FUMH_PIG
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 03-AUG-2022, entry version 124.
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.ENSSSCP00000026068; -.
DR ChEMBL; CHEMBL6143; -.
DR PaxDb; P10173; -.
DR PeptideAtlas; P10173; -.
DR PRIDE; P10173; -.
DR Ensembl; ENSSSCT00030040221; ENSSSCP00030018443; ENSSSCG00030028801. [P10173-1]
DR Ensembl; ENSSSCT00065105714; ENSSSCP00065046931; ENSSSCG00065076536. [P10173-1]
DR GeneID; 100627128; -.
DR KEGG; ssc:100627128; -.
DR CTD; 2271; -.
DR eggNOG; KOG1317; Eukaryota.
DR InParanoid; P10173; -.
DR OrthoDB; 1022919at2759; -.
DR Reactome; R-SSC-71403; Citric acid cycle (TCA cycle).
DR SABIO-RK; P10173; -.
DR UniPathway; UPA00223; UER01007.
DR Proteomes; UP000008227; Unplaced.
DR Proteomes; UP000314985; Unplaced.
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; IDA:UniProtKB.
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: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:0000415; P:negative regulation of histone H3-K36 methylation; ISS: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; 1.10.275.10; -; 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..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
