ID DYRA_STAAU Reviewed; 161 AA. AC P13955; DT 01-JAN-1990, integrated into UniProtKB/Swiss-Prot. DT 23-JAN-2007, sequence version 3. DT 03-MAY-2023, entry version 132. DE RecName: Full=Dihydrofolate reductase type 1 from Tn4003; DE EC=1.5.1.3; GN Name=dfrA; OS Staphylococcus aureus. OG Plasmid pSK1. OC Bacteria; Bacillota; Bacilli; Bacillales; Staphylococcaceae; OC Staphylococcus. OX NCBI_TaxID=1280; RN [1] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RC TRANSPOSON=Tn4003; RX PubMed=2548057; DOI=10.1111/j.1365-2958.1989.tb01805.x; RA Rouch D.A., Messeroti L.J., Loo L.S.L., Jackson C.A., Skurray R.A.; RT "Trimethoprim resistance transposon Tn4003 from Staphylococcus aureus RT encodes genes for a dihydrofolate reductase and thymidylate synthetase RT flanked by three copies of IS257."; RL Mol. Microbiol. 3:161-175(1989). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RC STRAIN=157/4696; RX PubMed=2365064; DOI=10.1016/0014-5793(90)81529-w; RA Burdeska A., Ott M., Bannwarth W., Then R.L.; RT "Identical genes for trimethoprim-resistant dihydrofolate reductase from RT Staphylococcus aureus in Australia and central Europe."; RL FEBS Lett. 266:159-162(1990). RN [3] RP X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) IN COMPLEX WITH NADPH AND RP TRIMETHOPRIM, AND MUTAGENESIS OF ALA-44 AND TYR-99. 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 plasmid-encoded and is resistant to trimethoprim. CC -!- SIMILARITY: Belongs to the dihydrofolate reductase family. CC {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; X13290; CAA31649.1; -; Genomic_DNA. DR EMBL; Y07536; CAA68824.1; -; Genomic_DNA. DR PIR; S04164; S04164. DR RefSeq; NP_877983.1; NC_005054.1. DR RefSeq; WP_000175735.1; NZ_VTZV01000057.1. DR RefSeq; YP_002790943.1; NC_012547.1. DR RefSeq; YP_003813115.1; NC_014369.1. DR RefSeq; YP_006937652.1; NC_013320.1. DR RefSeq; YP_006937707.1; NC_013321.1. DR RefSeq; YP_006938354.1; NC_013338.1. DR RefSeq; YP_006938562.1; NC_013343.1. DR PDB; 2W9S; X-ray; 1.80 A; A/B/C/D/E/F=1-161. DR PDB; 2W9T; X-ray; 2.35 A; A/B=1-161. DR PDBsum; 2W9S; -. DR PDBsum; 2W9T; -. DR AlphaFoldDB; P13955; -. DR SMR; P13955; -. DR BindingDB; P13955; -. DR OMA; MISFIFA; -. DR BRENDA; 1.5.1.3; 3352. DR UniPathway; UPA00077; UER00158. DR EvolutionaryTrace; P13955; -. 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:0046677; P:response to antibiotic; IEA:UniProtKB-KW. DR GO; GO:0031427; P:response to methotrexate; 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; Dihydrofolate Reductase, subunit A; 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; DIHYDROFOLATE REDUCTASE; 1. DR PANTHER; PTHR48069:SF3; DIHYDROFOLATE REDUCTASE; 1. DR Pfam; PF00186; DHFR_1; 1. DR PIRSF; PIRSF000194; DHFR; 1. DR PRINTS; PR00070; DHFR. DR SUPFAM; SSF53597; Dihydrofolate reductase-like; 1. DR PROSITE; PS00075; DHFR_1; 1. DR PROSITE; PS51330; DHFR_2; 1. PE 1: Evidence at protein level; KW 3D-structure; Antibiotic resistance; Methotrexate resistance; NADP; KW One-carbon metabolism; Oxidoreductase; Plasmid; Trimethoprim resistance. FT INIT_MET 1 FT /note="Removed" FT /evidence="ECO:0000250" FT CHAIN 2..161 FT /note="Dihydrofolate reductase type 1 from Tn4003" FT /id="PRO_0000186405" FT DOMAIN 2..157 FT /note="DHFR" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00660" FT BINDING 6..8 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 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 112 FT /ligand="substrate" FT /evidence="ECO:0000305|PubMed:19280600" FT MUTAGEN 44 FT /note="A->G: Increases trimethoprim sensitivity; when FT associated with F-99." FT /evidence="ECO:0000269|PubMed:19280600" FT MUTAGEN 99 FT /note="Y->F: Increases trimethoprim sensitivity; when FT associated with G-44." FT /evidence="ECO:0000269|PubMed:19280600" FT STRAND 3..10 FT /evidence="ECO:0007829|PDB:2W9S" FT STRAND 14..17 FT /evidence="ECO:0007829|PDB:2W9S" FT HELIX 26..36 FT /evidence="ECO:0007829|PDB:2W9S" FT STRAND 39..44 FT /evidence="ECO:0007829|PDB:2W9S" FT HELIX 45..51 FT /evidence="ECO:0007829|PDB:2W9S" FT STRAND 58..63 FT /evidence="ECO:0007829|PDB:2W9S" FT STRAND 75..77 FT /evidence="ECO:0007829|PDB:2W9S" FT HELIX 81..84 FT /evidence="ECO:0007829|PDB:2W9S" FT STRAND 90..94 FT /evidence="ECO:0007829|PDB:2W9S" FT HELIX 96..102 FT /evidence="ECO:0007829|PDB:2W9S" FT TURN 103..105 FT /evidence="ECO:0007829|PDB:2W9S" FT STRAND 107..116 FT /evidence="ECO:0007829|PDB:2W9S" FT STRAND 120..123 FT /evidence="ECO:0007829|PDB:2W9S" FT TURN 129..131 FT /evidence="ECO:0007829|PDB:2W9S" FT STRAND 132..139 FT /evidence="ECO:0007829|PDB:2W9S" FT STRAND 143..145 FT /evidence="ECO:0007829|PDB:2W9T" FT STRAND 150..157 FT /evidence="ECO:0007829|PDB:2W9S" SQ SEQUENCE 161 AA; 18461 MW; F829D6109A3AF3A0 CRC64; MTLSIIVAHD KQRVIGYQNQ LPWHLPNDLK HIKQLTTGNT LVMARKTFNS IGKPLPNRRN VVLTNQASFH HEGVDVINSL DEIKELSGHV FIFGGQTLYE AMIDQVDDMY ITVIDGKFQG DTFFPPYTFE NWEVESSVEG QLDEKNTIPH TFLHLVRRKG K //