ID FUMH_DANRE Reviewed; 509 AA.
AC Q7SX99;
DT 15-DEC-2003, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-2003, sequence version 1.
DT 27-MAR-2024, entry version 116.
DE RecName: Full=Fumarate hydratase, mitochondrial {ECO:0000250|UniProtKB:P07954};
DE Short=Fumarase {ECO:0000250|UniProtKB:P07954};
DE EC=4.2.1.2 {ECO:0000250|UniProtKB:P07954};
DE Flags: Precursor;
GN Name=fh {ECO:0000250|UniProtKB:P07954};
GN ORFNames=zgc:66253 {ECO:0000303|Ref.1};
OS Danio rerio (Zebrafish) (Brachydanio rerio).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Actinopterygii; Neopterygii; Teleostei; Ostariophysi; Cypriniformes;
OC Danionidae; Danioninae; Danio.
OX NCBI_TaxID=7955;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=AB; TISSUE=Kidney;
RG NIH - Zebrafish Gene Collection (ZGC) project;
RL Submitted (FEB-2004) to the EMBL/GenBank/DDBJ databases.
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 translocates to the nucleus and accumulates at
CC DNA double-strand breaks (DSBs): acts by catalyzing formation of
CC fumarate (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. {ECO:0000250|UniProtKB:P07954}.
CC -!- SUBCELLULAR LOCATION: [Isoform Mitochondrial]: Mitochondrion
CC {ECO:0000250|UniProtKB:P07954}.
CC -!- SUBCELLULAR LOCATION: [Isoform Cytoplasmic]: Cytoplasm, cytosol
CC {ECO:0000250|UniProtKB:P07954}. 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). {ECO:0000250|UniProtKB:P07954}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative initiation; Named isoforms=2;
CC Name=Mitochondrial;
CC IsoId=Q7SX99-1; Sequence=Displayed;
CC Name=Cytoplasmic;
CC IsoId=Q7SX99-2; Sequence=VSP_060137;
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; BC055566; AAH55566.1; -; mRNA.
DR EMBL; BC066484; AAH66484.1; -; mRNA.
DR RefSeq; NP_957257.1; NM_200963.1. [Q7SX99-1]
DR AlphaFoldDB; Q7SX99; -.
DR SMR; Q7SX99; -.
DR STRING; 7955.ENSDARP00000097494; -.
DR PaxDb; 7955-ENSDARP00000097494; -.
DR GeneID; 393938; -.
DR KEGG; dre:393938; -.
DR AGR; ZFIN:ZDB-GENE-010724-6; -.
DR CTD; 2271; -.
DR ZFIN; ZDB-GENE-010724-6; fh.
DR eggNOG; KOG1317; Eukaryota.
DR InParanoid; Q7SX99; -.
DR OrthoDB; 1341425at2759; -.
DR PhylomeDB; Q7SX99; -.
DR Reactome; R-DRE-71403; Citric acid cycle (TCA cycle).
DR UniPathway; UPA00223; UER01007.
DR PRO; PR:Q7SX99; -.
DR Proteomes; UP000000437; Chromosome 12.
DR GO; GO:0005694; C:chromosome; IEA:UniProtKB-SubCell.
DR GO; GO:0005829; C:cytosol; IEA:UniProtKB-SubCell.
DR GO; GO:0005739; C:mitochondrion; IBA:GO_Central.
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; ISS:UniProtKB.
DR GO; GO:0006974; P:DNA damage response; ISS:UniProtKB.
DR GO; GO:0006281; P:DNA repair; IEA:UniProtKB-KW.
DR GO; GO:0006106; P:fumarate metabolic process; ISS:UniProtKB.
DR GO; GO:0006108; P:malate metabolic process; ISS:UniProtKB.
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; 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; PR00145; ARGSUCLYASE.
DR PRINTS; PR00149; FUMRATELYASE.
DR SUPFAM; SSF48557; L-aspartase-like; 1.
DR PROSITE; PS00163; FUMARATE_LYASES; 1.
PE 2: Evidence at transcript level;
KW Alternative initiation; Chromosome; Cytoplasm; DNA damage; DNA repair;
KW Lyase; Mitochondrion; Nucleus; Reference proteome; Transit peptide;
KW Tricarboxylic acid cycle.
FT TRANSIT 1..43
FT /note="Mitochondrion"
FT /evidence="ECO:0000250|UniProtKB:P10173"
FT CHAIN 44..509
FT /note="Fumarate hydratase, mitochondrial"
FT /id="PRO_0000010327"
FT ACT_SITE 234
FT /note="Proton donor/acceptor"
FT /evidence="ECO:0000250|UniProtKB:P05042"
FT ACT_SITE 364
FT /evidence="ECO:0000250|UniProtKB:P9WN93"
FT BINDING 144..146
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P05042"
FT BINDING 175..178
FT /ligand="substrate"
FT /note="in site B"
FT /evidence="ECO:0000250|UniProtKB:P05042"
FT BINDING 185..187
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P05042"
FT BINDING 233
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P9WN93"
FT BINDING 365
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P9WN93"
FT BINDING 370..372
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P9WN93"
FT SITE 377
FT /note="Important for catalytic activity"
FT /evidence="ECO:0000250|UniProtKB:P05042"
FT VAR_SEQ 1..42
FT /note="Missing (in isoform Cytoplasmic)"
FT /id="VSP_060137"
FT INIT_MET Q7SX99-2:1
FT /note="Removed"
FT /evidence="ECO:0000250|UniProtKB:P07954"
SQ SEQUENCE 509 AA; 54861 MW; 36A829D58EE18678 CRC64;
MYRSARSLHR FSASLSDLRA AQRSIKARNV CPAPGLRHQT VRMASSEAFR IERDTFGELK
VPSDKYYGAQ TVRSTMNFRI GGVTERMPIQ VIRAFGILKK AAAEVNKDYG LDPKIADAIM
KAADEVESGK LDDHFPLVVW QTGSGTQTNM NVNEVISNRA IEMLGGKLGS KDPVHPNDHV
NKSQSSNDTF PTAMHIAAAK EVHEVLLPGL QTLHDALAAK AEQFKDIIKI GRTHTQDAVP
LSLGQEFGGY VQQVKYSIAR VKASLPRVYE LAAGGTAVGT GLNTRIGFAE KVADKVSALT
GLPFVTAANK FEALAAHDAL VELSGALNTV AVSMMKIAND IRFLGSGPRS GLGELILPEN
EPGSSIMPGK VNPTQCEAMT MVAAQVMGNH VAVTVGGSNG HFELNVFKPM IIKNVLNSAR
LLGDASVSFT NNCVVGIEAN TERINKLMSE SLMLVTALNP HIGYDKAAKI AKTAHKDGST
LKEAALKLGF LNEQQFEEWV RPHDMLGPK
//
