonan S.; RT "Nucleotide sequence of a cDNA coding for mitochondrial fumarase from human RT liver."; RL Biosci. Rep. 6:921-929(1986). RN [8] RP PROTEIN SEQUENCE OF 269-286 AND 422-444, AND IDENTIFICATION BY MASS RP SPECTROMETRY. RC TISSUE=Brain, and Cajal-Retzius cell; RA Lubec G., Afjehi-Sadat L.; RL Submitted (MAR-2007) to UniProtKB. RN [9] RP PARTIAL PROTEIN SEQUENCE (ISOFORM CYTOPLASMIC), CLEAVAGE OF INITIATOR RP METHIONINE (ISOFORM CYTOPLASMIC), ALTERNATIVE INITIATION (ISOFORMS RP MITOCHONDRIAL AND CYTOPLASMIC), AND SUBCELLULAR LOCATION (ISOFORMS RP MITOCHONDRIAL AND CYTOPLASMIC). RX PubMed=27037871; DOI=10.1111/tra.12397; RA Dik E., Naamati A., Asraf H., Lehming N., Pines O.; RT "Human fumarate hydratase is dual localized by an alternative transcription RT initiation mechanism."; RL Traffic 17:720-732(2016). RN [10] RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-66; LYS-80; LYS-94; LYS-256 AND RP LYS-292, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19608861; DOI=10.1126/science.1175371; RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C., RA Olsen J.V., Mann M.; RT "Lysine acetylation targets protein complexes and co-regulates major RT cellular functions."; RL Science 325:834-840(2009). RN [11] RP FUNCTION (ISOFORM CYTOPLASMIC), AND SUBCELLULAR LOCATION (ISOFORM RP CYTOPLASMIC). RX PubMed=20231875; DOI=10.1371/journal.pbio.1000328; RA Yogev O., Yogev O., Singer E., Shaulian E., Goldberg M., Fox T.D., RA Pines O.; RT "Fumarase: a mitochondrial metabolic enzyme and a cytosolic/nuclear RT component of the DNA damage response."; RL PLoS Biol. 8:E1000328-E1000328(2010). RN [12] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [13] RP TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION. RX PubMed=22509282; DOI=10.1371/journal.pone.0034237; RA von Lohneysen K., Scott T.M., Soldau K., Xu X., Friedman J.S.; RT "Assessment of the red cell proteome of young patients with unexplained RT hemolytic anemia by two-dimensional differential in-gel electrophoresis RT (DIGE)."; RL PLoS ONE 7:E34237-E34237(2012). RN [14] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=22814378; DOI=10.1073/pnas.1210303109; RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A., RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E., RA Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.; RT "N-terminal acetylome analyses and functional insights of the N-terminal RT acetyltransferase NatB."; RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012). RN [15] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-90, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [16] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-366, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [17] RP FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, INTERACTION WITH H2AZ1, RP PHOSPHORYLATION AT THR-236, MUTAGENESIS OF SER-46; THR-147; SER-187 AND RP THR-236, AND CHARACTERIZATION OF VARIANT HLRCC HIS-233. RX PubMed=26237645; DOI=10.1038/ncb3209; RA Jiang Y., Qian X., Shen J., Wang Y., Li X., Liu R., Xia Y., Chen Q., RA Peng G., Lin S.Y., Lu Z.; RT "Local generation of fumarate promotes DNA repair through inhibition of RT histone H3 demethylation."; RL Nat. Cell Biol. 17:1158-1168(2015). RN [18] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=25944712; DOI=10.1002/pmic.201400617; RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D., RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.; RT "N-terminome analysis of the human mitochondrial proteome."; RL Proteomics 15:2519-2524(2015). RN [19] RP CATALYTIC ACTIVITY, AND INVOLVEMENT IN HLRCC. RX PubMed=30718813; DOI=10.1038/s41589-018-0217-y; RA Kulkarni R.A., Bak D.W., Wei D., Bergholtz S.E., Briney C.A., Shrimp J.H., RA Alpsoy A., Thorpe A.L., Bavari A.E., Crooks D.R., Levy M., Florens L., RA Washburn M.P., Frizzell N., Dykhuizen E.C., Weerapana E., Linehan W.M., RA Meier J.L.; RT "A chemoproteomic portrait of the oncometabolite fumarate."; RL Nat. Chem. Biol. 15:391-400(2019). RN [20] {ECO:0007744|PDB:3E04} RP X-RAY CRYSTALLOGRAPHY (1.95 ANGSTROMS) OF 44-510, AND SUBUNIT. RX PubMed=21445611; DOI=10.1007/s10545-011-9294-8; RA Picaud S., Kavanagh K.L., Yue W.W., Lee W.H., Muller-Knapp S., Gileadi O., RA Sacchettini J., Oppermann U.; RT "Structural basis of fumarate hydratase deficiency."; RL J. Inherit. Metab. Dis. 34:671-676(2011). RN [21] {ECO:0007744|PDB:5D6B} RP X-RAY CRYSTALLOGRAPHY (2.10 ANGSTROMS) OF 49-510. RX PubMed=24419633; DOI=10.1107/s2053230x13033955; RA Pereira de Padua R.A., Nonato M.C.; RT "Cloning, expression, purification, crystallization and preliminary X-ray RT diffraction analysis of recombinant human fumarase."; RL Acta Crystallogr. F 70:120-122(2014). RN [22] {ECO:0007744|PDB:5UPP} RP X-RAY CRYSTALLOGRAPHY (1.80 ANGSTROMS) OF 45-510, FUNCTION, CATALYTIC RP ACTIVITY, AND BIOPHYSICOCHEMICAL PROPERTIES. RX PubMed=30761759; DOI=10.1111/febs.14782; RA Ajalla Aleixo M.A., Rangel V.L., Rustiguel J.K., de Padua R.A.P., RA Nonato M.C.; RT "Structural, biochemical and biophysical characterization of recombinant RT human fumarate hydratase."; RL FEBS J. 286:1925-1940(2019). RN [23] RP VARIANT FMRD THR-308. RA Coughlin E.M., Chalmers R.A., Slaugenhaupt S.A., Gusella J.F., Shih V.E., RA Ramesh V.; RT "Identification of a molecular defect in a fumarase deficient patient and RT mapping of the fumarase gene."; RL Am. J. Hum. Genet. 53:A896-A896(1993). RN [24] RP VARIANT HLRCC GLN-362. RX PubMed=8200987; DOI=10.1172/jci117261; RA Bourgeron T., Chretien D., Poggi-Bach J., Doonan S., Rabier D., Letouze P., RA Munnich A., Roetig A., Landrieu P., Rustin P.; RT "Mutation of the fumarase gene in two siblings with progressive RT encephalopathy and fumarase deficiency."; RL J. Clin. Invest. 93:2514-2518(1994). RN [25] RP VARIANTS FMRD ARG-230; THR-308; CYS-312 AND VAL-425. RX PubMed=9635293; DOI=10.1006/mgme.1998.2684; RA Coughlin E.M., Christensen E., Kunz P.L., Krishnamoorthy K.S., Walker V., RA Dennis N.R., Chalmers R.A., Elpeleg O.N., Whelan D., Pollitt R.J., RA Ramesh V., Mandell R., Shih V.E.; RT "Molecular analysis and prenatal diagnosis of human fumarase deficiency."; RL Mol. Genet. Metab. 63:254-262(1998). RN [26] RP VARIANTS HLRCC THR-107; PRO-117; ARG-180; ARG-185; ARG-230; HIS-233; RP VAL-282 AND ARG-328. RX PubMed=11865300; DOI=10.1038/ng849; RA Tomlinson I.P.M., Alam N.A., Rowan A.J., Barclay E., Jaeger E.E.M., RA Kelsell D., Leigh I., Gorman P., Lamlum H., Rahman S., Roylance R.R., RA Olpin S., Bevan S., Barker K., Hearle N., Houlston R.S., Kiuru M., RA Lehtonen R., Karhu A., Vilkki S., Laiho P., Eklund C., Vierimaa O., RA Aittomaeki K., Hietala M., Sistonen P., Paetau A., Salovaara R., Herva R., RA Launonen V., Aaltonen L.A.; RT "Germline mutations in FH predispose to dominantly inherited uterine RT fibroids, skin leiomyomata and papillary renal cell cancer."; RL Nat. Genet. 30:406-410(2002). CC -!- FUNCTION: Catalyzes the reversible stereospecific interconversion of CC fumarate to L-malate (PubMed:30761759). Experiments in other species CC have demonstrated that specific isoforms of this protein act in defined CC pathways and favor one direction over the other (Probable). CC {ECO:0000269|PubMed:30761759, ECO:0000305}. CC -!- FUNCTION: [Isoform Mitochondrial]: Catalyzes the hydration of fumarate CC to L-malate in the tricarboxylic acid (TCA) cycle to facilitate a CC transition step in the production of energy in the form of NADH. CC {ECO:0000250|UniProtKB:P10173}. CC -!- FUNCTION: [Isoform Cytoplasmic]: Catalyzes the dehydration of L-malate CC to fumarate (By similarity). Fumarate metabolism in the cytosol plays a CC role during urea cycle and arginine metabolism; fumarate being a by- CC product of the urea cycle and amino-acid catabolism (By similarity). CC Also plays a role in DNA repair by promoting non-homologous end-joining CC (NHEJ) (PubMed:20231875, PubMed:26237645). In response to DNA damage CC and phosphorylation by PRKDC, translocates to the nucleus and CC accumulates at DNA double-strand breaks (DSBs): acts by catalyzing CC formation of fumarate, an inhibitor of KDM2B histone demethylase CC activity, resulting in enhanced dimethylation of histone H3 'Lys-36' CC (H3K36me2) (PubMed:26237645). {ECO:0000250|UniProtKB:P97807, CC ECO:0000269|PubMed:20231875, ECO:0000269|PubMed:26237645}. CC -!- CATALYTIC ACTIVITY: CC Reaction=(S)-malate = fumarate + H2O; Xref=Rhea:RHEA:12460, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15589, ChEBI:CHEBI:29806; EC=4.2.1.2; CC Evidence={ECO:0000269|PubMed:30761759, ECO:0000305|PubMed:30718813}; CC -!- CATALYTIC ACTIVITY: [Isoform Mitochondrial]: CC Reaction=(S)-malate = fumarate + H2O; Xref=Rhea:RHEA:12460, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15589, ChEBI:CHEBI:29806; EC=4.2.1.2; CC Evidence={ECO:0000250|UniProtKB:P10173}; CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:12462; CC Evidence={ECO:0000250|UniProtKB:P10173}; CC -!- CATALYTIC ACTIVITY: [Isoform Cytoplasmic]: CC Reaction=(S)-malate = fumarate + H2O; Xref=Rhea:RHEA:12460, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15589, ChEBI:CHEBI:29806; EC=4.2.1.2; CC Evidence={ECO:0000250|UniProtKB:P97807}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:12461; CC Evidence={ECO:0000250|UniProtKB:P97807}; CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=1.4 mM for L-malate (at pH 8.5) {ECO:0000269|PubMed:30761759}; CC KM=0.2 mM for fumarate (at pH 8.5) {ECO:0000269|PubMed:30761759}; CC Note=kcat is 280 sec(-1) with L-malate (at pH 8.5) (PubMed:30761759). CC kcat is 170 sec(-1) with fumarate (at pH 8.5) (PubMed:30761759). CC {ECO:0000269|PubMed:30761759}; CC pH dependence: CC Optimum pH is 7.5-8.0. {ECO:0000269|PubMed:30761759}; CC -!- PATHWAY: Carbohydrate metabolism; tricarboxylic acid cycle; (S)-malate CC from fumarate: step 1/1. {ECO:0000250|UniProtKB:P10173}. CC -!- SUBUNIT: Homotetramer (PubMed:21445611, PubMed:30761759). Interacts CC with H2AZ1 (PubMed:26237645). {ECO:0000269|PubMed:21445611, CC ECO:0000269|PubMed:26237645, ECO:0000269|PubMed:30761759}. CC -!- INTERACTION: CC P07954; Q68D86: CCDC102B; NbExp=3; IntAct=EBI-1050358, EBI-10171570; CC P07954; Q2TAC2-2: CCDC57; NbExp=3; IntAct=EBI-1050358, EBI-10961624; CC P07954; Q9H6J7-2: CSTPP1; NbExp=3; IntAct=EBI-1050358, EBI-13328871; CC P07954; Q14129: DGCR6; NbExp=3; IntAct=EBI-1050358, EBI-12206931; CC P07954; Q9NQT4: EXOSC5; NbExp=3; IntAct=EBI-1050358, EBI-371876; CC P07954; P0C0S5: H2AZ1; NbExp=5; IntAct=EBI-1050358, EBI-1199859; CC P07954; Q8WZ60: KLHL6; NbExp=3; IntAct=EBI-1050358, EBI-6426464; CC P07954; Q03252: LMNB2; NbExp=3; IntAct=EBI-1050358, EBI-2830427; CC P07954; P11309: PIM1; NbExp=3; IntAct=EBI-1050358, EBI-696621; CC P07954; O15160: POLR1C; NbExp=3; IntAct=EBI-1050358, EBI-1055079; CC P07954; P21673: SAT1; NbExp=3; IntAct=EBI-1050358, EBI-711613; CC P07954; O14787-2: TNPO2; NbExp=3; IntAct=EBI-1050358, EBI-12076664; CC P07954; Q6DKK2: TTC19; NbExp=3; IntAct=EBI-1050358, EBI-948354; CC -!- SUBCELLULAR LOCATION: [Isoform Mitochondrial]: Mitochondrion CC {ECO:0000269|PubMed:27037871}. CC -!- SUBCELLULAR LOCATION: [Isoform Cytoplasmic]: Cytoplasm, cytosol CC {ECO:0000269|PubMed:20231875, ECO:0000269|PubMed:22509282, CC ECO:0000269|PubMed:26237645, ECO:0000269|PubMed:27037871}. Nucleus CC {ECO:0000269|PubMed:20231875, ECO:0000269|PubMed:26237645}. Chromosome CC {ECO:0000269|PubMed:26237645}. Note=Translocates to the nucleus in CC response to DNA damage: localizes to DNA double-strand breaks (DSBs) CC following phosphorylation by PRKDC. {ECO:0000269|PubMed:26237645}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative initiation; Named isoforms=2; CC Name=Mitochondrial {ECO:0000303|PubMed:27037871}; CC IsoId=P07954-1; Sequence=Displayed; CC Name=Cytoplasmic {ECO:0000303|PubMed:27037871}; CC IsoId=P07954-2; Sequence=VSP_018965; CC -!- TISSUE SPECIFICITY: Expressed in red blood cells; underexpressed in red CC blood cells (cytoplasm) of patients with hereditary non-spherocytic CC hemolytic anemia of unknown etiology. {ECO:0000269|PubMed:22509282}. CC -!- PTM: [Isoform Cytoplasmic]: Phosphorylation at Thr-236 by PRKDC in CC response to DNA damage promotes translocation to the nucleus and CC recruitment to DNA double-strand breaks (DSBs). CC {ECO:0000269|PubMed:26237645}. CC -!- DISEASE: Fumarase deficiency (FMRD) [MIM:606812]: A severe autosomal CC recessive metabolic disorder characterized by early-onset hypotonia, CC profound psychomotor retardation, and brain abnormalities, such as CC agenesis of the corpus callosum, gyral defects, and ventriculomegaly. CC Many patients show neonatal distress, metabolic acidosis, and/or CC encephalopathy. {ECO:0000269|PubMed:9635293, ECO:0000269|Ref.23}. CC Note=The disease is caused by variants affecting the gene represented CC in this entry. CC -!- DISEASE: [Isoform Cytoplasmic]: Hereditary leiomyomatosis and renal CC cell cancer (HLRCC) [MIM:150800]: A disorder characterized by CC predisposition to cutaneous and uterine leiomyomas, and papillary type CC 2 renal cancer which occurs in about 20% of patients. CC {ECO:0000269|PubMed:11865300, ECO:0000269|PubMed:26237645, CC ECO:0000269|PubMed:8200987}. Note=The disease is caused by variants CC affecting the gene represented in this entry. Isoform Cytoplasmic: CC HLRCC is probably caused by an accumulation of fumarate CC (PubMed:30718813). Accumulation of fumarate coupled with protonation CC promotes the formation of non-enzymatic post-translational modification CC cysteine S-succination (S-(2-succinyl)cysteine) on proteins, such as CC SMARCC1 (PubMed:30718813). {ECO:0000269|PubMed:30718813}. CC -!- MISCELLANEOUS: There are 2 substrate-binding sites: the catalytic A CC site, and the non-catalytic B site that may play a role in the transfer CC of substrate or product between the active site and the solvent. CC Alternatively, the B site may bind allosteric effectors. CC {ECO:0000250|UniProtKB:P05042, ECO:0000250|UniProtKB:P9WN93}. CC -!- SIMILARITY: Belongs to the class-II fumarase/aspartase family. Fumarase CC subfamily. {ECO:0000305}. CC -!- WEB RESOURCE: Name=TCA Cycle Gene Mutation Database; CC URL="https://databases.lovd.nl/shared/genes/FH"; CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and CC Haematology; CC URL="https://atlasgeneticsoncology.org/gene/40573/FH"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; U59309; AAB66354.1; -; mRNA. DR EMBL; U48857; AAD00071.1; -; mRNA. DR EMBL; BT009839; AAP88841.1; -; mRNA. DR EMBL; AK312415; BAG35325.1; -; mRNA. DR EMBL; CH471098; EAW70092.1; -; Genomic_DNA. DR EMBL; BC003108; AAH03108.1; -; mRNA. DR EMBL; BC017444; AAH17444.1; -; mRNA. DR EMBL; M15502; AAA52483.1; -; mRNA. DR CCDS; CCDS1617.1; -. [P07954-1] DR PIR; S06213; UFHUM. DR RefSeq; NP_000134.2; NM_000143.3. [P07954-1] DR PDB; 3E04; X-ray; 1.95 A; A/B/C/D=44-510. DR PDB; 5D6B; X-ray; 2.10 A; A=49-510. DR PDB; 5UPP; X-ray; 1.80 A; A/B=45-510. DR PDB; 6EBT; X-ray; 2.30 A; A/B=45-510. DR PDB; 6V8F; X-ray; 2.30 A; A/B=45-510. DR PDB; 6VBE; X-ray; 1.90 A; A/B=45-510. DR PDB; 7LUB; X-ray; 2.15 A; A/B=45-510. DR PDBsum; 3E04; -. DR PDBsum; 5D6B; -. DR PDBsum; 5UPP; -. DR PDBsum; 6EBT; -. DR PDBsum; 6V8F; -. DR PDBsum; 6VBE; -. DR PDBsum; 7LUB; -. DR AlphaFoldDB; P07954; -. DR SMR; P07954; -. DR BioGRID; 108562; 186. DR DIP; DIP-46920N; -. DR IntAct; P07954; 38. DR MINT; P07954; -. DR STRING; 9606.ENSP00000355518; -. DR GlyCosmos; P07954; 1 site, 1 glycan. DR GlyGen; P07954; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; P07954; -. DR MetOSite; P07954; -. DR PhosphoSitePlus; P07954; -. DR SwissPalm; P07954; -. DR BioMuta; FH; -. DR DMDM; 1730117; -. DR REPRODUCTION-2DPAGE; IPI00296053; -. DR CPTAC; CPTAC-2732; -. DR EPD; P07954; -. DR jPOST; P07954; -. DR MassIVE; P07954; -. DR MaxQB; P07954; -. DR PaxDb; 9606-ENSP00000355518; -. DR PeptideAtlas; P07954; -. DR ProteomicsDB; 52052; -. [P07954-1] DR ProteomicsDB; 52053; -. [P07954-2] DR Pumba; P07954; -. DR TopDownProteomics; P07954-2; -. [P07954-2] DR Antibodypedia; 34701; 763 antibodies from 42 providers. DR CPTC; P07954; 1 antibody. DR DNASU; 2271; -. DR Ensembl; ENST00000366560.4; ENSP00000355518.4; ENSG00000091483.8. [P07954-1] DR GeneID; 2271; -. DR KEGG; hsa:2271; -. DR MANE-Select; ENST00000366560.4; ENSP00000355518.4; NM_000143.4; NP_000134.2. DR UCSC; uc001hyx.4; human. [P07954-1] DR AGR; HGNC:3700; -. DR CTD; 2271; -. DR DisGeNET; 2271; -. DR GeneCards; FH; -. DR GeneReviews; FH; -. DR HGNC; HGNC:3700; FH. DR HPA; ENSG00000091483; Tissue enhanced (liver). DR MalaCards; FH; -. DR MIM; 136850; gene. DR MIM; 150800; phenotype. DR MIM; 606812; phenotype. DR neXtProt; NX_P07954; -. DR OpenTargets; ENSG00000091483; -. DR Orphanet; 24; Fumaric aciduria. DR Orphanet; 523; Hereditary leiomyomatosis and renal cell cancer. DR Orphanet; 29072; Hereditary pheochromocytoma-paraganglioma. DR PharmGKB; PA28139; -. DR VEuPathDB; HostDB:ENSG00000091483; -. DR eggNOG; KOG1317; Eukaryota. DR GeneTree; ENSGT00950000183122; -. DR HOGENOM; CLU_021594_4_1_1; -. DR InParanoid; P07954; -. DR OMA; AKWRAQT; -. DR OrthoDB; 1341425at2759; -. DR PhylomeDB; P07954; -. DR TreeFam; TF300441; -. DR BioCyc; MetaCyc:ENSG00000091483-MONOMER; -. DR BRENDA; 4.2.1.2; 2681. DR PathwayCommons; P07954; -. DR Reactome; R-HSA-71403; Citric acid cycle (TCA cycle). DR SABIO-RK; P07954; -. DR SignaLink; P07954; -. DR SIGNOR; P07954; -. DR UniPathway; UPA00223; UER01007. DR BioGRID-ORCS; 2271; 140 hits in 1169 CRISPR screens. DR EvolutionaryTrace; P07954; -. DR GenomeRNAi; 2271; -. DR Pharos; P07954; Tbio. DR PRO; PR:P07954; -. DR Proteomes; UP000005640; Chromosome 1. DR RNAct; P07954; Protein. DR Bgee; ENSG00000091483; Expressed in heart right ventricle and 212 other cell types or tissues. DR ExpressionAtlas; P07954; baseline and differential. DR GO; GO:0005694; C:chromosome; IEA:UniProtKB-SubCell. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:UniProtKB. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0005759; C:mitochondrial matrix; TAS:Reactome. DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0035861; C:site of double-strand break; IDA:UniProtKB. DR GO; GO:0045239; C:tricarboxylic acid cycle enzyme complex; IEA:InterPro. DR GO; GO:0004333; F:fumarate hydratase activity; IDA:UniProtKB. DR GO; GO:0042393; F:histone binding; IPI:UniProtKB. DR GO; GO:0006974; P:DNA damage response; IDA:UniProtKB. DR GO; GO:0006281; P:DNA repair; IEA:UniProtKB-KW. DR GO; GO:0006106; P:fumarate metabolic process; IDA:UniProtKB. DR GO; GO:0048873; P:homeostasis of number of cells within a tissue; IEA:Ensembl. DR GO; GO:0006108; P:malate metabolic process; IDA:UniProtKB. DR GO; GO:0120162; P:positive regulation of cold-induced thermogenesis; ISS:YuBioLab. DR GO; GO:2001034; P:positive regulation of double-strand break repair via nonhomologous end joining; IDA:UniProtKB. DR GO; GO:0000821; P:regulation of arginine metabolic process; ISS:UniProtKB. DR GO; GO:0006099; P:tricarboxylic acid cycle; IBA:GO_Central. DR GO; GO:0000050; P:urea cycle; ISS:UniProtKB. DR CDD; cd01362; Fumarase_classII; 1. DR Gene3D; 1.10.40.30; Fumarase/aspartase (C-terminal domain); 1. DR Gene3D; 1.20.200.10; Fumarase/aspartase (Central domain); 1. DR Gene3D; 1.10.275.10; Fumarase/aspartase (N-terminal domain); 1. DR HAMAP; MF_00743; FumaraseC; 1. DR InterPro; IPR005677; Fum_hydII. DR InterPro; IPR024083; Fumarase/histidase_N. DR InterPro; IPR018951; Fumarase_C_C. DR InterPro; IPR020557; Fumarate_lyase_CS. DR InterPro; IPR000362; Fumarate_lyase_fam. DR InterPro; IPR022761; Fumarate_lyase_N. DR InterPro; IPR008948; L-Aspartase-like. DR NCBIfam; TIGR00979; fumC_II; 1. DR PANTHER; PTHR11444; ASPARTATEAMMONIA/ARGININOSUCCINATE/ADENYLOSUCCINATE LYASE; 1. DR PANTHER; PTHR11444:SF1; FUMARATE HYDRATASE, MITOCHONDRIAL; 1. DR Pfam; PF10415; FumaraseC_C; 1. DR Pfam; PF00206; Lyase_1; 1. DR PRINTS; PR00149; FUMRATELYASE. DR SUPFAM; SSF48557; L-aspartase-like; 1. DR PROSITE; PS00163; FUMARATE_LYASES; 1. DR SWISS-2DPAGE; P07954; -. DR UCD-2DPAGE; P07954; -. DR Genevisible; P07954; HS. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Alternative initiation; Chromosome; Cytoplasm; KW Direct protein sequencing; Disease variant; DNA damage; DNA repair; Lyase; KW Mitochondrion; Nucleus; Phosphoprotein; Reference proteome; KW Transit peptide; Tricarboxylic acid cycle; Tumor suppressor. FT TRANSIT 1..44 FT /note="Mitochondrion" FT /evidence="ECO:0000250|UniProtKB:P10173" FT CHAIN 45..510 FT /note="Fumarate hydratase, mitochondrial" FT /id="PRO_0000010319" FT ACT_SITE 235 FT /note="Proton donor/acceptor" FT /evidence="ECO:0000250|UniProtKB:P05042" FT ACT_SITE 365 FT /evidence="ECO:0000250|UniProtKB:P9WN93" FT BINDING 145..147 FT /ligand="substrate" FT /evidence="ECO:0000250|UniProtKB:P05042" FT BINDING 176..179 FT /ligand="substrate" FT /note="in site B" FT /evidence="ECO:0000250|UniProtKB:P05042" FT BINDING 186..188 FT /ligand="substrate" FT /evidence="ECO:0000250|UniProtKB:P05042" FT BINDING 234 FT /ligand="substrate" FT /evidence="ECO:0000250|UniProtKB:P9WN93" FT BINDING 366 FT /ligand="substrate" FT /evidence="ECO:0000250|UniProtKB:P9WN93" FT BINDING 371..373 FT /ligand="substrate" FT /evidence="ECO:0000250|UniProtKB:P9WN93" FT SITE 378 FT /note="Important for catalytic activity" FT /evidence="ECO:0000250|UniProtKB:P05042" FT MOD_RES 61 FT /note="N6-acetyllysine; alternate" FT /evidence="ECO:0000250|UniProtKB:P97807" FT MOD_RES 61 FT /note="N6-succinyllysine; alternate" FT /evidence="ECO:0000250|UniProtKB:P97807" FT MOD_RES 66 FT /note="N6-acetyllysine; alternate" FT /evidence="ECO:0007744|PubMed:19608861" FT MOD_RES 66 FT /note="N6-succinyllysine; alternate" FT /evidence="ECO:0000250|UniProtKB:P97807" FT MOD_RES 80 FT /note="N6-acetyllysine; alternate" FT /evidence="ECO:0007744|PubMed:19608861" FT MOD_RES 80 FT /note="N6-succinyllysine; alternate" FT /evidence="ECO:0000250|UniProtKB:P97807" FT MOD_RES 85 FT /note="Phosphothreonine" FT /evidence="ECO:0000250|UniProtKB:P97807" FT MOD_RES 90 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 94 FT /note="N6-acetyllysine" FT /evidence="ECO:0007744|PubMed:19608861" FT MOD_RES 115 FT /note="N6-acetyllysine; alternate" FT /evidence="ECO:0000250|UniProtKB:P97807" FT MOD_RES 115 FT /note="N6-succinyllysine; alternate" FT /evidence="ECO:0000250|UniProtKB:P97807" FT MOD_RES 122 FT /note="N6-acetyllysine; alternate" FT /evidence="ECO:0000250|UniProtKB:P97807" FT MOD_RES 122 FT /note="N6-succinyllysine; alternate" FT /evidence="ECO:0000250|UniProtKB:P97807" FT MOD_RES 213 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:P97807" FT MOD_RES 223 FT /note="N6-acetyllysine; alternate" FT /evidence="ECO:0000250|UniProtKB:P97807" FT MOD_RES 223 FT /note="N6-succinyllysine; alternate" FT /evidence="ECO:0000250|UniProtKB:P97807" FT MOD_RES 236 FT /note="Phosphothreonine; by PRKDC" FT /evidence="ECO:0000269|PubMed:26237645" FT MOD_RES 256 FT /note="N6-acetyllysine" FT /evidence="ECO:0007744|PubMed:19608861" FT MOD_RES 292 FT /note="N6-acetyllysine; alternate" FT /evidence="ECO:0007744|PubMed:19608861" FT MOD_RES 292 FT /note="N6-succinyllysine; alternate" FT /evidence="ECO:0000250|UniProtKB:P97807" FT MOD_RES 366 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:24275569" FT MOD_RES 467 FT /note="N6-succinyllysine" FT /evidence="ECO:0000250|UniProtKB:P97807" FT MOD_RES 473 FT /note="N6-succinyllysine" FT /evidence="ECO:0000250|UniProtKB:P97807" FT MOD_RES 502 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:P97807" FT VAR_SEQ 1..43 FT /note="Missing (in isoform Cytoplasmic)" FT /evidence="ECO:0000269|PubMed:27037871" FT /id="VSP_018965" FT VARIANT 107 FT /note="N -> T (in HLRCC; dbSNP:rs121913121)" FT /evidence="ECO:0000269|PubMed:11865300" FT /id="VAR_013497" FT VARIANT 117 FT /note="A -> P (in HLRCC; dbSNP:rs886039363)" FT /evidence="ECO:0000269|PubMed:11865300" FT /id="VAR_013498" FT VARIANT 180 FT /note="H -> R (in HLRCC; dbSNP:rs863224015)" FT /evidence="ECO:0000269|PubMed:11865300" FT /id="VAR_013499" FT VARIANT 185 FT /note="Q -> R (in HLRCC; dbSNP:rs779707997)" FT /evidence="ECO:0000269|PubMed:11865300" FT /id="VAR_013500" FT VARIANT 230 FT /note="K -> R (in FMRD and HLRCC; dbSNP:rs752232718)" FT /evidence="ECO:0000269|PubMed:11865300, FT ECO:0000269|PubMed:9635293" FT /id="VAR_002445" FT VARIANT 233 FT /note="R -> H (in HLRCC; catalytically inactive mutant; FT abolished ability to promote DNA repair; FT dbSNP:rs121913123)" FT /evidence="ECO:0000269|PubMed:11865300, FT ECO:0000269|PubMed:26237645" FT /id="VAR_013501" FT VARIANT 282 FT /note="G -> V (in HLRCC; dbSNP:rs935002190)" FT /evidence="ECO:0000269|PubMed:11865300" FT /id="VAR_013502" FT VARIANT 308 FT /note="A -> T (in FMRD; dbSNP:rs121913118)" FT /evidence="ECO:0000269|PubMed:9635293, ECO:0000269|Ref.23" FT /id="VAR_002446" FT VARIANT 312 FT /note="F -> C (in FMRD; dbSNP:rs1553341046)" FT /evidence="ECO:0000269|PubMed:9635293" FT /id="VAR_002447" FT VARIANT 328 FT /note="M -> R (in HLRCC)" FT /evidence="ECO:0000269|PubMed:11865300" FT /id="VAR_013503" FT VARIANT 362 FT /note="E -> Q (in HLRCC; dbSNP:rs121913119)" FT /evidence="ECO:0000269|PubMed:8200987" FT /id="VAR_081606" FT VARIANT 425 FT /note="D -> V (in FMRD)" FT /evidence="ECO:0000269|PubMed:9635293" FT /id="VAR_002448" FT MUTAGEN 46 FT /note="S->A: Does not affect phosphorylation by PRKDC." FT /evidence="ECO:0000269|PubMed:26237645" FT MUTAGEN 147 FT /note="T->A: Does not affect phosphorylation by PRKDC." FT /evidence="ECO:0000269|PubMed:26237645" FT MUTAGEN 187 FT /note="S->A: Does not affect phosphorylation by PRKDC." FT /evidence="ECO:0000269|PubMed:26237645" FT MUTAGEN 236 FT /note="T->A: Abolished interaction with H2AZ1 and FT localization to chromatin in response to DNA damage." FT /evidence="ECO:0000269|PubMed:26237645" FT MUTAGEN 236 FT /note="T->D: Phosphomimetic mutant; promotes interaction FT with H2AZ1, leading to increased localization to chromatin FT in response to DNA damage." FT /evidence="ECO:0000269|PubMed:26237645" FT STRAND 50..55 FT /evidence="ECO:0007829|PDB:5UPP" FT STRAND 58..63 FT /evidence="ECO:0007829|PDB:5UPP" FT HELIX 70..78 FT /evidence="ECO:0007829|PDB:5UPP" FT HELIX 84..86 FT /evidence="ECO:0007829|PDB:5UPP" FT HELIX 90..107 FT /evidence="ECO:0007829|PDB:5UPP" FT HELIX 108..110 FT /evidence="ECO:0007829|PDB:5UPP" FT HELIX 114..128 FT /evidence="ECO:0007829|PDB:5UPP" FT TURN 129..132 FT /evidence="ECO:0007829|PDB:6VBE" FT HELIX 133..135 FT /evidence="ECO:0007829|PDB:5UPP" FT STRAND 139..142 FT /evidence="ECO:0007829|PDB:5UPP" FT HELIX 147..164 FT /evidence="ECO:0007829|PDB:5UPP" FT HELIX 177..181 FT /evidence="ECO:0007829|PDB:5UPP" FT TURN 182..184 FT /evidence="ECO:0007829|PDB:5UPP" FT TURN 187..189 FT /evidence="ECO:0007829|PDB:5UPP" FT HELIX 190..205 FT /evidence="ECO:0007829|PDB:5UPP" FT HELIX 207..224 FT /evidence="ECO:0007829|PDB:5UPP" FT TURN 225..227 FT /evidence="ECO:0007829|PDB:5UPP" FT STRAND 229..234 FT /evidence="ECO:0007829|PDB:5UPP" FT STRAND 237..243 FT /evidence="ECO:0007829|PDB:5UPP" FT HELIX 244..264 FT /evidence="ECO:0007829|PDB:5UPP" FT TURN 267..270 FT /evidence="ECO:0007829|PDB:5UPP" FT TURN 277..279 FT /evidence="ECO:0007829|PDB:5UPP" FT HELIX 289..301 FT /evidence="ECO:0007829|PDB:5UPP" FT HELIX 311..316 FT /evidence="ECO:0007829|PDB:5UPP" FT HELIX 319..345 FT /evidence="ECO:0007829|PDB:5UPP" FT STRAND 349..352 FT /evidence="ECO:0007829|PDB:5UPP" FT STRAND 366..368 FT /evidence="ECO:0007829|PDB:3E04" FT HELIX 375..399 FT /evidence="ECO:0007829|PDB:5UPP" FT HELIX 409..433 FT /evidence="ECO:0007829|PDB:5UPP" FT HELIX 435..437 FT /evidence="ECO:0007829|PDB:5UPP" FT HELIX 442..451 FT /evidence="ECO:0007829|PDB:5UPP" FT HELIX 454..459 FT /evidence="ECO:0007829|PDB:5UPP" FT HELIX 460..463 FT /evidence="ECO:0007829|PDB:5UPP" FT HELIX 465..478 FT /evidence="ECO:0007829|PDB:5UPP" FT HELIX 482..488 FT /evidence="ECO:0007829|PDB:5UPP" FT HELIX 494..500 FT /evidence="ECO:0007829|PDB:5UPP" FT HELIX 503..505 FT /evidence="ECO:0007829|PDB:5UPP" FT STRAND 506..508 FT /evidence="ECO:0007829|PDB:5UPP" FT INIT_MET P07954-2:1 FT /note="Removed" FT /evidence="ECO:0000269|PubMed:27037871" SQ SEQUENCE 510 AA; 54637 MW; 86F91F95DC046F64 CRC64; MYRALRLLAR SRPLVRAPAA ALASAPGLGG AAVPSFWPPN AARMASQNSF RIEYDTFGEL KVPNDKYYGA QTVRSTMNFK IGGVTERMPT PVIKAFGILK RAAAEVNQDY GLDPKIANAI MKAADEVAEG KLNDHFPLVV WQTGSGTQTN MNVNEVISNR AIEMLGGELG SKIPVHPNDH VNKSQSSNDT FPTAMHIAAA IEVHEVLLPG LQKLHDALDA KSKEFAQIIK IGRTHTQDAV PLTLGQEFSG YVQQVKYAMT RIKAAMPRIY ELAAGGTAVG TGLNTRIGFA EKVAAKVAAL TGLPFVTAPN KFEALAAHDA LVELSGAMNT TACSLMKIAN DIRFLGSGPR SGLGELILPE NEPGSSIMPG KVNPTQCEAM TMVAAQVMGN HVAVTVGGSN GHFELNVFKP MMIKNVLHSA RLLGDASVSF TENCVVGIQA NTERINKLMN ESLMLVTALN PHIGYDKAAK IAKTAHKNGS TLKETAIELG YLTAEQFDEW VKPKDMLGPK //