FUMH_RAT
ID FUMH_RAT Reviewed; 507 AA.
AC P14408; Q5M964;
DT 01-JAN-1990, integrated into UniProtKB/Swiss-Prot.
DT 08-MAY-2019, sequence version 2.
DT 03-AUG-2022, entry version 167.
DE RecName: Full=Fumarate hydratase, mitochondrial {ECO:0000250|UniProtKB:P07954};
DE Short=Fumarase {ECO:0000303|PubMed:2914923};
DE EC=4.2.1.2 {ECO:0000250|UniProtKB:P07954};
DE Flags: Precursor;
GN Name=Fh {ECO:0000312|RGD:2614};
GN Synonyms=Fh1 {ECO:0000250|UniProtKB:P97807};
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS MITOCHONDRIAL AND CYTOPLASMIC),
RP PARTIAL PROTEIN SEQUENCE, AND SUBCELLULAR LOCATION.
RC TISSUE=Liver;
RX PubMed=2914923; DOI=10.1016/s0021-9258(19)81652-6;
RA Suzuki T., Sato M., Yoshida T., Tuboi S.;
RT "Rat liver mitochondrial and cytosolic fumarases with identical amino acid
RT sequences are encoded from a single gene.";
RL J. Biol. Chem. 264:2581-2586(1989).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Brown Norway;
RX PubMed=15057822; DOI=10.1038/nature02426;
RA Gibbs R.A., Weinstock G.M., Metzker M.L., Muzny D.M., Sodergren E.J.,
RA Scherer S., Scott G., Steffen D., Worley K.C., Burch P.E., Okwuonu G.,
RA Hines S., Lewis L., Deramo C., Delgado O., Dugan-Rocha S., Miner G.,
RA Morgan M., Hawes A., Gill R., Holt R.A., Adams M.D., Amanatides P.G.,
RA Baden-Tillson H., Barnstead M., Chin S., Evans C.A., Ferriera S.,
RA Fosler C., Glodek A., Gu Z., Jennings D., Kraft C.L., Nguyen T.,
RA Pfannkoch C.M., Sitter C., Sutton G.G., Venter J.C., Woodage T., Smith D.,
RA Lee H.-M., Gustafson E., Cahill P., Kana A., Doucette-Stamm L.,
RA Weinstock K., Fechtel K., Weiss R.B., Dunn D.M., Green E.D.,
RA Blakesley R.W., Bouffard G.G., De Jong P.J., Osoegawa K., Zhu B., Marra M.,
RA Schein J., Bosdet I., Fjell C., Jones S., Krzywinski M., Mathewson C.,
RA Siddiqui A., Wye N., McPherson J., Zhao S., Fraser C.M., Shetty J.,
RA Shatsman S., Geer K., Chen Y., Abramzon S., Nierman W.C., Havlak P.H.,
RA Chen R., Durbin K.J., Egan A., Ren Y., Song X.-Z., Li B., Liu Y., Qin X.,
RA Cawley S., Cooney A.J., D'Souza L.M., Martin K., Wu J.Q.,
RA Gonzalez-Garay M.L., Jackson A.R., Kalafus K.J., McLeod M.P.,
RA Milosavljevic A., Virk D., Volkov A., Wheeler D.A., Zhang Z., Bailey J.A.,
RA Eichler E.E., Tuzun E., Birney E., Mongin E., Ureta-Vidal A., Woodwark C.,
RA Zdobnov E., Bork P., Suyama M., Torrents D., Alexandersson M., Trask B.J.,
RA Young J.M., Huang H., Wang H., Xing H., Daniels S., Gietzen D., Schmidt J.,
RA Stevens K., Vitt U., Wingrove J., Camara F., Mar Alba M., Abril J.F.,
RA Guigo R., Smit A., Dubchak I., Rubin E.M., Couronne O., Poliakov A.,
RA Huebner N., Ganten D., Goesele C., Hummel O., Kreitler T., Lee Y.-A.,
RA Monti J., Schulz H., Zimdahl H., Himmelbauer H., Lehrach H., Jacob H.J.,
RA Bromberg S., Gullings-Handley J., Jensen-Seaman M.I., Kwitek A.E.,
RA Lazar J., Pasko D., Tonellato P.J., Twigger S., Ponting C.P., Duarte J.M.,
RA Rice S., Goodstadt L., Beatson S.A., Emes R.D., Winter E.E., Webber C.,
RA Brandt P., Nyakatura G., Adetobi M., Chiaromonte F., Elnitski L.,
RA Eswara P., Hardison R.C., Hou M., Kolbe D., Makova K., Miller W.,
RA Nekrutenko A., Riemer C., Schwartz S., Taylor J., Yang S., Zhang Y.,
RA Lindpaintner K., Andrews T.D., Caccamo M., Clamp M., Clarke L., Curwen V.,
RA Durbin R.M., Eyras E., Searle S.M., Cooper G.M., Batzoglou S., Brudno M.,
RA Sidow A., Stone E.A., Payseur B.A., Bourque G., Lopez-Otin C., Puente X.S.,
RA Chakrabarti K., Chatterji S., Dewey C., Pachter L., Bray N., Yap V.B.,
RA Caspi A., Tesler G., Pevzner P.A., Haussler D., Roskin K.M., Baertsch R.,
RA Clawson H., Furey T.S., Hinrichs A.S., Karolchik D., Kent W.J.,
RA Rosenbloom K.R., Trumbower H., Weirauch M., Cooper D.N., Stenson P.D.,
RA Ma B., Brent M., Arumugam M., Shteynberg D., Copley R.R., Taylor M.S.,
RA Riethman H., Mudunuri U., Peterson J., Guyer M., Felsenfeld A., Old S.,
RA Mockrin S., Collins F.S.;
RT "Genome sequence of the Brown Norway rat yields insights into mammalian
RT evolution.";
RL Nature 428:493-521(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Brown Norway {ECO:0000312|EMBL:EDL94769.1};
RA Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain {ECO:0000312|EMBL:AAH87598.1};
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 [5]
RP PROTEIN SEQUENCE OF 266-283 AND 420-441, AND IDENTIFICATION BY MASS
RP SPECTROMETRY.
RC STRAIN=Sprague-Dawley; TISSUE=Hippocampus, and Spinal cord;
RA Lubec G., Afjehi-Sadat L., Chen W.-Q.;
RL Submitted (APR-2007) to UniProtKB.
CC -!- FUNCTION: Catalyzes the reversible stereospecific interconversion of
CC fumarate to L-malate (By similarity). Experiments in other species have
CC demonstrated that specific isoforms of this protein act in defined
CC pathways and favor one direction over the other (Probable).
CC {ECO:0000250|UniProtKB:P07954, 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. Fumarate metabolism in the cytosol plays a role during
CC urea cycle and arginine metabolism; fumarate being a by-product of the
CC urea cycle and amino-acid catabolism (By similarity). Also plays a role
CC in DNA repair by promoting non-homologous end-joining (NHEJ). In
CC response to DNA damage and phosphorylation by PRKDC, translocates to
CC the nucleus and accumulates at DNA double-strand breaks (DSBs): acts by
CC catalyzing formation of fumarate, an inhibitor of KDM2B histone
CC demethylase activity, resulting in enhanced dimethylation of histone H3
CC 'Lys-36' (H3K36me2) (By similarity). {ECO:0000250|UniProtKB:P07954,
CC ECO:0000250|UniProtKB:P97807}.
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 -!- PATHWAY: Carbohydrate metabolism; tricarboxylic acid cycle; (S)-malate
CC from fumarate: step 1/1. {ECO:0000250|UniProtKB:P10173}.
CC -!- SUBUNIT: Homotetramer. Interacts with H2AZ1.
CC {ECO:0000250|UniProtKB:P07954}.
CC -!- SUBCELLULAR LOCATION: [Isoform Mitochondrial]: Mitochondrion
CC {ECO:0000269|PubMed:2914923}.
CC -!- SUBCELLULAR LOCATION: [Isoform Cytoplasmic]: Cytoplasm, cytosol
CC {ECO:0000269|PubMed:2914923}. Nucleus {ECO:0000250|UniProtKB:P07954}.
CC Chromosome {ECO:0000250|UniProtKB:P07954}. Note=Translocates to the
CC nucleus in response to DNA damage: localizes to DNA double-strand
CC breaks (DSBs) following phosphorylation by PRKDC.
CC {ECO:0000250|UniProtKB:P07954}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative initiation; Named isoforms=2;
CC Name=Mitochondrial {ECO:0000303|PubMed:2914923};
CC IsoId=P14408-1; Sequence=Displayed;
CC Name=Cytoplasmic {ECO:0000303|PubMed:2914923};
CC IsoId=P14408-2; Sequence=VSP_018968;
CC -!- PTM: [Isoform Cytoplasmic]: Phosphorylation at Thr-233 by PRKDC in
CC response to DNA damage promotes translocation to the nucleus and
CC recruitment to DNA double-strand breaks (DSBs).
CC {ECO:0000250|UniProtKB:P07954}.
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}.
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DR EMBL; J04473; AAA41177.1; -; mRNA.
DR EMBL; AC109958; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC087598; AAH87598.1; -; mRNA.
DR EMBL; AC119639; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH473985; EDL94769.1; -; Genomic_DNA.
DR PIR; A31424; UFRT.
DR RefSeq; NP_058701.2; NM_017005.2. [P14408-1]
DR AlphaFoldDB; P14408; -.
DR SMR; P14408; -.
DR IntAct; P14408; 1.
DR STRING; 10116.ENSRNOP00000004917; -.
DR iPTMnet; P14408; -.
DR PhosphoSitePlus; P14408; -.
DR jPOST; P14408; -.
DR PaxDb; P14408; -.
DR PeptideAtlas; P14408; -.
DR PRIDE; P14408; -.
DR Ensembl; ENSRNOT00000004917; ENSRNOP00000004917; ENSRNOG00000003653. [P14408-1]
DR GeneID; 24368; -.
DR KEGG; rno:24368; -.
DR UCSC; RGD:2614; rat. [P14408-1]
DR CTD; 2271; -.
DR RGD; 2614; Fh.
DR eggNOG; KOG1317; Eukaryota.
DR GeneTree; ENSGT00950000183122; -.
DR HOGENOM; CLU_021594_4_1_1; -.
DR InParanoid; P14408; -.
DR OMA; HDSMGEV; -.
DR OrthoDB; 1022919at2759; -.
DR PhylomeDB; P14408; -.
DR TreeFam; TF300441; -.
DR BRENDA; 4.2.1.2; 5301.
DR Reactome; R-RNO-71403; Citric acid cycle (TCA cycle).
DR SABIO-RK; P14408; -.
DR UniPathway; UPA00223; UER01007.
DR PRO; PR:P14408; -.
DR Proteomes; UP000002494; Chromosome 13.
DR Proteomes; UP000234681; Chromosome 13.
DR Bgee; ENSRNOG00000003653; Expressed in heart and 20 other tissues.
DR GO; GO:0005694; C:chromosome; IEA:UniProtKB-SubCell.
DR GO; GO:0005829; C:cytosol; IEA:UniProtKB-SubCell.
DR GO; GO:0005739; C:mitochondrion; IDA:RGD.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0045239; C:tricarboxylic acid cycle enzyme complex; IEA:InterPro.
DR GO; GO:0004333; F:fumarate hydratase activity; IDA:RGD.
DR GO; GO:0006974; P:cellular response to DNA damage stimulus; ISS:UniProtKB.
DR GO; GO:0006281; P:DNA repair; IEA:UniProtKB-KW.
DR GO; GO:0006106; P:fumarate metabolic process; IDA:RGD.
DR GO; GO:0048873; P:homeostasis of number of cells within a tissue; ISO:RGD.
DR GO; GO:0006108; P:malate metabolic process; IDA:RGD.
DR GO; GO:0000415; P:negative regulation of histone H3-K36 methylation; ISS: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; ISS:UniProtKB.
DR GO; GO:0000821; P:regulation of arginine metabolic process; ISS:UniProtKB.
DR GO; GO:0006099; P:tricarboxylic acid cycle; IDA:RGD.
DR GO; GO:0000050; P:urea cycle; ISS:UniProtKB.
DR CDD; cd01362; Fumarase_classII; 1.
DR Gene3D; 1.10.275.10; -; 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 PANTHER; PTHR11444; PTHR11444; 1.
DR Pfam; PF10415; FumaraseC_C; 1.
DR Pfam; PF00206; Lyase_1; 1.
DR PRINTS; PR00149; FUMRATELYASE.
DR SUPFAM; SSF48557; SSF48557; 1.
DR TIGRFAMs; TIGR00979; fumC_II; 1.
DR PROSITE; PS00163; FUMARATE_LYASES; 1.
PE 1: Evidence at protein level;
KW Acetylation; Alternative initiation; Chromosome; Cytoplasm;
KW Direct protein sequencing; DNA damage; DNA repair; Lyase; Mitochondrion;
KW Nucleus; Phosphoprotein; Reference proteome; Transit peptide;
KW Tricarboxylic acid cycle.
FT TRANSIT 1..41
FT /note="Mitochondrion"
FT /evidence="ECO:0000269|PubMed:2914923"
FT CHAIN 42..507
FT /note="Fumarate hydratase, mitochondrial"
FT /id="PRO_0000010325"
FT ACT_SITE 232
FT /note="Proton donor/acceptor"
FT /evidence="ECO:0000250|UniProtKB:P05042"
FT ACT_SITE 362
FT /evidence="ECO:0000250|UniProtKB:P9WN93"
FT BINDING 142..144
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P05042"
FT BINDING 173..176
FT /ligand="substrate"
FT /note="in site B"
FT /evidence="ECO:0000250|UniProtKB:P05042"
FT BINDING 183..185
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P05042"
FT BINDING 231
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P9WN93"
FT BINDING 363
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P9WN93"
FT BINDING 368..370
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P9WN93"
FT SITE 375
FT /note="Important for catalytic activity"
FT /evidence="ECO:0000250|UniProtKB:P05042"
FT MOD_RES 58
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P97807"
FT MOD_RES 58
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P97807"
FT MOD_RES 63
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P07954"
FT MOD_RES 63
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P97807"
FT MOD_RES 77
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P07954"
FT MOD_RES 77
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P97807"
FT MOD_RES 82
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:P97807"
FT MOD_RES 91
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P07954"
FT MOD_RES 112
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P97807"
FT MOD_RES 112
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P97807"
FT MOD_RES 119
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P97807"
FT MOD_RES 119
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P97807"
FT MOD_RES 210
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P97807"
FT MOD_RES 220
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P97807"
FT MOD_RES 220
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P97807"
FT MOD_RES 233
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:P07954"
FT MOD_RES 289
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P07954"
FT MOD_RES 289
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P97807"
FT MOD_RES 363
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P07954"
FT MOD_RES 464
FT /note="N6-succinyllysine"
FT /evidence="ECO:0000250|UniProtKB:P97807"
FT MOD_RES 470
FT /note="N6-succinyllysine"
FT /evidence="ECO:0000250|UniProtKB:P97807"
FT MOD_RES 499
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P97807"
FT VAR_SEQ 1..40
FT /note="Missing (in isoform Cytoplasmic)"
FT /evidence="ECO:0000305"
FT /id="VSP_018968"
FT CONFLICT 481
FT /note="E -> K (in Ref. 1; AAA41177)"
FT /evidence="ECO:0000305"
FT INIT_MET P14408-2:1
FT /note="Removed"
FT /evidence="ECO:0000250|UniProtKB:P07954"
SQ SEQUENCE 507 AA; 54465 MW; 03042BBEEAC0D7D8 CRC64;
MNRAFCLLAR SRRFPRVPSA GAVLSGEAAT LPRCAPNVVR MASQNSFRIE YDTFGELKVP
TDKYYGAQTV RSTMNFKIGG ATERMPIPVI KAFGILKRAA AEVNQEYGLD PKIASAIMKA
ADEVAEGKLN DHFPLVVWQT GSGTQTNMNV NEVISNRAIE MLGGELGSKK PVHPNDHVNK
SQSSNDTFPT AMHIAAALEV HQVLLPGLQK LHDALSAKSK EFAQVIKIGR THTQDAVPLT
LGQEFSGYVQ QVQYAMERIK AAMPRIYELA AGGTAVGTGL NTRIGFAEKV AAKVAALTGL
PFVTAPNKFE ALAAHDALVE LSGAMNTTAC SLMKIANDIR FLGSGPRSGL GELILPENEP
GSSIMPGKVN PTQCEAMTMV AAQVMGNHVA VTVGGSNGHF ELNVFKPMMI KNVLHSARLL
GDASVSFTEN CVVGIQANTE RINKLMNESL MLVTALNPHI GYDKAAKIAK TAHKNGSTLK
ETAIELGYLT AEQFDEWVKP KDMLGPK
