ID   FUMH_PIG                Reviewed;         512 AA.
AC   P10173; A0A287AR55;
DT   01-JUL-1989, integrated into UniProtKB/Swiss-Prot.
DT   08-MAY-2019, sequence version 2.
DT   24-JAN-2024, entry version 132.
DE   RecName: Full=Fumarate hydratase, mitochondrial {ECO:0000250|UniProtKB:P07954};
DE            Short=Fumarase {ECO:0000303|PubMed:3377794};
DE            EC=4.2.1.2 {ECO:0000269|PubMed:21498518};
DE   Flags: Precursor;
GN   Name=FH {ECO:0000250|UniProtKB:P07954};
OS   Sus scrofa (Pig).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Laurasiatheria; Artiodactyla; Suina; Suidae; Sus.
OX   NCBI_TaxID=9823;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RG   Porcine genome sequencing project;
RL   Submitted (NOV-2009) to the EMBL/GenBank/DDBJ databases.
RN   [2]
RP   PROTEIN SEQUENCE OF 47-512, AND SUBUNIT.
RC   TISSUE=Heart;
RX   PubMed=3377794; DOI=10.1016/s0006-291x(88)81243-9;
RA   Sacchettini J.C., Frazier M.W., Chiara D.C., Banaszak L.J., Grant G.A.;
RT   "Amino acid sequence of porcine heart fumarase.";
RL   Biochem. Biophys. Res. Commun. 153:435-440(1988).
RN   [3]
RP   FUNCTION, CATALYTIC ACTIVITY, AND PATHWAY.
RX   PubMed=21498518; DOI=10.1074/jbc.m110.214452;
RA   Mescam M., Vinnakota K.C., Beard D.A.;
RT   "Identification of the catalytic mechanism and estimation of kinetic
RT   parameters for fumarase.";
RL   J. Biol. Chem. 286:21100-21109(2011).
CC   -!- FUNCTION: Catalyzes the reversible stereospecific interconversion of
CC       fumarate to L-malate (PubMed:21498518). Experiments in different
CC       species have demonstrated that specific isoforms of this protein act in
CC       defined pathways and favor one direction over the other (Probable).
CC       {ECO:0000269|PubMed:21498518, 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:0000269|PubMed:21498518}.
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:0000269|PubMed:21498518};
CC       PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:12462;
CC         Evidence={ECO:0000269|PubMed:21498518};
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:0000269|PubMed:21498518}.
CC   -!- SUBUNIT: Homotetramer (PubMed:21498518). Interacts with H2AZ1 (By
CC       similarity). {ECO:0000250|UniProtKB:P07954,
CC       ECO:0000269|PubMed:21498518}.
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) following phosphorylation by PRKDC.
CC       {ECO:0000250|UniProtKB:P07954}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative initiation; Named isoforms=2;
CC       Name=Mitochondrial {ECO:0000250|UniProtKB:P07954};
CC         IsoId=P10173-1; Sequence=Displayed;
CC       Name=Cytoplasmic {ECO:0000250|UniProtKB:P07954};
CC         IsoId=P10173-2; Sequence=VSP_060136;
CC   -!- PTM: [Isoform Cytoplasmic]: Phosphorylation at Thr-238 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; AEMK02000071; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   PIR; A27657; UFPG.
DR   RefSeq; NP_001230517.1; NM_001243588.1. [P10173-1]
DR   AlphaFoldDB; P10173; -.
DR   SMR; P10173; -.
DR   STRING; 9823.ENSSSCP00000046547; -.
DR   BindingDB; P10173; -.
DR   ChEMBL; CHEMBL6143; -.
DR   PaxDb; 9823-ENSSSCP00000026068; -.
DR   PeptideAtlas; P10173; -.
DR   Ensembl; ENSSSCT00000030683.4; ENSSSCP00000026068.4; ENSSSCG00000028178.4. [P10173-1]
DR   Ensembl; ENSSSCT00030040221.1; ENSSSCP00030018443.1; ENSSSCG00030028801.1. [P10173-1]
DR   Ensembl; ENSSSCT00065105714.1; ENSSSCP00065046931.1; ENSSSCG00065076536.1. [P10173-1]
DR   GeneID; 100627128; -.
DR   KEGG; ssc:100627128; -.
DR   CTD; 2271; -.
DR   eggNOG; KOG1317; Eukaryota.
DR   GeneTree; ENSGT00950000183122; -.
DR   InParanoid; P10173; -.
DR   OrthoDB; 1341425at2759; -.
DR   Reactome; R-SSC-71403; Citric acid cycle (TCA cycle).
DR   SABIO-RK; P10173; -.
DR   UniPathway; UPA00223; UER01007.
DR   Proteomes; UP000008227; Chromosome 10.
DR   Proteomes; UP000314985; Unplaced.
DR   Proteomes; UP000694570; Unplaced.
DR   Proteomes; UP000694571; Unplaced.
DR   Proteomes; UP000694720; Unplaced.
DR   Proteomes; UP000694722; Unplaced.
DR   Proteomes; UP000694723; Unplaced.
DR   Proteomes; UP000694724; Unplaced.
DR   Proteomes; UP000694725; Unplaced.
DR   Proteomes; UP000694726; Unplaced.
DR   Proteomes; UP000694727; Unplaced.
DR   Proteomes; UP000694728; Unplaced.
DR   GO; GO:0005694; C:chromosome; IEA:UniProtKB-SubCell.
DR   GO; GO:0005829; C:cytosol; IEA:UniProtKB-SubCell.
DR   GO; GO:0005759; C:mitochondrial matrix; IEA:Ensembl.
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; IDA: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; 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; IEA:Ensembl.
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; PR00149; FUMRATELYASE.
DR   SUPFAM; SSF48557; L-aspartase-like; 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..46
FT                   /note="Mitochondrion"
FT                   /evidence="ECO:0000269|PubMed:3377794"
FT   CHAIN           47..512
FT                   /note="Fumarate hydratase, mitochondrial"
FT                   /id="PRO_0000161335"
FT   REGION          17..36
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   ACT_SITE        237
FT                   /note="Proton donor/acceptor"
FT                   /evidence="ECO:0000250|UniProtKB:P05042"
FT   ACT_SITE        367
FT                   /evidence="ECO:0000250|UniProtKB:P9WN93"
FT   BINDING         147..149
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250|UniProtKB:P05042"
FT   BINDING         178..181
FT                   /ligand="substrate"
FT                   /note="in site B"
FT                   /evidence="ECO:0000250|UniProtKB:P05042"
FT   BINDING         188..190
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250|UniProtKB:P05042"
FT   BINDING         236
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250|UniProtKB:P9WN93"
FT   BINDING         368
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250|UniProtKB:P9WN93"
FT   BINDING         373..375
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250|UniProtKB:P9WN93"
FT   SITE            380
FT                   /note="Important for catalytic activity"
FT                   /evidence="ECO:0000250|UniProtKB:P05042"
FT   MOD_RES         63
FT                   /note="N6-acetyllysine; alternate"
FT                   /evidence="ECO:0000250|UniProtKB:P97807"
FT   MOD_RES         63
FT                   /note="N6-succinyllysine; alternate"
FT                   /evidence="ECO:0000250|UniProtKB:P97807"
FT   MOD_RES         68
FT                   /note="N6-acetyllysine; alternate"
FT                   /evidence="ECO:0000250|UniProtKB:P07954"
FT   MOD_RES         68
FT                   /note="N6-succinyllysine; alternate"
FT                   /evidence="ECO:0000250|UniProtKB:P97807"
FT   MOD_RES         82
FT                   /note="N6-acetyllysine; alternate"
FT                   /evidence="ECO:0000250|UniProtKB:P07954"
FT   MOD_RES         82
FT                   /note="N6-succinyllysine; alternate"
FT                   /evidence="ECO:0000250|UniProtKB:P97807"
FT   MOD_RES         87
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0000250|UniProtKB:P97807"
FT   MOD_RES         96
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:P07954"
FT   MOD_RES         117
FT                   /note="N6-acetyllysine; alternate"
FT                   /evidence="ECO:0000250|UniProtKB:P97807"
FT   MOD_RES         117
FT                   /note="N6-succinyllysine; alternate"
FT                   /evidence="ECO:0000250|UniProtKB:P97807"
FT   MOD_RES         124
FT                   /note="N6-acetyllysine; alternate"
FT                   /evidence="ECO:0000250|UniProtKB:P97807"
FT   MOD_RES         124
FT                   /note="N6-succinyllysine; alternate"
FT                   /evidence="ECO:0000250|UniProtKB:P97807"
FT   MOD_RES         215
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:P97807"
FT   MOD_RES         238
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0000250|UniProtKB:P07954"
FT   MOD_RES         258
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:P07954"
FT   MOD_RES         294
FT                   /note="N6-acetyllysine; alternate"
FT                   /evidence="ECO:0000250|UniProtKB:P07954"
FT   MOD_RES         294
FT                   /note="N6-succinyllysine; alternate"
FT                   /evidence="ECO:0000250|UniProtKB:P97807"
FT   MOD_RES         368
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:P07954"
FT   MOD_RES         469
FT                   /note="N6-succinyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:P97807"
FT   MOD_RES         475
FT                   /note="N6-succinyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:P97807"
FT   MOD_RES         504
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:P97807"
FT   VAR_SEQ         1..45
FT                   /note="Missing (in isoform Cytoplasmic)"
FT                   /id="VSP_060136"
FT   CONFLICT        95
FT                   /note="I -> L (in Ref. 2; AA sequence)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        313
FT                   /note="K -> N (in Ref. 2; AA sequence)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        326
FT                   /note="L -> H (in Ref. 2; AA sequence)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        506
FT                   /note="K -> R (in Ref. 2; AA sequence)"
FT                   /evidence="ECO:0000305"
FT   INIT_MET        P10173-2:1
FT                   /note="Removed"
FT                   /evidence="ECO:0000250|UniProtKB:P07954"
SQ   SEQUENCE   512 AA;  54749 MW;  34BB2284D1F5AF20 CRC64;
     MDRALRLLAR SRCLSRVPAS APGPGPGSSP SGVSRLLLRP PNAARMASQN SFRIEYDTFG
     ELKVPNDKYY GAQTVRSTMN FKIGGVTERM PIPVIKAFGI LKRAAAEVNQ DYGLDPKIAN
     AIMKAADEVA EGKLNDHFPL VVWQTGSGTQ TNMNVNEVIS NRAIEMLGGE LGSKKPVHPN
     DHVNKSQSSN DTFPTAMHIA AAVEVHEALL PGLQKLHDAL DAKSREFAQI IKIGRTHTQD
     AVPLTLGQEF SGYVQQVKYA ITRIKAAMPR IYELAAGGTA VGTGLNTRIG FAEKVAAKVA
     ALTGLPFVTA PNKFEALAAH DALVELSGAM NTTACSLMKI ANDIRFLGSG PRSGLGELIL
     PENEPGSSIM PGKVNPTQCE ALTMVAAQVM GNHVAVTVGG SNGHFELNVF KPMMIKNVLH
     SARLLGDAAV SFTENCVVGI QANTERINKL MNESLMLVTA LNPHIGYDKA AKIAKTAHKN
     GSTLKATAVE LGYLTAEQFD EWVKPKDMLG PK
//