FUM2_LEIMA
ID FUM2_LEIMA Reviewed; 568 AA.
AC E9AE57;
DT 08-MAY-2019, integrated into UniProtKB/Swiss-Prot.
DT 05-APR-2011, sequence version 1.
DT 03-AUG-2022, entry version 69.
DE RecName: Full=Fumarate hydratase 2;
DE Short=Fumarase 2 {ECO:0000303|PubMed:22569531};
DE Short=LmFH-2 {ECO:0000303|PubMed:22569531};
DE EC=4.2.1.2 {ECO:0000269|PubMed:22569531, ECO:0000269|PubMed:27528683, ECO:0000269|PubMed:30645090};
GN Name=FH2 {ECO:0000303|PubMed:22569531};
GN ORFNames=LMJF_29_1960 {ECO:0000312|EMBL:CBZ12536.1};
OS Leishmania major.
OC Eukaryota; Discoba; Euglenozoa; Kinetoplastea; Metakinetoplastina;
OC Trypanosomatida; Trypanosomatidae; Leishmaniinae; Leishmania.
OX NCBI_TaxID=5664;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=MHOM/IL/81/Friedlin;
RX PubMed=16020728; DOI=10.1126/science.1112680;
RA Ivens A.C., Peacock C.S., Worthey E.A., Murphy L., Aggarwal G.,
RA Berriman M., Sisk E., Rajandream M.A., Adlem E., Aert R., Anupama A.,
RA Apostolou Z., Attipoe P., Bason N., Bauser C., Beck A., Beverley S.M.,
RA Bianchettin G., Borzym K., Bothe G., Bruschi C.V., Collins M., Cadag E.,
RA Ciarloni L., Clayton C., Coulson R.M.R., Cronin A., Cruz A.K., Davies R.M.,
RA De Gaudenzi J., Dobson D.E., Duesterhoeft A., Fazelina G., Fosker N.,
RA Frasch A.C., Fraser A., Fuchs M., Gabel C., Goble A., Goffeau A.,
RA Harris D., Hertz-Fowler C., Hilbert H., Horn D., Huang Y., Klages S.,
RA Knights A., Kube M., Larke N., Litvin L., Lord A., Louie T., Marra M.,
RA Masuy D., Matthews K., Michaeli S., Mottram J.C., Mueller-Auer S.,
RA Munden H., Nelson S., Norbertczak H., Oliver K., O'neil S., Pentony M.,
RA Pohl T.M., Price C., Purnelle B., Quail M.A., Rabbinowitsch E.,
RA Reinhardt R., Rieger M., Rinta J., Robben J., Robertson L., Ruiz J.C.,
RA Rutter S., Saunders D., Schaefer M., Schein J., Schwartz D.C., Seeger K.,
RA Seyler A., Sharp S., Shin H., Sivam D., Squares R., Squares S., Tosato V.,
RA Vogt C., Volckaert G., Wambutt R., Warren T., Wedler H., Woodward J.,
RA Zhou S., Zimmermann W., Smith D.F., Blackwell J.M., Stuart K.D.,
RA Barrell B.G., Myler P.J.;
RT "The genome of the kinetoplastid parasite, Leishmania major.";
RL Science 309:436-442(2005).
RN [2]
RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, AND
RP SUBCELLULAR LOCATION.
RX PubMed=22569531; DOI=10.1016/j.ijbiomac.2012.04.025;
RA Feliciano P.R., Gupta S., Dyszy F., Dias-Baruffi M., Costa-Filho A.J.,
RA Michels P.A., Nonato M.C.;
RT "Fumarate hydratase isoforms of Leishmania major: subcellular localization,
RT structural and kinetic properties.";
RL Int. J. Biol. Macromol. 51:25-31(2012).
RN [3] {ECO:0007744|PDB:5L2R}
RP X-RAY CRYSTALLOGRAPHY (2.05 ANGSTROMS) IN COMPLEX WITH IRON-SULFUR; MALATE
RP AND MALONATE, FUNCTION, CATALYTIC ACTIVITY, COFACTOR, SUBUNIT, AND ACTIVITY
RP REGULATION.
RX PubMed=27528683; DOI=10.1073/pnas.1605031113;
RA Feliciano P.R., Drennan C.L., Nonato M.C.;
RT "Crystal structure of an Fe-S cluster-containing fumarate hydratase enzyme
RT from Leishmania major reveals a unique protein fold.";
RL Proc. Natl. Acad. Sci. U.S.A. 113:9804-9809(2016).
RN [4]
RP X-RAY CRYSTALLOGRAPHY (1.59 ANGSTROMS) OF 28-568 IN COMPLEX WITH
RP 2-THIOMALATE INHIBITOR, FUNCTION, CATALYTIC ACTIVITY, SUBUNIT, AND ACTIVITY
RP REGULATION.
RX PubMed=30645090; DOI=10.1021/acschembio.8b00972;
RA Feliciano P.R., Drennan C.L., Nonato M.C.;
RT "Crystal structures of fumarate hydratases from Leishmania major in a
RT complex with inhibitor 2-thiomalate.";
RL ACS Chem. Biol. 14:266-275(2019).
CC -!- FUNCTION: Cytosolic fumarate hydratase that catalyzes the reversible
CC hydration of fumarate to (S)-malate. {ECO:0000269|PubMed:22569531,
CC ECO:0000269|PubMed:27528683, ECO:0000269|PubMed:30645090}.
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:22569531, ECO:0000269|PubMed:27528683,
CC ECO:0000269|PubMed:30645090};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:12461;
CC Evidence={ECO:0000269|PubMed:22569531};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:12462;
CC Evidence={ECO:0000269|PubMed:22569531};
CC -!- COFACTOR:
CC Name=[4Fe-4S] cluster; Xref=ChEBI:CHEBI:49883;
CC Evidence={ECO:0000269|PubMed:27528683};
CC Note=Binds 1 [4Fe-4S] cluster per subunit.
CC {ECO:0000269|PubMed:27528683};
CC -!- ACTIVITY REGULATION: Specifically and competitively inhibited by 2-
CC thiomalate, which coordinates with the catalytic [4Fe-4S] cluster
CC (PubMed:30645090). Weakly inhibited by malonate (PubMed:27528683).
CC {ECO:0000269|PubMed:27528683, ECO:0000269|PubMed:30645090}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=5.7 mM for fumarate (in anaerobic conditions)
CC {ECO:0000269|PubMed:22569531};
CC KM=1.9 mM for fumarate (in aerobic conditions)
CC {ECO:0000269|PubMed:22569531};
CC KM=12.6 mM for (S)-malate (in anaerobic conditions)
CC {ECO:0000269|PubMed:22569531};
CC KM=5.7 mM for (S)-malate (in aerobic conditions)
CC {ECO:0000269|PubMed:22569531};
CC Vmax=186.2 umol/min/mg enzyme with fumarate as substrate (in
CC anaerobic conditions);
CC Vmax=44.3 umol/min/mg enzyme with fumarate as substrate (in aerobic
CC conditions);
CC Vmax=138.1 umol/min/mg enzyme with (S)-malate as substrate (in
CC anaerobic conditions);
CC Vmax=22.7 umol/min/mg enzyme with (S)-malate as substrate (in aerobic
CC conditions);
CC Note=kcat is 204.2 sec(-1) for fumarate (in anaerobic conditions)
CC (PubMed:22569531). kcat is 48.6 sec(-1) for fumarate (in aerobic
CC conditions) (PubMed:22569531). kcat is 151.4 sec(-1) for (S)-malate
CC (in anaerobic conditions) (PubMed:22569531). kcat is 24.9 sec(-1) for
CC (S)-malate (in aerobic conditions) (PubMed:22569531).
CC {ECO:0000269|PubMed:22569531};
CC pH dependence:
CC Optimum pH is 9. {ECO:0000269|PubMed:22569531};
CC -!- SUBUNIT: Homodimer. {ECO:0000269|PubMed:27528683,
CC ECO:0000269|PubMed:30645090}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000269|PubMed:22569531}.
CC -!- SIMILARITY: Belongs to the class-I fumarase family. {ECO:0000305}.
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DR EMBL; FR796425; CBZ12536.1; -; Genomic_DNA.
DR RefSeq; XP_003722278.1; XM_003722230.1.
DR PDB; 5L2R; X-ray; 2.05 A; A/B=1-568.
DR PDB; 6MSN; X-ray; 1.59 A; A/B=1-568.
DR PDB; 6UNZ; X-ray; 3.19 A; A/B/C/D/E/F/G/H=1-568.
DR PDB; 6UO0; X-ray; 1.85 A; A/B=1-568.
DR PDB; 6UOI; X-ray; 1.95 A; A/B=1-568.
DR PDB; 6UOJ; X-ray; 2.35 A; A/B=1-568.
DR PDB; 6UP9; X-ray; 1.95 A; A/B=1-568.
DR PDB; 6UPM; X-ray; 2.03 A; A/B=1-568.
DR PDB; 6UPO; X-ray; 3.11 A; A/B=1-568.
DR PDB; 6UQ8; X-ray; 1.34 A; A/B=1-568.
DR PDB; 6UQ9; X-ray; 2.30 A; A/B=1-568.
DR PDB; 6UQB; X-ray; 1.95 A; A/B=1-568.
DR PDB; 6UQL; X-ray; 2.10 A; A/B=1-568.
DR PDB; 6UQM; X-ray; 2.00 A; A/B=1-568.
DR PDB; 6UQN; X-ray; 3.30 A; A/B=1-568.
DR PDBsum; 5L2R; -.
DR PDBsum; 6MSN; -.
DR PDBsum; 6UNZ; -.
DR PDBsum; 6UO0; -.
DR PDBsum; 6UOI; -.
DR PDBsum; 6UOJ; -.
DR PDBsum; 6UP9; -.
DR PDBsum; 6UPM; -.
DR PDBsum; 6UPO; -.
DR PDBsum; 6UQ8; -.
DR PDBsum; 6UQ9; -.
DR PDBsum; 6UQB; -.
DR PDBsum; 6UQL; -.
DR PDBsum; 6UQM; -.
DR PDBsum; 6UQN; -.
DR AlphaFoldDB; E9AE57; -.
DR SMR; E9AE57; -.
DR STRING; 5664.LmjF.29.1960; -.
DR EnsemblProtists; CBZ12536; CBZ12536; LMJF_29_1960.
DR GeneID; 12981057; -.
DR KEGG; lma:LMJF_29_1960; -.
DR VEuPathDB; TriTrypDB:LmjF.29.1960; -.
DR VEuPathDB; TriTrypDB:LMJLV39_290027300; -.
DR VEuPathDB; TriTrypDB:LMJSD75_290027500; -.
DR eggNOG; ENOG502QT04; Eukaryota.
DR HOGENOM; CLU_026758_0_0_1; -.
DR InParanoid; E9AE57; -.
DR OMA; AGVLPMC; -.
DR Proteomes; UP000000542; Chromosome 29.
DR GO; GO:0097014; C:ciliary plasm; ISO:GeneDB.
DR GO; GO:0005737; C:cytoplasm; ISO:GeneDB.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0020015; C:glycosome; ISO:GeneDB.
DR GO; GO:0051539; F:4 iron, 4 sulfur cluster binding; IDA:UniProtKB.
DR GO; GO:0004333; F:fumarate hydratase activity; IDA:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB.
DR GO; GO:0006106; P:fumarate metabolic process; IDA:UniProtKB.
DR GO; GO:0006091; P:generation of precursor metabolites and energy; IEA:InterPro.
DR GO; GO:0006108; P:malate metabolic process; IDA:UniProtKB.
DR Gene3D; 3.20.130.10; -; 1.
DR InterPro; IPR004646; Fe-S_hydro-lyase_TtdA-typ_cat.
DR InterPro; IPR004647; Fe-S_hydro-lyase_TtdB-typ_cat.
DR InterPro; IPR036660; Fe-S_hydroAse_TtdB_cat_sf.
DR InterPro; IPR011167; Fe_dep_fumarate_hydratase.
DR Pfam; PF05681; Fumerase; 1.
DR Pfam; PF05683; Fumerase_C; 1.
DR PIRSF; PIRSF001394; Fe_dep_fumar_hy; 1.
DR SUPFAM; SSF117457; SSF117457; 1.
DR TIGRFAMs; TIGR00723; ttdB_fumA_fumB; 1.
PE 1: Evidence at protein level;
KW 3D-structure; 4Fe-4S; Cytoplasm; Iron; Iron-sulfur; Lyase; Metal-binding;
KW Reference proteome.
FT CHAIN 1..568
FT /note="Fumarate hydratase 2"
FT /id="PRO_0000447006"
FT BINDING 133
FT /ligand="[4Fe-4S] cluster"
FT /ligand_id="ChEBI:CHEBI:49883"
FT /evidence="ECO:0000269|PubMed:27528683,
FT ECO:0007744|PDB:5L2R"
FT BINDING 134..135
FT /ligand="(S)-malate"
FT /ligand_id="ChEBI:CHEBI:15589"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:27528683,
FT ECO:0007744|PDB:5L2R"
FT BINDING 173
FT /ligand="(S)-malate"
FT /ligand_id="ChEBI:CHEBI:15589"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:27528683,
FT ECO:0007744|PDB:5L2R"
FT BINDING 216
FT /ligand="(S)-malate"
FT /ligand_id="ChEBI:CHEBI:15589"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:27528683,
FT ECO:0007744|PDB:5L2R"
FT BINDING 219..225
FT /ligand="(S)-malate"
FT /ligand_id="ChEBI:CHEBI:15589"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:27528683,
FT ECO:0007744|PDB:5L2R"
FT BINDING 252
FT /ligand="[4Fe-4S] cluster"
FT /ligand_id="ChEBI:CHEBI:49883"
FT /evidence="ECO:0000269|PubMed:27528683,
FT ECO:0007744|PDB:5L2R"
FT BINDING 346
FT /ligand="[4Fe-4S] cluster"
FT /ligand_id="ChEBI:CHEBI:49883"
FT /evidence="ECO:0000269|PubMed:27528683,
FT ECO:0007744|PDB:5L2R"
FT BINDING 421
FT /ligand="(S)-malate"
FT /ligand_id="ChEBI:CHEBI:15589"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:27528683,
FT ECO:0007744|PDB:5L2R"
FT BINDING 467..471
FT /ligand="(S)-malate"
FT /ligand_id="ChEBI:CHEBI:15589"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:27528683,
FT ECO:0007744|PDB:5L2R"
FT BINDING 491
FT /ligand="(S)-malate"
FT /ligand_id="ChEBI:CHEBI:15589"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:27528683,
FT ECO:0007744|PDB:5L2R"
FT STRAND 43..45
FT /evidence="ECO:0007829|PDB:6UQN"
FT STRAND 47..49
FT /evidence="ECO:0007829|PDB:6UQ8"
FT HELIX 53..56
FT /evidence="ECO:0007829|PDB:6UQ8"
FT STRAND 57..62
FT /evidence="ECO:0007829|PDB:6UQ8"
FT STRAND 65..70
FT /evidence="ECO:0007829|PDB:6UQ8"
FT HELIX 73..85
FT /evidence="ECO:0007829|PDB:6UQ8"
FT TURN 86..88
FT /evidence="ECO:0007829|PDB:6UQ8"
FT HELIX 92..103
FT /evidence="ECO:0007829|PDB:6UQ8"
FT HELIX 109..125
FT /evidence="ECO:0007829|PDB:6UQ8"
FT STRAND 128..130
FT /evidence="ECO:0007829|PDB:6UQ8"
FT STRAND 132..134
FT /evidence="ECO:0007829|PDB:6UQ8"
FT STRAND 138..146
FT /evidence="ECO:0007829|PDB:6UQ8"
FT HELIX 155..169
FT /evidence="ECO:0007829|PDB:6UQ8"
FT STRAND 176..183
FT /evidence="ECO:0007829|PDB:6UQ8"
FT STRAND 185..187
FT /evidence="ECO:0007829|PDB:6UQ8"
FT STRAND 189..191
FT /evidence="ECO:0007829|PDB:6UQ8"
FT STRAND 195..204
FT /evidence="ECO:0007829|PDB:6UQ8"
FT STRAND 206..213
FT /evidence="ECO:0007829|PDB:6UQ8"
FT HELIX 215..218
FT /evidence="ECO:0007829|PDB:6UQ8"
FT STRAND 221..226
FT /evidence="ECO:0007829|PDB:6UQ8"
FT HELIX 228..230
FT /evidence="ECO:0007829|PDB:6UQ8"
FT HELIX 233..247
FT /evidence="ECO:0007829|PDB:6UQ8"
FT TURN 248..251
FT /evidence="ECO:0007829|PDB:6UQ8"
FT STRAND 253..261
FT /evidence="ECO:0007829|PDB:6UQ8"
FT HELIX 266..277
FT /evidence="ECO:0007829|PDB:6UQ8"
FT TURN 278..283
FT /evidence="ECO:0007829|PDB:6UQ8"
FT HELIX 298..310
FT /evidence="ECO:0007829|PDB:6UQ8"
FT TURN 314..317
FT /evidence="ECO:0007829|PDB:6UQ8"
FT STRAND 318..320
FT /evidence="ECO:0007829|PDB:6UQ8"
FT STRAND 322..330
FT /evidence="ECO:0007829|PDB:6UQ8"
FT STRAND 338..345
FT /evidence="ECO:0007829|PDB:6UQ8"
FT STRAND 351..357
FT /evidence="ECO:0007829|PDB:6UQ8"
FT STRAND 360..364
FT /evidence="ECO:0007829|PDB:6UQ8"
FT HELIX 370..373
FT /evidence="ECO:0007829|PDB:6UQ8"
FT STRAND 387..390
FT /evidence="ECO:0007829|PDB:6UQ8"
FT HELIX 395..402
FT /evidence="ECO:0007829|PDB:6UQ8"
FT STRAND 410..419
FT /evidence="ECO:0007829|PDB:6UQ8"
FT HELIX 422..433
FT /evidence="ECO:0007829|PDB:6UQ8"
FT HELIX 440..442
FT /evidence="ECO:0007829|PDB:6UQ8"
FT STRAND 443..445
FT /evidence="ECO:0007829|PDB:6UQ8"
FT HELIX 469..475
FT /evidence="ECO:0007829|PDB:6UQ8"
FT HELIX 476..480
FT /evidence="ECO:0007829|PDB:6UQ8"
FT TURN 481..483
FT /evidence="ECO:0007829|PDB:6UQ8"
FT STRAND 486..492
FT /evidence="ECO:0007829|PDB:6UQ8"
FT HELIX 496..505
FT /evidence="ECO:0007829|PDB:6UQ8"
FT STRAND 508..512
FT /evidence="ECO:0007829|PDB:6UQ8"
FT HELIX 517..523
FT /evidence="ECO:0007829|PDB:6UQ8"
FT STRAND 525..532
FT /evidence="ECO:0007829|PDB:6UQ8"
FT HELIX 534..539
FT /evidence="ECO:0007829|PDB:6UQ8"
FT STRAND 540..555
FT /evidence="ECO:0007829|PDB:6UQ8"
FT STRAND 557..559
FT /evidence="ECO:0007829|PDB:6UQ8"
FT TURN 562..567
FT /evidence="ECO:0007829|PDB:6UQ8"
SQ SEQUENCE 568 AA; 62602 MW; E41D7C1C995872EC CRC64;
MSLCDQCEIG CRRVGIKDIE DASAVNADFH FSAIFQPTDP HHHQTEFAKV EGSEKYVEEV
EVFGRQALKV NPEALTILAH RAFSDVHHFF RKDHLEGWRR AIEDPEASDN DRYVATTLLK
NACIAAGRVL PSCQDTGTAI VLGKRGELCW TGGEDEKYLS KGIWNAYRYH NLRYSQTAAL
DMFKECNTGD NLPAQLDLLA VPGSDYEFLF IAKGGGSANK AYLYQETKAL LNPKSLRAFI
EEKLKTLGTA ACPPYHIALV IGGTSAEMTM KTVKLASCRY YDSLPTTGDK YGRAFRDPEW
EKIVMEVAQK SGIGAQFGGK YFAHQARVIR LPRHGASCPV GLAVSCSADR QILAHINKSG
IYIEQLEQNP AQYLPDIPEV HLSTTSVKVD LKRPIDKVRQ QLSQYPVGTR VMLNGTLIVA
RDIAHAKIKE MMDNGEPLPE YMKTSPIYYA GPAKTPEGYA SGSFGPTTAG RMDSYVDLFQ
SHGGSYITLA KGNRSKQVTD ACKKHGGFYL GSIGGPAAIL AKDSIKQVTC LAFPELGMEA
VWKIEVEDFP AFIVVDDKGN DMYSKTLA
