FUM1_LEIMA
ID FUM1_LEIMA Reviewed; 549 AA.
AC Q4QAU9;
DT 08-MAY-2019, integrated into UniProtKB/Swiss-Prot.
DT 19-JUL-2005, sequence version 1.
DT 03-AUG-2022, entry version 87.
DE RecName: Full=Fumarate hydratase 1, mitochondrial;
DE Short=Fumarase 1 {ECO:0000303|PubMed:22569531};
DE Short=LmFH-1 {ECO:0000303|PubMed:22569531};
DE EC=4.2.1.2 {ECO:0000269|PubMed:22569531, ECO:0000269|PubMed:30645090};
DE Flags: Precursor;
GN Name=FH1 {ECO:0000303|PubMed:22569531};
GN ORFNames=LMJF_24_0320 {ECO:0000312|EMBL:CAJ04118.1};
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]
RP X-RAY CRYSTALLOGRAPHY (2.05 ANGSTROMS) OF 10-549 IN COMPLEX WITH
RP IRON-SULFUR AND 2-THIOMALATE INHIBITOR, FUNCTION, CATALYTIC ACTIVITY,
RP COFACTOR, SUBUNIT, AND ACTIVITY 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: Catalyzes the reversible hydration of fumarate to (S)-malate
CC (PubMed:22569531, PubMed:30645090). 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 (Probable). {ECO:0000269|PubMed:22569531, ECO:0000269|PubMed:30645090,
CC ECO:0000305}.
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: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:30645090};
CC Note=Binds 1 [4Fe-4S] cluster per subunit.
CC {ECO:0000269|PubMed:30645090};
CC -!- ACTIVITY REGULATION: Specifically and competitively inhibited by 2-
CC thiomalate, which coordinates with the catalytic [4Fe-4S] cluster.
CC {ECO:0000269|PubMed:30645090}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=1.3 mM for fumarate (in anaerobic conditions)
CC {ECO:0000269|PubMed:22569531};
CC KM=2.5 mM for fumarate (in aerobic conditions)
CC {ECO:0000269|PubMed:22569531};
CC KM=2.3 mM for (S)-malate (in anaerobic conditions)
CC {ECO:0000269|PubMed:22569531};
CC KM=1.2 mM for (S)-malate (in aerobic conditions)
CC {ECO:0000269|PubMed:22569531};
CC Vmax=26.4 umol/min/mg enzyme with fumarate as substrate (in anaerobic
CC conditions);
CC Vmax=1.8 umol/min/mg enzyme with fumarate as substrate (in aerobic
CC conditions);
CC Vmax=11.8 umol/min/mg enzyme with (S)-malate as substrate (in
CC anaerobic conditions);
CC Vmax=0.5 umol/min/mg enzyme with (S)-malate as substrate (in aerobic
CC conditions);
CC Note=kcat is 28.3 sec(-1) for fumarate (in anaerobic conditions)
CC (PubMed:22569531). kcat is 1.9 sec(-1) for fumarate (in aerobic
CC conditions) (PubMed:22569531). kcat is 12.9 sec(-1) for (S)-malate
CC (in anaerobic conditions) (PubMed:22569531). kcat is 0.55 sec(-1) for
CC (S)-malate (in aerobic conditions) (PubMed:22569531).
CC {ECO:0000269|PubMed:22569531};
CC pH dependence:
CC Optimum pH is 8.7. {ECO:0000269|PubMed:22569531};
CC -!- PATHWAY: Carbohydrate metabolism; tricarboxylic acid cycle; (S)-malate
CC from fumarate: step 1/1. {ECO:0000250|UniProtKB:P0AC33}.
CC -!- SUBUNIT: Homodimer. {ECO:0000269|PubMed:30645090}.
CC -!- SUBCELLULAR LOCATION: Mitochondrion {ECO:0000269|PubMed:22569531}.
CC -!- SIMILARITY: Belongs to the class-I fumarase family. {ECO:0000305}.
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DR EMBL; FR796420; CAJ04118.1; -; Genomic_DNA.
DR RefSeq; XP_001683549.1; XM_001683497.1.
DR PDB; 6MSO; X-ray; 2.05 A; A/B/C/D=10-549.
DR PDBsum; 6MSO; -.
DR AlphaFoldDB; Q4QAU9; -.
DR SMR; Q4QAU9; -.
DR STRING; 5664.LmjF.24.0320; -.
DR EnsemblProtists; CAJ04118; CAJ04118; LMJF_24_0320.
DR GeneID; 5652198; -.
DR KEGG; lma:LMJF_24_0320; -.
DR VEuPathDB; TriTrypDB:LmjF.24.0320; -.
DR VEuPathDB; TriTrypDB:LMJLV39_240008400; -.
DR VEuPathDB; TriTrypDB:LMJSD75_240008100; -.
DR eggNOG; ENOG502QT04; Eukaryota.
DR HOGENOM; CLU_026758_0_0_1; -.
DR InParanoid; Q4QAU9; -.
DR OMA; SMYDEKN; -.
DR UniPathway; UPA00223; UER01007.
DR Proteomes; UP000000542; Chromosome 24.
DR GO; GO:0005737; C:cytoplasm; ISO:GeneDB.
DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB.
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:0006108; P:malate metabolic process; IDA:UniProtKB.
DR GO; GO:0006099; P:tricarboxylic acid cycle; IEA:UniProtKB-UniPathway.
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 InterPro; IPR020557; Fumarate_lyase_CS.
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.
DR PROSITE; PS00163; FUMARATE_LYASES; 1.
PE 1: Evidence at protein level;
KW 3D-structure; 4Fe-4S; Iron; Iron-sulfur; Lyase; Metal-binding;
KW Mitochondrion; Reference proteome; Transit peptide;
KW Tricarboxylic acid cycle.
FT TRANSIT 1..?
FT /note="Mitochondrion"
FT /evidence="ECO:0000255"
FT CHAIN ?..549
FT /note="Fumarate hydratase 1, mitochondrial"
FT /id="PRO_0000447005"
FT BINDING 114
FT /ligand="[4Fe-4S] cluster"
FT /ligand_id="ChEBI:CHEBI:49883"
FT /evidence="ECO:0000269|PubMed:30645090,
FT ECO:0007744|PDB:6MSO"
FT BINDING 115..116
FT /ligand="(S)-malate"
FT /ligand_id="ChEBI:CHEBI:15589"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:E9AE57"
FT BINDING 154
FT /ligand="(S)-malate"
FT /ligand_id="ChEBI:CHEBI:15589"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:E9AE57"
FT BINDING 197
FT /ligand="(S)-malate"
FT /ligand_id="ChEBI:CHEBI:15589"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:E9AE57"
FT BINDING 200..206
FT /ligand="(S)-malate"
FT /ligand_id="ChEBI:CHEBI:15589"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:E9AE57"
FT BINDING 233
FT /ligand="[4Fe-4S] cluster"
FT /ligand_id="ChEBI:CHEBI:49883"
FT /evidence="ECO:0000269|PubMed:30645090,
FT ECO:0007744|PDB:6MSO"
FT BINDING 328
FT /ligand="[4Fe-4S] cluster"
FT /ligand_id="ChEBI:CHEBI:49883"
FT /evidence="ECO:0000269|PubMed:30645090,
FT ECO:0007744|PDB:6MSO"
FT BINDING 404
FT /ligand="(S)-malate"
FT /ligand_id="ChEBI:CHEBI:15589"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:E9AE57"
FT BINDING 450..454
FT /ligand="(S)-malate"
FT /ligand_id="ChEBI:CHEBI:15589"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:E9AE57"
FT BINDING 474
FT /ligand="(S)-malate"
FT /ligand_id="ChEBI:CHEBI:15589"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:E9AE57"
FT STRAND 28..33
FT /evidence="ECO:0007829|PDB:6MSO"
FT STRAND 36..39
FT /evidence="ECO:0007829|PDB:6MSO"
FT STRAND 48..51
FT /evidence="ECO:0007829|PDB:6MSO"
FT HELIX 54..69
FT /evidence="ECO:0007829|PDB:6MSO"
FT HELIX 73..84
FT /evidence="ECO:0007829|PDB:6MSO"
FT HELIX 90..106
FT /evidence="ECO:0007829|PDB:6MSO"
FT STRAND 109..111
FT /evidence="ECO:0007829|PDB:6MSO"
FT STRAND 113..115
FT /evidence="ECO:0007829|PDB:6MSO"
FT STRAND 119..127
FT /evidence="ECO:0007829|PDB:6MSO"
FT HELIX 136..150
FT /evidence="ECO:0007829|PDB:6MSO"
FT STRAND 157..164
FT /evidence="ECO:0007829|PDB:6MSO"
FT STRAND 166..168
FT /evidence="ECO:0007829|PDB:6MSO"
FT STRAND 176..185
FT /evidence="ECO:0007829|PDB:6MSO"
FT STRAND 187..194
FT /evidence="ECO:0007829|PDB:6MSO"
FT HELIX 196..199
FT /evidence="ECO:0007829|PDB:6MSO"
FT STRAND 203..207
FT /evidence="ECO:0007829|PDB:6MSO"
FT HELIX 209..211
FT /evidence="ECO:0007829|PDB:6MSO"
FT HELIX 214..225
FT /evidence="ECO:0007829|PDB:6MSO"
FT TURN 229..232
FT /evidence="ECO:0007829|PDB:6MSO"
FT STRAND 234..242
FT /evidence="ECO:0007829|PDB:6MSO"
FT HELIX 247..258
FT /evidence="ECO:0007829|PDB:6MSO"
FT TURN 259..264
FT /evidence="ECO:0007829|PDB:6MSO"
FT STRAND 271..273
FT /evidence="ECO:0007829|PDB:6MSO"
FT HELIX 280..291
FT /evidence="ECO:0007829|PDB:6MSO"
FT STRAND 293..295
FT /evidence="ECO:0007829|PDB:6MSO"
FT TURN 296..299
FT /evidence="ECO:0007829|PDB:6MSO"
FT STRAND 300..302
FT /evidence="ECO:0007829|PDB:6MSO"
FT STRAND 304..312
FT /evidence="ECO:0007829|PDB:6MSO"
FT STRAND 320..327
FT /evidence="ECO:0007829|PDB:6MSO"
FT STRAND 333..339
FT /evidence="ECO:0007829|PDB:6MSO"
FT STRAND 342..346
FT /evidence="ECO:0007829|PDB:6MSO"
FT HELIX 352..355
FT /evidence="ECO:0007829|PDB:6MSO"
FT HELIX 361..363
FT /evidence="ECO:0007829|PDB:6MSO"
FT STRAND 370..373
FT /evidence="ECO:0007829|PDB:6MSO"
FT HELIX 378..385
FT /evidence="ECO:0007829|PDB:6MSO"
FT STRAND 393..402
FT /evidence="ECO:0007829|PDB:6MSO"
FT HELIX 405..416
FT /evidence="ECO:0007829|PDB:6MSO"
FT HELIX 424..427
FT /evidence="ECO:0007829|PDB:6MSO"
FT HELIX 452..458
FT /evidence="ECO:0007829|PDB:6MSO"
FT HELIX 459..464
FT /evidence="ECO:0007829|PDB:6MSO"
FT STRAND 470..475
FT /evidence="ECO:0007829|PDB:6MSO"
FT HELIX 479..488
FT /evidence="ECO:0007829|PDB:6MSO"
FT STRAND 491..494
FT /evidence="ECO:0007829|PDB:6MSO"
FT HELIX 500..506
FT /evidence="ECO:0007829|PDB:6MSO"
FT STRAND 508..515
FT /evidence="ECO:0007829|PDB:6MSO"
FT HELIX 517..522
FT /evidence="ECO:0007829|PDB:6MSO"
FT STRAND 523..538
FT /evidence="ECO:0007829|PDB:6MSO"
FT HELIX 545..548
FT /evidence="ECO:0007829|PDB:6MSO"
SQ SEQUENCE 549 AA; 60808 MW; 608C35DB92700C1A CRC64;
MLRRLAPLLA EFNFVPLVSK VSHKETKYRL LTKDYVSVVQ PGAGLPEMLR VDPAALTLLS
STAFDDVEHL LRSSHLMSLR KIFDDPEASD NDKFVALQLL KNANISSARL LPGCQDTGTA
IIAGYRGDQV FVPGNDEEAL SRGVYDIFQK RNFRYSQNVP LSMYDEKNTG TNLPAQIDLY
ASKGMEYSFM FVAKGGGSAN KSFLLQETKS VLNPKSLRNF LKEKLAMFGT SACPPYHVAV
VIGGTSAEMT MKVLKYASCH YYDDLITKPD MKTGYTFRDL ELEEEVLKVC QNIGMGAQFG
GKYYAHDVRV IRMPRHGASC PIGIGVSCSA DRQALGKINK DGVWLEELEM EPSQYLPDLK
EDELLKTPAV MVNLNRPMPE VLQELSKHPV RTRLSLTGTI IVARDSAHAR MREMLEAGKP
LPQYMKEHPV YYAGPAKQPD GLPSGSFGPT TAGRMDPFVD LFQSHGGSMV MLAKGNRSKQ
VTKACHKYGG FYLGSIGGPA AVLAQNAIKK VECLDMKDLG MEAVWRIEVE NFPAFIVVDD
KGNDFFEQL
