ID FUMH_MACFA Reviewed; 510 AA.
AC Q60HF9;
DT 12-APR-2005, integrated into UniProtKB/Swiss-Prot.
DT 23-NOV-2004, sequence version 1.
DT 24-JAN-2024, entry version 89.
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=QorA-13820 {ECO:0000303|Ref.1};
OS Macaca fascicularis (Crab-eating macaque) (Cynomolgus monkey).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini;
OC Cercopithecidae; Cercopithecinae; Macaca.
OX NCBI_TaxID=9541;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Occipital cortex;
RA Kusuda J., Osada N., Tanuma R., Hirata M., Sugano S., Hashimoto K.;
RT "Isolation and characterization of cDNA for macaque neurological disease
RT genes.";
RL Submitted (OCT-2003) 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 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: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=Q60HF9-1; Sequence=Displayed;
CC Name=Cytoplasmic {ECO:0000250|UniProtKB:P07954};
CC IsoId=Q60HF9-2; Sequence=VSP_018966;
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: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; AB125168; BAD51956.1; -; mRNA.
DR AlphaFoldDB; Q60HF9; -.
DR SMR; Q60HF9; -.
DR STRING; 9541.ENSMFAP00000028430; -.
DR eggNOG; KOG1317; Eukaryota.
DR UniPathway; UPA00223; UER01007.
DR Proteomes; UP000233100; 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; IEA:UniProtKB-SubCell.
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; IEA:UniProtKB-UniPathway.
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 2: Evidence at transcript level;
KW Acetylation; Alternative initiation; Chromosome; Cytoplasm; DNA damage;
KW DNA repair; Lyase; Mitochondrion; Nucleus; Phosphoprotein;
KW Reference proteome; Transit peptide; Tricarboxylic acid cycle.
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_0000010321"
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:0000250|UniProtKB:P07954"
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:0000250|UniProtKB:P07954"
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:0000250|UniProtKB:P07954"
FT MOD_RES 94
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P07954"
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"
FT /evidence="ECO:0000250|UniProtKB:P07954"
FT MOD_RES 256
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P07954"
FT MOD_RES 292
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P07954"
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:0000250|UniProtKB:P07954"
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:0000305"
FT /id="VSP_018966"
FT INIT_MET Q60HF9-2:1
FT /note="Removed"
FT /evidence="ECO:0000250|UniProtKB:P07954"
SQ SEQUENCE 510 AA; 54766 MW; F5FC970E977DEA09 CRC64;
MYRALWLLAR SRRLVRPPAS ALASAPGLSG AAVPSFWPPN AARMASQNSF RIEYDTFGEL
KVPNDKYYGA QTVRSTMNFK IGGVTERMPT PVIKAFGILK RAAAEVNQDY GLDPKIANAI
MKAADEVAEG KLNDHFPLVV WQTGSGTQTN MNVNEVISNR AIEMLGGELG SKIPVHPNDH
VNKSQSSNDT FPTAMHIAAA IEVHEVLLPG LQKLHDALDA KSKEFAQIIK IGRTHTQDAV
PLTLGQEFSG YVQQVKYAVT 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
//
