DYR_STAAU
ID DYR_STAAU Reviewed; 159 AA.
AC P0A017; P10167;
DT 01-MAR-2005, integrated into UniProtKB/Swiss-Prot.
DT 23-JAN-2007, sequence version 2.
DT 03-AUG-2022, entry version 109.
DE RecName: Full=Dihydrofolate reductase;
DE Short=DHFR;
DE EC=1.5.1.3;
GN Name=folA;
OS Staphylococcus aureus.
OC Bacteria; Firmicutes; Bacilli; Bacillales; Staphylococcaceae;
OC Staphylococcus.
OX NCBI_TaxID=1280;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC STRAIN=ATCC 25923 / DSM 1104 / JCM 2413 / NBRC 14462 / NCIMB 12702 / NCTC
RC 12981 / Seattle 1945;
RX PubMed=8363365; DOI=10.1128/aac.37.7.1400;
RA Dale G.E., Then R.L., Stueber D.;
RT "Characterization of the gene for chromosomal trimethoprim-sensitive
RT dihydrofolate reductase of Staphylococcus aureus ATCC 25923.";
RL Antimicrob. Agents Chemother. 37:1400-1405(1993).
RN [2]
RP PROTEIN SEQUENCE OF 2-36.
RC STRAIN=157/4696;
RX PubMed=3060373; DOI=10.1016/0014-5793(88)81006-8;
RA Hartman P.G., Stahli M., Kocher H.P., Then R.L.;
RT "N-terminal amino acid sequence of the chromosomal dihydrofolate reductase
RT purified from trimethoprim-resistant Staphylococcus aureus.";
RL FEBS Lett. 242:157-160(1988).
RN [3]
RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 2-159.
RX PubMed=19622858; DOI=10.1107/s0907444909013936;
RA Oefner C., Parisi S., Schulz H., Lociuro S., Dale G.E.;
RT "Inhibitory properties and X-ray crystallographic study of the binding of
RT AR-101, AR-102 and iclaprim in ternary complexes with NADPH and
RT dihydrofolate reductase from Staphylococcus aureus.";
RL Acta Crystallogr. D 65:751-757(2009).
RN [4]
RP X-RAY CRYSTALLOGRAPHY (1.48 ANGSTROMS) IN COMPLEX WITH NADPH AND
RP TRIMETHOPRIM.
RX PubMed=19280600; DOI=10.1002/prot.22383;
RA Heaslet H., Harris M., Fahnoe K., Sarver R., Putz H., Chang J.,
RA Subramanyam C., Barreiro G., Miller J.R.;
RT "Structural comparison of chromosomal and exogenous dihydrofolate reductase
RT from Staphylococcus aureus in complex with the potent inhibitor
RT trimethoprim.";
RL Proteins 76:706-717(2009).
CC -!- FUNCTION: Key enzyme in folate metabolism. Catalyzes an essential
CC reaction for de novo glycine and purine synthesis, and for DNA
CC precursor synthesis.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(6S)-5,6,7,8-tetrahydrofolate + NADP(+) = 7,8-dihydrofolate +
CC H(+) + NADPH; Xref=Rhea:RHEA:15009, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:57451, ChEBI:CHEBI:57453, ChEBI:CHEBI:57783,
CC ChEBI:CHEBI:58349; EC=1.5.1.3; Evidence={ECO:0000255|PROSITE-
CC ProRule:PRU00660};
CC -!- PATHWAY: Cofactor biosynthesis; tetrahydrofolate biosynthesis; 5,6,7,8-
CC tetrahydrofolate from 7,8-dihydrofolate: step 1/1.
CC -!- MISCELLANEOUS: There are two DhfR isozymes in S.aureus, this one is
CC chromosomal and is sensitive to trimethoprim.
CC -!- SIMILARITY: Belongs to the dihydrofolate reductase family.
CC {ECO:0000305}.
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DR EMBL; Z16422; CAA78910.1; -; Genomic_DNA.
DR PIR; S32014; S32014.
DR RefSeq; WP_000175746.1; NZ_WYDB01000002.1.
DR PDB; 2W9G; X-ray; 1.95 A; A=1-159.
DR PDB; 2W9H; X-ray; 1.48 A; A=1-159.
DR PDB; 3FRA; X-ray; 2.35 A; X=2-159.
DR PDB; 3FRB; X-ray; 2.00 A; X=2-159.
DR PDB; 3FRD; X-ray; 2.10 A; X=2-159.
DR PDB; 3FRE; X-ray; 2.20 A; X=2-159.
DR PDB; 3FRF; X-ray; 2.20 A; X=2-159.
DR PDB; 3FY8; X-ray; 2.20 A; X=2-159.
DR PDB; 3FY9; X-ray; 2.25 A; X=2-159.
DR PDB; 3FYV; X-ray; 2.20 A; X=2-159.
DR PDB; 3FYW; X-ray; 2.10 A; X=2-159.
DR PDB; 3I8A; X-ray; 2.41 A; X=2-158.
DR PDB; 3LG4; X-ray; 3.15 A; A/B=1-158.
DR PDB; 3M08; X-ray; 2.01 A; A=2-158.
DR PDB; 3M09; X-ray; 2.01 A; A=2-158.
DR PDB; 3SGY; X-ray; 2.60 A; A/B=2-158.
DR PDB; 3SH2; X-ray; 3.00 A; A/B=2-158.
DR PDB; 3SQY; X-ray; 1.50 A; X=1-159.
DR PDB; 3SR5; X-ray; 1.68 A; X=2-159.
DR PDB; 3SRQ; X-ray; 1.69 A; X=1-159.
DR PDB; 3SRR; X-ray; 1.70 A; X=1-159.
DR PDB; 3SRS; X-ray; 1.70 A; X=1-159.
DR PDB; 3SRU; X-ray; 1.70 A; X=1-159.
DR PDB; 3SRW; X-ray; 1.70 A; X=1-159.
DR PDB; 4FGG; X-ray; 2.30 A; A=1-159.
DR PDB; 4FGH; X-ray; 2.50 A; A=1-159.
DR PDB; 4LAE; X-ray; 1.69 A; X=1-159.
DR PDB; 4LAG; X-ray; 1.70 A; X=1-159.
DR PDB; 4LAH; X-ray; 1.88 A; X=1-159.
DR PDB; 4LEK; X-ray; 1.70 A; X=1-159.
DR PDB; 4XE6; X-ray; 2.69 A; X=1-157.
DR PDB; 4XEC; X-ray; 2.69 A; X=2-158.
DR PDB; 5HF0; X-ray; 2.25 A; X=2-158.
DR PDB; 5HF2; X-ray; 1.81 A; X=2-158.
DR PDB; 5ISP; X-ray; 1.84 A; X=2-158.
DR PDB; 5ISQ; X-ray; 1.90 A; X=2-158.
DR PDB; 5IST; X-ray; 1.72 A; X=2-158.
DR PDB; 5JG0; X-ray; 1.88 A; X=2-158.
DR PDB; 6E4E; X-ray; 1.90 A; A=1-159.
DR PDB; 6ND2; X-ray; 2.24 A; X=2-158.
DR PDB; 6P9Z; X-ray; 1.86 A; X=2-158.
DR PDB; 6PBO; X-ray; 1.65 A; X=2-158.
DR PDB; 6PR6; X-ray; 2.01 A; A=1-159.
DR PDB; 6PR7; X-ray; 2.01 A; A=1-159.
DR PDB; 6PR8; X-ray; 2.01 A; A=2-159.
DR PDB; 6PR9; X-ray; 2.01 A; A=2-159.
DR PDB; 6PRA; X-ray; 2.01 A; A=1-159.
DR PDB; 6PRB; X-ray; 2.00 A; A=2-159.
DR PDB; 6PRD; X-ray; 2.01 A; A=2-159.
DR PDB; 7T7Q; X-ray; 2.20 A; X=2-158.
DR PDB; 7T7S; X-ray; 2.20 A; X=2-158.
DR PDBsum; 2W9G; -.
DR PDBsum; 2W9H; -.
DR PDBsum; 3FRA; -.
DR PDBsum; 3FRB; -.
DR PDBsum; 3FRD; -.
DR PDBsum; 3FRE; -.
DR PDBsum; 3FRF; -.
DR PDBsum; 3FY8; -.
DR PDBsum; 3FY9; -.
DR PDBsum; 3FYV; -.
DR PDBsum; 3FYW; -.
DR PDBsum; 3I8A; -.
DR PDBsum; 3LG4; -.
DR PDBsum; 3M08; -.
DR PDBsum; 3M09; -.
DR PDBsum; 3SGY; -.
DR PDBsum; 3SH2; -.
DR PDBsum; 3SQY; -.
DR PDBsum; 3SR5; -.
DR PDBsum; 3SRQ; -.
DR PDBsum; 3SRR; -.
DR PDBsum; 3SRS; -.
DR PDBsum; 3SRU; -.
DR PDBsum; 3SRW; -.
DR PDBsum; 4FGG; -.
DR PDBsum; 4FGH; -.
DR PDBsum; 4LAE; -.
DR PDBsum; 4LAG; -.
DR PDBsum; 4LAH; -.
DR PDBsum; 4LEK; -.
DR PDBsum; 4XE6; -.
DR PDBsum; 4XEC; -.
DR PDBsum; 5HF0; -.
DR PDBsum; 5HF2; -.
DR PDBsum; 5ISP; -.
DR PDBsum; 5ISQ; -.
DR PDBsum; 5IST; -.
DR PDBsum; 5JG0; -.
DR PDBsum; 6E4E; -.
DR PDBsum; 6ND2; -.
DR PDBsum; 6P9Z; -.
DR PDBsum; 6PBO; -.
DR PDBsum; 6PR6; -.
DR PDBsum; 6PR7; -.
DR PDBsum; 6PR8; -.
DR PDBsum; 6PR9; -.
DR PDBsum; 6PRA; -.
DR PDBsum; 6PRB; -.
DR PDBsum; 6PRD; -.
DR PDBsum; 7T7Q; -.
DR PDBsum; 7T7S; -.
DR AlphaFoldDB; P0A017; -.
DR BMRB; P0A017; -.
DR SMR; P0A017; -.
DR BindingDB; P0A017; -.
DR ChEMBL; CHEMBL1681620; -.
DR DrugBank; DB07938; (S)-iclaprim.
DR DrugBank; DB08234; 5-[3-(2,5-dimethoxyphenyl)prop-1-yn-1-yl]-6-ethylpyrimidine-2,4-diamine.
DR DrugBank; DB08741; 5-[[(2R)-2-cyclopropyl-7,8-dimethoxy-2H-chromen-5-yl]methyl]pyrimidine-2,4-diamine.
DR DrugCentral; P0A017; -.
DR OMA; RDNQLPW; -.
DR BRENDA; 1.5.1.3; 3352.
DR UniPathway; UPA00077; UER00158.
DR EvolutionaryTrace; P0A017; -.
DR PRO; PR:P0A017; -.
DR GO; GO:0004146; F:dihydrofolate reductase activity; IEA:UniProtKB-EC.
DR GO; GO:0050661; F:NADP binding; IEA:InterPro.
DR GO; GO:0006545; P:glycine biosynthetic process; IEA:InterPro.
DR GO; GO:0006730; P:one-carbon metabolic process; IEA:UniProtKB-KW.
DR GO; GO:0046654; P:tetrahydrofolate biosynthetic process; IEA:UniProtKB-UniPathway.
DR CDD; cd00209; DHFR; 1.
DR Gene3D; 3.40.430.10; -; 1.
DR InterPro; IPR012259; DHFR.
DR InterPro; IPR024072; DHFR-like_dom_sf.
DR InterPro; IPR017925; DHFR_CS.
DR InterPro; IPR001796; DHFR_dom.
DR PANTHER; PTHR48069; PTHR48069; 1.
DR Pfam; PF00186; DHFR_1; 1.
DR PIRSF; PIRSF000194; DHFR; 1.
DR SUPFAM; SSF53597; SSF53597; 1.
DR PROSITE; PS00075; DHFR_1; 1.
DR PROSITE; PS51330; DHFR_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Direct protein sequencing; NADP; One-carbon metabolism;
KW Oxidoreductase.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000269|PubMed:3060373"
FT CHAIN 2..159
FT /note="Dihydrofolate reductase"
FT /id="PRO_0000186411"
FT DOMAIN 2..157
FT /note="DHFR"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00660"
FT BINDING 6..7
FT /ligand="substrate"
FT /evidence="ECO:0000305|PubMed:19280600"
FT BINDING 7..8
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:19280600"
FT BINDING 15..20
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:19280600"
FT BINDING 28
FT /ligand="substrate"
FT /evidence="ECO:0000305|PubMed:19280600"
FT BINDING 44..47
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:19280600"
FT BINDING 50
FT /ligand="substrate"
FT /evidence="ECO:0000305|PubMed:19280600"
FT BINDING 58
FT /ligand="substrate"
FT /evidence="ECO:0000305|PubMed:19280600"
FT BINDING 63..66
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:19280600"
FT BINDING 93..98
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:19280600"
FT BINDING 93
FT /ligand="substrate"
FT /evidence="ECO:0000305|PubMed:19280600"
FT BINDING 101
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:19280600"
FT BINDING 122
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:19280600"
FT STRAND 3..10
FT /evidence="ECO:0007829|PDB:2W9H"
FT STRAND 14..17
FT /evidence="ECO:0007829|PDB:2W9H"
FT HELIX 26..36
FT /evidence="ECO:0007829|PDB:2W9H"
FT STRAND 39..44
FT /evidence="ECO:0007829|PDB:2W9H"
FT HELIX 45..51
FT /evidence="ECO:0007829|PDB:2W9H"
FT STRAND 58..63
FT /evidence="ECO:0007829|PDB:2W9H"
FT STRAND 75..77
FT /evidence="ECO:0007829|PDB:2W9H"
FT HELIX 80..85
FT /evidence="ECO:0007829|PDB:2W9H"
FT STRAND 90..94
FT /evidence="ECO:0007829|PDB:2W9H"
FT HELIX 96..102
FT /evidence="ECO:0007829|PDB:2W9H"
FT TURN 103..105
FT /evidence="ECO:0007829|PDB:2W9H"
FT STRAND 107..114
FT /evidence="ECO:0007829|PDB:2W9H"
FT STRAND 121..123
FT /evidence="ECO:0007829|PDB:2W9H"
FT TURN 129..131
FT /evidence="ECO:0007829|PDB:2W9H"
FT STRAND 132..139
FT /evidence="ECO:0007829|PDB:2W9H"
FT STRAND 150..157
FT /evidence="ECO:0007829|PDB:2W9H"
SQ SEQUENCE 159 AA; 18251 MW; 811898409FEAFAAB CRC64;
MTLSILVAHD LQRVIGFENQ LPWHLPNDLK HVKKLSTGHT LVMGRKTFES IGKPLPNRRN
VVLTSDTSFN VEGVDVIHSI EDIYQLPGHV FIFGGQTLFE EMIDKVDDMY ITVIEGKFRG
DTFFPPYTFE DWEVASSVEG KLDEKNTIPH TFLHLIRKK
