FUMH_YEAST
ID FUMH_YEAST Reviewed; 488 AA.
AC P08417; D6W3A8; Q08978;
DT 01-AUG-1988, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1997, sequence version 2.
DT 03-AUG-2022, entry version 210.
DE RecName: Full=Fumarate hydratase, mitochondrial;
DE Short=Fumarase {ECO:0000303|PubMed:3040736};
DE EC=4.2.1.2 {ECO:0000269|PubMed:11585823, ECO:0000269|PubMed:20231875, ECO:0000269|PubMed:3040736};
DE Flags: Precursor;
GN Name=FUM1 {ECO:0000303|PubMed:3040736, ECO:0000312|SGD:S000006183};
GN OrderedLocusNames=YPL262W;
OS Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (Baker's yeast).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Saccharomycotina; Saccharomycetes;
OC Saccharomycetales; Saccharomycetaceae; Saccharomyces.
OX NCBI_TaxID=559292;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND SUBCELLULAR LOCATION.
RX PubMed=3040736; DOI=10.1016/s0021-9258(18)45347-1;
RA Wu M., Tzagoloff A.;
RT "Mitochondrial and cytoplasmic fumarases in Saccharomyces cerevisiae are
RT encoded by a single nuclear gene FUM1.";
RL J. Biol. Chem. 262:12275-12282(1987).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=ATCC 204508 / S288c;
RX PubMed=9169875;
RA Bussey H., Storms R.K., Ahmed A., Albermann K., Allen E., Ansorge W.,
RA Araujo R., Aparicio A., Barrell B.G., Badcock K., Benes V., Botstein D.,
RA Bowman S., Brueckner M., Carpenter J., Cherry J.M., Chung E.,
RA Churcher C.M., Coster F., Davis K., Davis R.W., Dietrich F.S., Delius H.,
RA DiPaolo T., Dubois E., Duesterhoeft A., Duncan M., Floeth M., Fortin N.,
RA Friesen J.D., Fritz C., Goffeau A., Hall J., Hebling U., Heumann K.,
RA Hilbert H., Hillier L.W., Hunicke-Smith S., Hyman R.W., Johnston M.,
RA Kalman S., Kleine K., Komp C., Kurdi O., Lashkari D., Lew H., Lin A.,
RA Lin D., Louis E.J., Marathe R., Messenguy F., Mewes H.-W., Mirtipati S.,
RA Moestl D., Mueller-Auer S., Namath A., Nentwich U., Oefner P., Pearson D.,
RA Petel F.X., Pohl T.M., Purnelle B., Rajandream M.A., Rechmann S.,
RA Rieger M., Riles L., Roberts D., Schaefer M., Scharfe M., Scherens B.,
RA Schramm S., Schroeder M., Sdicu A.-M., Tettelin H., Urrestarazu L.A.,
RA Ushinsky S., Vierendeels F., Vissers S., Voss H., Walsh S.V., Wambutt R.,
RA Wang Y., Wedler E., Wedler H., Winnett E., Zhong W.-W., Zollner A.,
RA Vo D.H., Hani J.;
RT "The nucleotide sequence of Saccharomyces cerevisiae chromosome XVI.";
RL Nature 387:103-105(1997).
RN [3]
RP GENOME REANNOTATION.
RC STRAIN=ATCC 204508 / S288c;
RX PubMed=24374639; DOI=10.1534/g3.113.008995;
RA Engel S.R., Dietrich F.S., Fisk D.G., Binkley G., Balakrishnan R.,
RA Costanzo M.C., Dwight S.S., Hitz B.C., Karra K., Nash R.S., Weng S.,
RA Wong E.D., Lloyd P., Skrzypek M.S., Miyasato S.R., Simison M., Cherry J.M.;
RT "The reference genome sequence of Saccharomyces cerevisiae: Then and now.";
RL G3 (Bethesda) 4:389-398(2014).
RN [4]
RP PROTEIN SEQUENCE OF 25-29, FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR
RP LOCATION, AND MUTAGENESIS OF MET-24; 24-MET-ASN-25 AND 29-ARG--LYS-44.
RX PubMed=11585823; DOI=10.1074/jbc.m106061200;
RA Sass E., Blachinsky E., Karniely S., Pines O.;
RT "Mitochondrial and cytosolic isoforms of yeast fumarase are derivatives of
RT a single translation product and have identical amino termini.";
RL J. Biol. Chem. 276:46111-46117(2001).
RN [5]
RP PROTEIN SEQUENCE OF 44-52, AND SUBCELLULAR LOCATION.
RC STRAIN=ATCC 201238 / W303-1B;
RX PubMed=11502169; DOI=10.1021/bi010277r;
RA Grandier-Vazeille X., Bathany K., Chaignepain S., Camougrand N., Manon S.,
RA Schmitter J.-M.;
RT "Yeast mitochondrial dehydrogenases are associated in a supramolecular
RT complex.";
RL Biochemistry 40:9758-9769(2001).
RN [6]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=1587456; DOI=10.1016/0378-1097(92)90667-d;
RA Kaclikova E., Lachowicz T.M., Gbelska Y., Subik J.;
RT "Fumaric acid overproduction in yeast mutants deficient in fumarase.";
RL FEMS Microbiol. Lett. 70:101-106(1992).
RN [7]
RP LEVEL OF PROTEIN EXPRESSION [LARGE SCALE ANALYSIS].
RX PubMed=14562106; DOI=10.1038/nature02046;
RA Ghaemmaghami S., Huh W.-K., Bower K., Howson R.W., Belle A., Dephoure N.,
RA O'Shea E.K., Weissman J.S.;
RT "Global analysis of protein expression in yeast.";
RL Nature 425:737-741(2003).
RN [8]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-428, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC STRAIN=ATCC 76625 / YPH499;
RX PubMed=17761666; DOI=10.1074/mcp.m700098-mcp200;
RA Reinders J., Wagner K., Zahedi R.P., Stojanovski D., Eyrich B.,
RA van der Laan M., Rehling P., Sickmann A., Pfanner N., Meisinger C.;
RT "Profiling phosphoproteins of yeast mitochondria reveals a role of
RT phosphorylation in assembly of the ATP synthase.";
RL Mol. Cell. Proteomics 6:1896-1906(2007).
RN [9]
RP FUNCTION, CATALYTIC ACTIVITY, PATHWAY, SUBCELLULAR LOCATION, AND
RP MUTAGENESIS OF HIS-154.
RX PubMed=20231875; DOI=10.1371/journal.pbio.1000328;
RA Yogev O., Yogev O., Singer E., Shaulian E., Goldberg M., Fox T.D.,
RA Pines O.;
RT "Fumarase: a mitochondrial metabolic enzyme and a cytosolic/nuclear
RT component of the DNA damage response.";
RL PLoS Biol. 8:E1000328-E1000328(2010).
RN [10]
RP X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS), AND SUBUNIT.
RX PubMed=9665847; DOI=10.1006/jmbi.1998.1862;
RA Weaver T., Lees M., Zaitsev V., Zaitseva I., Duke E., Lindley P.,
RA McSweeny S., Svensson A., Keruchenko J., Keruchenko I., Gladilin K.,
RA Banaszak L.;
RT "Crystal structures of native and recombinant yeast fumarase.";
RL J. Mol. Biol. 280:431-442(1998).
CC -!- FUNCTION: Catalyzes the reversible stereospecific interconversion of
CC fumarate to L-malate (PubMed:3040736, PubMed:11585823, PubMed:1587456,
CC PubMed:20231875). In mitochondrion, 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 (PubMed:1587456, PubMed:20231875). In cytoplasm and nucleus, involved
CC in DNA repair in response to DNA damage: following DNA double-strand
CC breaks (DSBs), translocates from the cytosol to the nucleus and
CC promotes DNA repair by catalyzing the dehydration of L-malate to
CC fumarate (PubMed:20231875). {ECO:0000269|PubMed:11585823,
CC ECO:0000269|PubMed:1587456, ECO:0000269|PubMed:20231875,
CC ECO:0000269|PubMed:3040736}.
CC -!- CATALYTIC ACTIVITY:
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:11585823, ECO:0000269|PubMed:20231875,
CC ECO:0000269|PubMed:3040736};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:12461;
CC Evidence={ECO:0000269|PubMed:20231875};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:12462;
CC Evidence={ECO:0000269|PubMed:20231875};
CC -!- PATHWAY: Carbohydrate metabolism; tricarboxylic acid cycle; (S)-malate
CC from fumarate: step 1/1. {ECO:0000269|PubMed:20231875}.
CC -!- SUBUNIT: Homotetramer. {ECO:0000269|PubMed:9665847}.
CC -!- SUBCELLULAR LOCATION: Mitochondrion matrix
CC {ECO:0000269|PubMed:11502169, ECO:0000269|PubMed:11585823,
CC ECO:0000269|PubMed:20231875, ECO:0000269|PubMed:3040736}. Cytoplasm
CC {ECO:0000269|PubMed:11502169, ECO:0000269|PubMed:11585823,
CC ECO:0000269|PubMed:20231875, ECO:0000269|PubMed:3040736}. Nucleus
CC {ECO:0000269|PubMed:20231875}. Note=Mitochondrial, cytoplasmic and
CC nuclear forms are derived from a single translation product and not by
CC alternative initiation of the transcript (PubMed:11585823). The
CC mitochondrial transit peptide is cleaved by the mitochondrial
CC processing peptidase, promoting mitochondrial targeting of around 70%
CC of the proteins (PubMed:11585823). The remaining 30% of the processed
CC proteins localize in the cytosol: they probably undergo rapid folding
CC into an import-incompetent state, leading to retrograde movement of the
CC processed proteins back to the cytosol through the translocation pore
CC (PubMed:11585823). Translocates from the cytosol to the nucleus in
CC response to DNA damage (PubMed:20231875). {ECO:0000269|PubMed:11585823,
CC ECO:0000269|PubMed:20231875}.
CC -!- DISRUPTION PHENOTYPE: Cells accumulate extracellular fumarate.
CC {ECO:0000269|PubMed:1587456}.
CC -!- MISCELLANEOUS: Present with 6920 molecules/cell in log phase SD medium.
CC {ECO:0000269|PubMed:14562106}.
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; J02802; AAA66909.1; -; Genomic_DNA.
DR EMBL; Z73618; CAA97997.1; -; Genomic_DNA.
DR EMBL; BK006949; DAA11174.1; -; Genomic_DNA.
DR PIR; S65295; UFBYM.
DR RefSeq; NP_015061.1; NM_001184076.1.
DR PDB; 1YFM; X-ray; 2.60 A; A=1-488.
DR PDBsum; 1YFM; -.
DR AlphaFoldDB; P08417; -.
DR SMR; P08417; -.
DR BioGRID; 35951; 441.
DR DIP; DIP-6451N; -.
DR IntAct; P08417; 12.
DR MINT; P08417; -.
DR STRING; 4932.YPL262W; -.
DR iPTMnet; P08417; -.
DR MaxQB; P08417; -.
DR PaxDb; P08417; -.
DR PRIDE; P08417; -.
DR EnsemblFungi; YPL262W_mRNA; YPL262W; YPL262W.
DR GeneID; 855866; -.
DR KEGG; sce:YPL262W; -.
DR SGD; S000006183; FUM1.
DR VEuPathDB; FungiDB:YPL262W; -.
DR eggNOG; KOG1317; Eukaryota.
DR GeneTree; ENSGT00950000183122; -.
DR HOGENOM; CLU_021594_4_0_1; -.
DR InParanoid; P08417; -.
DR OMA; RIATIWN; -.
DR BioCyc; YEAST:YPL262W-MON; -.
DR BRENDA; 4.2.1.2; 984.
DR Reactome; R-SCE-71403; Citric acid cycle (TCA cycle).
DR SABIO-RK; P08417; -.
DR UniPathway; UPA00223; UER01007.
DR EvolutionaryTrace; P08417; -.
DR PRO; PR:P08417; -.
DR Proteomes; UP000002311; Chromosome XVI.
DR RNAct; P08417; protein.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0005759; C:mitochondrial matrix; IDA:SGD.
DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
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; IDA:UniProtKB.
DR GO; GO:0006302; P:double-strand break repair; IDA:UniProtKB.
DR GO; GO:0006106; P:fumarate metabolic process; IDA:UniProtKB.
DR GO; GO:0006108; P:malate metabolic process; IBA:GO_Central.
DR GO; GO:0006099; P:tricarboxylic acid cycle; IMP:SGD.
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 3D-structure; Cytoplasm; Direct protein sequencing; DNA damage; DNA repair;
KW Lyase; Mitochondrion; Nucleus; Phosphoprotein; Reference proteome;
KW Transit peptide; Tricarboxylic acid cycle.
FT TRANSIT 1..24
FT /note="Mitochondrion"
FT /evidence="ECO:0000269|PubMed:11585823"
FT CHAIN 25..488
FT /note="Fumarate hydratase, mitochondrial"
FT /id="PRO_0000010333"
FT ACT_SITE 213
FT /note="Proton donor/acceptor"
FT /evidence="ECO:0000250|UniProtKB:P05042"
FT ACT_SITE 343
FT /evidence="ECO:0000250|UniProtKB:P9WN93"
FT BINDING 124..126
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P05042"
FT BINDING 154..157
FT /ligand="substrate"
FT /note="in site B"
FT /evidence="ECO:0000250|UniProtKB:P05042"
FT BINDING 164..166
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P05042"
FT BINDING 212
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P9WN93"
FT BINDING 344
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P9WN93"
FT BINDING 349..351
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P9WN93"
FT SITE 356
FT /note="Important for catalytic activity"
FT /evidence="ECO:0000250|UniProtKB:P05042"
FT MOD_RES 428
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:17761666"
FT MUTAGEN 24..25
FT /note="MN->SF: Does not affect processing by the
FT mitochondrial processing peptidase. Localizes both in the
FT mitochondrion and cytosol. Exhibits high fumarate hydratase
FT activity."
FT /evidence="ECO:0000269|PubMed:11585823"
FT MUTAGEN 24
FT /note="M->S: Does not affect processing by the
FT mitochondrial processing peptidase. Localizes both in the
FT mitochondrion and cytosol. Exhibits high fumarate hydratase
FT activity."
FT /evidence="ECO:0000269|PubMed:11585823"
FT MUTAGEN 24
FT /note="M->V,I: Abolishes processing by the mitochondrial
FT processing peptidase. Mainly localizes in the cytosol, with
FT a small fraction in the mitochondrion. Reduced fumarate
FT hydratase activity."
FT /evidence="ECO:0000269|PubMed:11585823"
FT MUTAGEN 29..44
FT /note="Missing: Does not affect subcellular location."
FT /evidence="ECO:0000269|PubMed:11585823"
FT MUTAGEN 154
FT /note="H->R: Abolished fumarate hydratase activity and
FT ability to participate in DNA repair."
FT /evidence="ECO:0000269|PubMed:20231875"
FT CONFLICT 173
FT /note="M -> V (in Ref. 1; AAA66909)"
FT /evidence="ECO:0000305"
FT CONFLICT 289
FT /note="K -> R (in Ref. 1; AAA66909)"
FT /evidence="ECO:0000305"
FT CONFLICT 392
FT /note="A -> V (in Ref. 1; AAA66909)"
FT /evidence="ECO:0000305"
FT STRAND 28..31
FT /evidence="ECO:0007829|PDB:1YFM"
FT STRAND 33..35
FT /evidence="ECO:0007829|PDB:1YFM"
FT STRAND 38..43
FT /evidence="ECO:0007829|PDB:1YFM"
FT HELIX 48..54
FT /evidence="ECO:0007829|PDB:1YFM"
FT HELIX 61..64
FT /evidence="ECO:0007829|PDB:1YFM"
FT HELIX 68..87
FT /evidence="ECO:0007829|PDB:1YFM"
FT HELIX 93..107
FT /evidence="ECO:0007829|PDB:1YFM"
FT HELIX 112..114
FT /evidence="ECO:0007829|PDB:1YFM"
FT STRAND 118..121
FT /evidence="ECO:0007829|PDB:1YFM"
FT HELIX 126..142
FT /evidence="ECO:0007829|PDB:1YFM"
FT HELIX 155..159
FT /evidence="ECO:0007829|PDB:1YFM"
FT TURN 160..162
FT /evidence="ECO:0007829|PDB:1YFM"
FT HELIX 165..182
FT /evidence="ECO:0007829|PDB:1YFM"
FT HELIX 185..202
FT /evidence="ECO:0007829|PDB:1YFM"
FT TURN 203..205
FT /evidence="ECO:0007829|PDB:1YFM"
FT STRAND 207..212
FT /evidence="ECO:0007829|PDB:1YFM"
FT STRAND 215..221
FT /evidence="ECO:0007829|PDB:1YFM"
FT HELIX 222..247
FT /evidence="ECO:0007829|PDB:1YFM"
FT TURN 255..257
FT /evidence="ECO:0007829|PDB:1YFM"
FT HELIX 267..279
FT /evidence="ECO:0007829|PDB:1YFM"
FT HELIX 289..294
FT /evidence="ECO:0007829|PDB:1YFM"
FT HELIX 297..323
FT /evidence="ECO:0007829|PDB:1YFM"
FT STRAND 327..330
FT /evidence="ECO:0007829|PDB:1YFM"
FT HELIX 353..377
FT /evidence="ECO:0007829|PDB:1YFM"
FT HELIX 387..411
FT /evidence="ECO:0007829|PDB:1YFM"
FT HELIX 413..415
FT /evidence="ECO:0007829|PDB:1YFM"
FT HELIX 420..429
FT /evidence="ECO:0007829|PDB:1YFM"
FT HELIX 432..434
FT /evidence="ECO:0007829|PDB:1YFM"
FT TURN 435..437
FT /evidence="ECO:0007829|PDB:1YFM"
FT HELIX 438..440
FT /evidence="ECO:0007829|PDB:1YFM"
FT HELIX 443..456
FT /evidence="ECO:0007829|PDB:1YFM"
FT HELIX 460..466
FT /evidence="ECO:0007829|PDB:1YFM"
FT HELIX 472..478
FT /evidence="ECO:0007829|PDB:1YFM"
FT HELIX 481..483
FT /evidence="ECO:0007829|PDB:1YFM"
SQ SEQUENCE 488 AA; 53152 MW; C099A02409A210E6 CRC64;
MLRFTNCSCK TFVKSSYKLN IRRMNSSFRT ETDAFGEIHV PADKYWGAQT QRSFQNFKIG
GARERMPLPL VHAFGVLKKS AAIVNESLGG LDPKISKAIQ QAADEVASGK LDDHFPLVVF
QTGSGTQSNM NANEVISNRA IEILGGKIGS KQVHPNNHCN QSQSSNDTFP TVMHIAASLQ
IQNELIPELT NLKNALEAKS KEFDHIVKIG RTHLQDATPL TLGQEFSGYV QQVENGIQRV
AHSLKTLSFL AQGGTAVGTG LNTKPGFDVK IAEQISKETG LKFQTAPNKF EALAAHDAIV
ECSGALNTLA CSLFKIAQDI RYLGSGPRCG YHELMLPENE PGSSIMPGKV NPTQNEALTQ
VCVQVMGNNA AITFAGSQGQ FELNVFKPVM IANLLNSIRL ITDAAYSFRV HCVEGIKANE
PRIHELLTKS LMLVTALNPK IGYDAASKVA KNAHKKGITL KESALELGVL TEKEFDEWVV
PEHMLGPK
