PYRD_PLAF7
ID PYRD_PLAF7 Reviewed; 569 AA.
AC Q08210; Q6LFN3;
DT 01-FEB-1995, integrated into UniProtKB/Swiss-Prot.
DT 01-FEB-1995, sequence version 1.
DT 03-AUG-2022, entry version 154.
DE RecName: Full=Dihydroorotate dehydrogenase (quinone), mitochondrial;
DE Short=DHOdehase;
DE EC=1.3.5.2;
DE AltName: Full=Dihydroorotate oxidase;
DE Flags: Precursor;
GN ORFNames=PFF0160c;
OS Plasmodium falciparum (isolate 3D7).
OC Eukaryota; Sar; Alveolata; Apicomplexa; Aconoidasida; Haemosporida;
OC Plasmodiidae; Plasmodium; Plasmodium (Laverania).
OX NCBI_TaxID=36329;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=8232427; DOI=10.1016/0166-6851(93)90148-q;
RA Leblanc S.B., Wilson C.M.;
RT "The dihydroorotate dehydrogenase gene homologue of Plasmodium
RT falciparum.";
RL Mol. Biochem. Parasitol. 60:349-352(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=3D7;
RX PubMed=12368864; DOI=10.1038/nature01097;
RA Gardner M.J., Hall N., Fung E., White O., Berriman M., Hyman R.W.,
RA Carlton J.M., Pain A., Nelson K.E., Bowman S., Paulsen I.T., James K.D.,
RA Eisen J.A., Rutherford K.M., Salzberg S.L., Craig A., Kyes S., Chan M.-S.,
RA Nene V., Shallom S.J., Suh B., Peterson J., Angiuoli S., Pertea M.,
RA Allen J., Selengut J., Haft D., Mather M.W., Vaidya A.B., Martin D.M.A.,
RA Fairlamb A.H., Fraunholz M.J., Roos D.S., Ralph S.A., McFadden G.I.,
RA Cummings L.M., Subramanian G.M., Mungall C., Venter J.C., Carucci D.J.,
RA Hoffman S.L., Newbold C., Davis R.W., Fraser C.M., Barrell B.G.;
RT "Genome sequence of the human malaria parasite Plasmodium falciparum.";
RL Nature 419:498-511(2002).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=3D7;
RX PubMed=12368867; DOI=10.1038/nature01095;
RA Hall N., Pain A., Berriman M., Churcher C.M., Harris B., Harris D.,
RA Mungall K.L., Bowman S., Atkin R., Baker S., Barron A., Brooks K.,
RA Buckee C.O., Burrows C., Cherevach I., Chillingworth C., Chillingworth T.,
RA Christodoulou Z., Clark L., Clark R., Corton C., Cronin A., Davies R.M.,
RA Davis P., Dear P., Dearden F., Doggett J., Feltwell T., Goble A.,
RA Goodhead I., Gwilliam R., Hamlin N., Hance Z., Harper D., Hauser H.,
RA Hornsby T., Holroyd S., Horrocks P., Humphray S., Jagels K., James K.D.,
RA Johnson D., Kerhornou A., Knights A., Konfortov B., Kyes S., Larke N.,
RA Lawson D., Lennard N., Line A., Maddison M., Mclean J., Mooney P.,
RA Moule S., Murphy L., Oliver K., Ormond D., Price C., Quail M.A.,
RA Rabbinowitsch E., Rajandream M.A., Rutter S., Rutherford K.M., Sanders M.,
RA Simmonds M., Seeger K., Sharp S., Smith R., Squares R., Squares S.,
RA Stevens K., Taylor K., Tivey A., Unwin L., Whitehead S., Woodward J.R.,
RA Sulston J.E., Craig A., Newbold C., Barrell B.G.;
RT "Sequence of Plasmodium falciparum chromosomes 1, 3-9 and 13.";
RL Nature 419:527-531(2002).
RN [4]
RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 158-569 IN COMPLEX WITH FMN;
RP OROTATE AND INHIBITOR, COFACTOR, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=16510978; DOI=10.1107/s0907444905042642;
RA Hurt D.E., Widom J., Clardy J.;
RT "Structure of Plasmodium falciparum dihydroorotate dehydrogenase with a
RT bound inhibitor.";
RL Acta Crystallogr. D 62:312-323(2006).
RN [5]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 158-569 IN COMPLEXES WITH FMN;
RP OROTATE AND INHIBITORS, AND COFACTOR.
RX PubMed=19640844; DOI=10.1074/jbc.m109.028589;
RA Deng X., Gujjar R., El Mazouni F., Kaminsky W., Malmquist N.A.,
RA Goldsmith E.J., Rathod P.K., Phillips M.A.;
RT "Structural plasticity of malaria dihydroorotate dehydrogenase allows
RT selective binding of diverse chemical scaffolds.";
RL J. Biol. Chem. 284:26999-27009(2009).
RN [6]
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 158-569 IN COMPLEX WITH FMN;
RP OROTATE AND INHIBITOR, AND COFACTOR.
RX PubMed=20702404; DOI=10.1074/jbc.m110.162081;
RA Booker M.L., Bastos C.M., Kramer M.L., Barker R.H. Jr., Skerlj R.,
RA Sidhu A.B., Deng X., Celatka C., Cortese J.F., Guerrero Bravo J.E.,
RA Crespo Llado K.N., Serrano A.E., Angulo-Barturen I., Jimenez-Diaz M.B.,
RA Viera S., Garuti H., Wittlin S., Papastogiannidis P., Lin J.W., Janse C.J.,
RA Khan S.M., Duraisingh M., Coleman B., Goldsmith E.J., Phillips M.A.,
RA Munoz B., Wirth D.F., Klinger J.D., Wiegand R., Sybertz E.;
RT "Novel inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase
RT with anti-malarial activity in the mouse model.";
RL J. Biol. Chem. 285:33054-33064(2010).
CC -!- FUNCTION: Catalyzes the conversion of dihydroorotate to orotate with
CC quinone as electron acceptor.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(S)-dihydroorotate + a quinone = a quinol + orotate;
CC Xref=Rhea:RHEA:30187, ChEBI:CHEBI:24646, ChEBI:CHEBI:30839,
CC ChEBI:CHEBI:30864, ChEBI:CHEBI:132124; EC=1.3.5.2;
CC -!- COFACTOR:
CC Name=FMN; Xref=ChEBI:CHEBI:58210;
CC Evidence={ECO:0000269|PubMed:16510978, ECO:0000269|PubMed:19640844,
CC ECO:0000269|PubMed:20702404};
CC Note=Binds 1 FMN per subunit. {ECO:0000269|PubMed:16510978,
CC ECO:0000269|PubMed:19640844, ECO:0000269|PubMed:20702404};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=13.1 uM for 2,3-dimethoxy-5-methyl-6-(3-methyl-2-butenyl)-1,4-
CC benzoquinone (CoQ(1)) {ECO:0000269|PubMed:16510978};
CC -!- PATHWAY: Pyrimidine metabolism; UMP biosynthesis via de novo pathway;
CC orotate from (S)-dihydroorotate (quinone route): step 1/1.
CC -!- SUBUNIT: Monomer. {ECO:0000250}.
CC -!- SUBCELLULAR LOCATION: Mitochondrion inner membrane {ECO:0000250};
CC Single-pass membrane protein {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the dihydroorotate dehydrogenase family. Type 2
CC subfamily. {ECO:0000305}.
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DR EMBL; L15446; AAC37170.1; -; Unassigned_DNA.
DR EMBL; AL844505; CAG25203.1; -; Genomic_DNA.
DR RefSeq; XP_966023.1; XM_960930.1.
DR PDB; 1TV5; X-ray; 2.40 A; A=158-569.
DR PDB; 3I65; X-ray; 2.00 A; A=158-569.
DR PDB; 3I68; X-ray; 2.40 A; A=158-569.
DR PDB; 3I6R; X-ray; 2.50 A; A=158-569.
DR PDB; 3O8A; X-ray; 2.30 A; A=158-569.
DR PDB; 3SFK; X-ray; 2.95 A; A=158-569.
DR PDB; 4CQ8; X-ray; 1.98 A; A/B=158-569.
DR PDB; 4CQ9; X-ray; 2.72 A; A/B=158-569.
DR PDB; 4CQA; X-ray; 2.82 A; A/B=158-569.
DR PDB; 4ORM; X-ray; 2.07 A; A=158-569.
DR PDB; 4RX0; X-ray; 2.25 A; A=158-569.
DR PDB; 5BOO; X-ray; 2.80 A; A/B=158-569.
DR PDB; 5DEL; X-ray; 2.20 A; A=158-569.
DR PDB; 5FI8; X-ray; 2.32 A; A=158-569.
DR PDB; 5TBO; X-ray; 2.15 A; A=158-569.
DR PDB; 6E0B; X-ray; 2.10 A; A=158-569.
DR PDB; 6GJG; X-ray; 1.99 A; A/B=158-569.
DR PDB; 6I4B; X-ray; 1.98 A; A/B=158-569.
DR PDB; 6VTN; X-ray; 2.25 A; A=158-569.
DR PDB; 6VTY; X-ray; 1.78 A; A/B/C/D=158-569.
DR PDB; 7KYK; X-ray; 2.15 A; A/B/C/D=158-569.
DR PDB; 7KYV; X-ray; 2.40 A; A=158-569.
DR PDB; 7KYY; X-ray; 2.00 A; A/B/C/D=158-569.
DR PDB; 7KZ4; X-ray; 1.75 A; A/B=158-569.
DR PDB; 7KZY; X-ray; 1.75 A; A/B=158-569.
DR PDB; 7L01; X-ray; 1.60 A; A/B=158-569.
DR PDB; 7L0K; X-ray; 1.96 A; A/B=158-569.
DR PDB; 7S87; X-ray; 2.75 A; A/B=158-569.
DR PDBsum; 1TV5; -.
DR PDBsum; 3I65; -.
DR PDBsum; 3I68; -.
DR PDBsum; 3I6R; -.
DR PDBsum; 3O8A; -.
DR PDBsum; 3SFK; -.
DR PDBsum; 4CQ8; -.
DR PDBsum; 4CQ9; -.
DR PDBsum; 4CQA; -.
DR PDBsum; 4ORM; -.
DR PDBsum; 4RX0; -.
DR PDBsum; 5BOO; -.
DR PDBsum; 5DEL; -.
DR PDBsum; 5FI8; -.
DR PDBsum; 5TBO; -.
DR PDBsum; 6E0B; -.
DR PDBsum; 6GJG; -.
DR PDBsum; 6I4B; -.
DR PDBsum; 6VTN; -.
DR PDBsum; 6VTY; -.
DR PDBsum; 7KYK; -.
DR PDBsum; 7KYV; -.
DR PDBsum; 7KYY; -.
DR PDBsum; 7KZ4; -.
DR PDBsum; 7KZY; -.
DR PDBsum; 7L01; -.
DR PDBsum; 7L0K; -.
DR PDBsum; 7S87; -.
DR AlphaFoldDB; Q08210; -.
DR SMR; Q08210; -.
DR STRING; 5833.PFF0160c; -.
DR BindingDB; Q08210; -.
DR ChEMBL; CHEMBL3588732; -.
DR DrugBank; DB01117; Atovaquone.
DR DrugCentral; Q08210; -.
DR GuidetoPHARMACOLOGY; 2949; -.
DR PRIDE; Q08210; -.
DR EnsemblProtists; CAG25203; CAG25203; PF3D7_0603300.
DR GeneID; 3885966; -.
DR KEGG; pfa:PF3D7_0603300; -.
DR VEuPathDB; PlasmoDB:PF3D7_0603300; -.
DR HOGENOM; CLU_013640_0_1_1; -.
DR InParanoid; Q08210; -.
DR OMA; ERIKMGA; -.
DR PhylomeDB; Q08210; -.
DR Reactome; R-PFA-500753; Pyrimidine biosynthesis.
DR UniPathway; UPA00070; UER00946.
DR EvolutionaryTrace; Q08210; -.
DR Proteomes; UP000001450; Chromosome 6.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0005743; C:mitochondrial inner membrane; IDA:GeneDB.
DR GO; GO:0004152; F:dihydroorotate dehydrogenase activity; IDA:GeneDB.
DR GO; GO:0006207; P:'de novo' pyrimidine nucleobase biosynthetic process; IDA:GeneDB.
DR GO; GO:0044205; P:'de novo' UMP biosynthetic process; IEA:UniProtKB-UniPathway.
DR GO; GO:0009220; P:pyrimidine ribonucleotide biosynthetic process; IBA:GO_Central.
DR CDD; cd04738; DHOD_2_like; 1.
DR Gene3D; 3.20.20.70; -; 1.
DR InterPro; IPR013785; Aldolase_TIM.
DR InterPro; IPR005720; Dihydroorotate_DH.
DR InterPro; IPR005719; Dihydroorotate_DH_2.
DR InterPro; IPR001295; Dihydroorotate_DH_CS.
DR Pfam; PF01180; DHO_dh; 1.
DR PROSITE; PS00911; DHODEHASE_1; 1.
DR PROSITE; PS00912; DHODEHASE_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Flavoprotein; FMN; Membrane; Mitochondrion;
KW Mitochondrion inner membrane; Oxidoreductase; Pyrimidine biosynthesis;
KW Reference proteome; Transit peptide; Transmembrane; Transmembrane helix.
FT TRANSIT 1..23
FT /note="Mitochondrion"
FT /evidence="ECO:0000255"
FT CHAIN 24..569
FT /note="Dihydroorotate dehydrogenase (quinone),
FT mitochondrial"
FT /id="PRO_0000029888"
FT TRANSMEM 143..163
FT /note="Helical"
FT /evidence="ECO:0000255"
FT ACT_SITE 345
FT /note="Nucleophile"
FT /evidence="ECO:0000250"
FT BINDING 225..229
FT /ligand="FMN"
FT /ligand_id="ChEBI:CHEBI:58210"
FT /evidence="ECO:0000269|PubMed:16510978,
FT ECO:0000269|PubMed:20702404"
FT BINDING 229
FT /ligand="substrate"
FT BINDING 249
FT /ligand="FMN"
FT /ligand_id="ChEBI:CHEBI:58210"
FT /evidence="ECO:0000269|PubMed:16510978,
FT ECO:0000269|PubMed:20702404"
FT BINDING 274..278
FT /ligand="substrate"
FT BINDING 342
FT /ligand="FMN"
FT /ligand_id="ChEBI:CHEBI:58210"
FT /evidence="ECO:0000269|PubMed:16510978,
FT ECO:0000269|PubMed:20702404"
FT BINDING 342
FT /ligand="substrate"
FT BINDING 347
FT /ligand="substrate"
FT BINDING 429
FT /ligand="FMN"
FT /ligand_id="ChEBI:CHEBI:58210"
FT /evidence="ECO:0000269|PubMed:16510978,
FT ECO:0000269|PubMed:20702404"
FT BINDING 458..459
FT /ligand="substrate"
FT BINDING 477..478
FT /ligand="FMN"
FT /ligand_id="ChEBI:CHEBI:58210"
FT /evidence="ECO:0000269|PubMed:16510978,
FT ECO:0000269|PubMed:20702404"
FT BINDING 505..507
FT /ligand="FMN"
FT /ligand_id="ChEBI:CHEBI:58210"
FT /evidence="ECO:0000269|PubMed:16510978,
FT ECO:0000269|PubMed:20702404"
FT BINDING 528..529
FT /ligand="FMN"
FT /ligand_id="ChEBI:CHEBI:58210"
FT /evidence="ECO:0000269|PubMed:16510978,
FT ECO:0000269|PubMed:20702404"
FT STRAND 158..160
FT /evidence="ECO:0007829|PDB:7KYY"
FT HELIX 166..178
FT /evidence="ECO:0007829|PDB:7L01"
FT HELIX 181..193
FT /evidence="ECO:0007829|PDB:7L01"
FT HELIX 206..208
FT /evidence="ECO:0007829|PDB:7L01"
FT STRAND 210..212
FT /evidence="ECO:0007829|PDB:7L01"
FT STRAND 215..223
FT /evidence="ECO:0007829|PDB:7L01"
FT TURN 225..230
FT /evidence="ECO:0007829|PDB:7KZ4"
FT STRAND 231..233
FT /evidence="ECO:0007829|PDB:7L01"
FT HELIX 234..238
FT /evidence="ECO:0007829|PDB:7L01"
FT TURN 239..241
FT /evidence="ECO:0007829|PDB:7L01"
FT STRAND 243..250
FT /evidence="ECO:0007829|PDB:7L01"
FT STRAND 252..255
FT /evidence="ECO:0007829|PDB:7KYK"
FT STRAND 263..266
FT /evidence="ECO:0007829|PDB:7L01"
FT TURN 267..270
FT /evidence="ECO:0007829|PDB:7L01"
FT STRAND 271..274
FT /evidence="ECO:0007829|PDB:7L01"
FT STRAND 280..282
FT /evidence="ECO:0007829|PDB:7KYK"
FT HELIX 283..298
FT /evidence="ECO:0007829|PDB:7L01"
FT HELIX 301..303
FT /evidence="ECO:0007829|PDB:7L01"
FT STRAND 307..312
FT /evidence="ECO:0007829|PDB:7L01"
FT HELIX 321..332
FT /evidence="ECO:0007829|PDB:7L01"
FT HELIX 333..335
FT /evidence="ECO:0007829|PDB:7L01"
FT STRAND 337..342
FT /evidence="ECO:0007829|PDB:7L01"
FT STRAND 346..348
FT /evidence="ECO:0007829|PDB:7KZ4"
FT HELIX 351..355
FT /evidence="ECO:0007829|PDB:7L01"
FT HELIX 357..376
FT /evidence="ECO:0007829|PDB:7L01"
FT TURN 378..380
FT /evidence="ECO:0007829|PDB:7KZ4"
FT STRAND 381..383
FT /evidence="ECO:0007829|PDB:7L01"
FT STRAND 418..422
FT /evidence="ECO:0007829|PDB:7L01"
FT STRAND 425..430
FT /evidence="ECO:0007829|PDB:7L01"
FT HELIX 436..449
FT /evidence="ECO:0007829|PDB:7L01"
FT STRAND 452..456
FT /evidence="ECO:0007829|PDB:7L01"
FT HELIX 467..469
FT /evidence="ECO:0007829|PDB:7L01"
FT STRAND 474..478
FT /evidence="ECO:0007829|PDB:7L01"
FT HELIX 479..481
FT /evidence="ECO:0007829|PDB:7L01"
FT HELIX 482..495
FT /evidence="ECO:0007829|PDB:7L01"
FT TURN 496..498
FT /evidence="ECO:0007829|PDB:7L01"
FT STRAND 502..507
FT /evidence="ECO:0007829|PDB:7L01"
FT HELIX 511..520
FT /evidence="ECO:0007829|PDB:7L01"
FT STRAND 522..528
FT /evidence="ECO:0007829|PDB:7L01"
FT HELIX 529..534
FT /evidence="ECO:0007829|PDB:7L01"
FT HELIX 535..537
FT /evidence="ECO:0007829|PDB:7L01"
FT HELIX 538..553
FT /evidence="ECO:0007829|PDB:7L01"
FT STRAND 556..558
FT /evidence="ECO:0007829|PDB:7L01"
FT HELIX 559..561
FT /evidence="ECO:0007829|PDB:7L01"
FT TURN 562..565
FT /evidence="ECO:0007829|PDB:7L01"
SQ SEQUENCE 569 AA; 65558 MW; 88880384EBD52FE3 CRC64;
MISKLKPQFM FLPKKHILSY CRKDVLNLFE QKFYYTSKRK ESNNMKNESL LRLINYNRYY
NKIDSNNYYN GGKILSNDRQ YIYSPLCEYK KKINDISSYV SVPFKINIRN LGTSNFVNNK
KDVLDNDYIY ENIKKEKSKH KKIIFLLFVS LFGLYGFFES YNPEFFLYDI FLKFCLKYID
GEICHDLFLL LGKYNILPYD TSNDSIYACT NIKHLDFINP FGVAAGFDKN GVCIDSILKL
GFSFIEIGTI TPRGQTGNAK PRIFRDVESR SIINSCGFNN MGCDKVTENL ILFRKRQEED
KLLSKHIVGV SIGKNKDTVN IVDDLKYCIN KIGRYADYIA INVSSPNTPG LRDNQEAGKL
KNIILSVKEE IDNLEKNNIM NDESTYNEDN KIVEKKNNFN KNNSHMMKDA KDNFLWFNTT
KKKPLVFVKL APDLNQEQKK EIADVLLETN IDGMIISNTT TQINDIKSFE NKKGGVSGAK
LKDISTKFIC EMYNYTNKQI PIIASGGIFS GLDALEKIEA GASVCQLYSC LVFNGMKSAV
QIKRELNHLL YQRGYYNLKE AIGRKHSKS
