ID Q81R22_BACAN Unreviewed; 162 AA. AC Q81R22; A0A2B6BBC4; A0A6L7HIW5; E9R6R2; E9R6R3; E9R6R4; Q68SA0; Q6HZ92; AC Q6KT86; DT 01-JUN-2003, integrated into UniProtKB/TrEMBL. DT 01-JUN-2003, sequence version 1. DT 27-MAR-2024, entry version 183. DE RecName: Full=Dihydrofolate reductase {ECO:0000256|ARBA:ARBA00012856, ECO:0000256|PIRNR:PIRNR000194}; DE EC=1.5.1.3 {ECO:0000256|ARBA:ARBA00012856, ECO:0000256|PIRNR:PIRNR000194}; GN Name=dfrA {ECO:0000313|EMBL:AAT31357.1}; GN OrderedLocusNames=GBAA_2237 {ECO:0000313|EMBL:AAT31357.1}; OS Bacillus anthracis. OC Bacteria; Bacillota; Bacilli; Bacillales; Bacillaceae; Bacillus; OC Bacillus cereus group. OX NCBI_TaxID=1392 {ECO:0000313|EMBL:AAT31357.1, ECO:0000313|Proteomes:UP000000594}; RN [1] {ECO:0000313|EMBL:AAT40581.1} RP NUCLEOTIDE SEQUENCE. RC STRAIN=Sterne {ECO:0000313|EMBL:AAT40581.1}; RX PubMed=15561838; DOI=10.1128/AAC.48.12.4643-4649.2004; RA Barrow E.W., Bourne P.C., Barrow W.W.; RT "Functional cloning of Bacillus anthracis dihydrofolate reductase and RT confirmation of natural resistance to trimethoprim."; RL Antimicrob. Agents Chemother. 48:4643-4649(2004). RN [2] {ECO:0007829|PDB:2QK8} RP X-RAY CRYSTALLOGRAPHY (2.40 ANGSTROMS). RX PubMed=17696333; DOI=10.1021/jm070319v; RA Bennett B.C., Xu H., Simmerman R.F., Lee R.E., Dealwis C.G.; RT "Crystal structure of the anthrax drug target, Bacillus anthracis RT dihydrofolate reductase."; RL J. Med. Chem. 50:4374-4381(2007). RN [3] {ECO:0007829|PDB:3E0B} RP X-RAY CRYSTALLOGRAPHY (2.25 ANGSTROMS) IN COMPLEX WITH NADPH. RX PubMed=19007108; DOI=10.1021/jm800776a; RA Beierlein J.M., Frey K.M., Bolstad D.B., Pelphrey P.M., Joska T.M., RA Smith A.E., Priestley N.D., Wright D.L., Anderson A.C.; RT "Synthetic and crystallographic studies of a new inhibitor series targeting RT Bacillus anthracis dihydrofolate reductase."; RL J. Med. Chem. 51:7532-7540(2008). RN [4] {ECO:0007829|PDB:3FL8, ECO:0007829|PDB:3FL9} RP X-RAY CRYSTALLOGRAPHY (2.29 ANGSTROMS) IN COMPLEX WITH CALCIUM. RX PubMed=19364848; DOI=10.1128/aac.01666-08; RA Bourne C.R., Bunce R.A., Bourne P.C., Berlin K.D., Barrow E.W., RA Barrow W.W.; RT "Crystal structure of Bacillus anthracis dihydrofolate reductase with the RT dihydrophthalazine-based trimethoprim derivative RAB1 provides a structural RT explanation of potency and selectivity."; RL Antimicrob. Agents Chemother. 53:3065-3073(2009). RN [5] {ECO:0007829|PDB:2KGK} RP STRUCTURE BY NMR IN COMPLEX WITH NADP. RX PubMed=19323450; DOI=10.1021/bi802319w; RA Beierlein J.M., Deshmukh L., Frey K.M., Vinogradova O., Anderson A.C.; RT "The solution structure of Bacillus anthracis dihydrofolate reductase RT yields insight into the analysis of structure-activity relationships for RT novel inhibitors."; RL Biochemistry 48:4100-4108(2009). RN [6] {ECO:0000313|EMBL:AAT31357.1, ECO:0000313|Proteomes:UP000000594} RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RC STRAIN=Ames ancestor {ECO:0000313|Proteomes:UP000000594}, and Ames RC Ancestor {ECO:0000313|EMBL:AAT31357.1}; RX PubMed=18952800; DOI=10.1128/JB.01347-08; RA Ravel J., Jiang L., Stanley S.T., Wilson M.R., Decker R.S., Read T.D., RA Worsham P., Keim P.S., Salzberg S.L., Fraser-Liggett C.M., Rasko D.A.; RT "The complete genome sequence of Bacillus anthracis Ames 'Ancestor'."; RL J. Bacteriol. 191:445-446(2009). RN [7] {ECO:0007829|PDB:3DAT} RP X-RAY CRYSTALLOGRAPHY (2.30 ANGSTROMS) IN COMPLEX WITH NADPH. RX PubMed=19374017; DOI=.1016/j.jsb.2009.01.001; RA Bennett B.C., Wan Q., Ahmad M.F., Langan P., Dealwis C.G.; RT "X-ray structure of the ternary MTX.NADPH complex of the anthrax RT dihydrofolate reductase: a pharmacophore for dual-site inhibitor design."; RL J. Struct. Biol. 166:162-171(2009). RN [8] {ECO:0007829|PDB:3JVX, ECO:0007829|PDB:3JW3} RP X-RAY CRYSTALLOGRAPHY (2.25 ANGSTROMS) IN COMPLEX WITH NADPH. RA Beierlein J.M., Karri N.G., Anderson A.C.; RT "Mutational Studies into Trimethoprim Resistance in Bacillus anthracis RT Dihydrofolate Reductase."; RL Submitted (SEP-2009) to the PDB data bank. RN [9] {ECO:0007829|PDB:3JWC, ECO:0007829|PDB:3JWF} RP X-RAY CRYSTALLOGRAPHY (2.08 ANGSTROMS) IN COMPLEX WITH NADPH. RA Beierlein J.M., Karri N.G., Anderson A.C.; RT "Targeted Mutations in Bacillus anthracis Dihydrofolate Reductase Condense RT Complex Structure-Activity Relationships."; RL J. Med. Chem. 0:0-0(2010). RN [10] {ECO:0007829|PDB:3SAI} RP X-RAY CRYSTALLOGRAPHY (2.25 ANGSTROMS) IN COMPLEX WITH NADP(+). RA Anderson A.C., Beierlein J.M., Viswanathan K., Wright D.L.; RT "SAR studies of heterocyclic propargyl-linked TMP analogs targeting RT Bacillus dihydrofolate reductase."; RL Submitted (JUN-2011) to the PDB data bank. RN [11] {ECO:0007829|PDB:3SA1, ECO:0007829|PDB:3SA2} RP X-RAY CRYSTALLOGRAPHY (2.25 ANGSTROMS) IN COMPLEX WITH NADP(+). RA Anderson A.C., Beierlein J.M., Viswanathan K., Wright D.L.; RT "SAR studies of heterocyclic propargyl-linked TMP analogs to Bacillus RT dihydrofolate reductase."; RL Submitted (JUN-2011) to the PDB data bank. RN [12] {ECO:0007829|PDB:3S9U} RP X-RAY CRYSTALLOGRAPHY (1.90 ANGSTROMS) IN COMPLEX WITH NADP(+). RA Anderson A.C., Beierlein J.M., Viswanathan K., Wright D.L.; RT "Structure-Activity Studies of Heterocyclic Propargyl-linked TMP Analogs RT Targeting Bacillus anthracis Dihydrofolate Reductase."; RL Submitted (JUN-2011) to the PDB data bank. RN [13] {ECO:0007829|PDB:4ELB, ECO:0007829|PDB:4ELE} RP X-RAY CRYSTALLOGRAPHY (2.10 ANGSTROMS) IN COMPLEX WITH CALCIUM. RX PubMed=22999981; DOI=10.1016/j.bbapap.2012.09.001; RA Bourne C.R., Wakeham N., Nammalwar B., Tseitin V., Bourne P.C., RA Barrow E.W., Mylvaganam S., Ramnarayan K., Bunce R.A., Berlin K.D., RA Barrow W.W.; RT "Structure-activity relationship for enantiomers of potent inhibitors of B. RT anthracis dihydrofolate reductase."; RL Biochim. Biophys. Acta 1834:46-52(2013). RN [14] {ECO:0007829|PDB:8SSX} RP X-RAY CRYSTALLOGRAPHY (1.65 ANGSTROMS). RA Shaw G.X., Li Y., Wu Y., Yan H., Ji X.; RT "Crystal structure of Bacillus anthracis dihydrofolate reductase at 1.65-A RT resolution."; RL Submitted (MAY-2023) to the PDB data bank. 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. {ECO:0000256|PIRNR:PIRNR000194}. 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; CC Evidence={ECO:0000256|PIRNR:PIRNR000194}; CC -!- PATHWAY: Cofactor biosynthesis; tetrahydrofolate biosynthesis; 5,6,7,8- CC tetrahydrofolate from 7,8-dihydrofolate: step 1/1. CC {ECO:0000256|ARBA:ARBA00004903, ECO:0000256|PIRNR:PIRNR000194}. CC -!- SIMILARITY: Belongs to the dihydrofolate reductase family. CC {ECO:0000256|ARBA:ARBA00009539, ECO:0000256|PIRNR:PIRNR000194, CC ECO:0000256|RuleBase:RU004474}. 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; AE017334; AAT31357.1; -; Genomic_DNA. DR EMBL; AY569129; AAT40581.1; -; Genomic_DNA. DR RefSeq; WP_000637198.1; NZ_WXXJ01000017.1. DR PDB; 2KGK; NMR; -; A=1-162. DR PDB; 2QK8; X-ray; 2.40 A; A=1-162. DR PDB; 3DAT; X-ray; 2.30 A; A=1-162. DR PDB; 3E0B; X-ray; 2.25 A; A/B=1-162. DR PDB; 3FL8; X-ray; 2.29 A; A/B/C/D/E/F/G/H=1-162. DR PDB; 3FL9; X-ray; 2.40 A; A/B/C/D/E/F/G/H=1-162. DR PDB; 3JVX; X-ray; 2.25 A; A/B=1-162. DR PDB; 3JW3; X-ray; 2.57 A; A/B=1-162. DR PDB; 3JW5; X-ray; 2.89 A; A/B=1-162. DR PDB; 3JWC; X-ray; 2.57 A; A/B=1-162. DR PDB; 3JWF; X-ray; 2.57 A; A/B=1-162. DR PDB; 3JWK; X-ray; 2.08 A; A/B=1-162. DR PDB; 3JWM; X-ray; 2.57 A; A/B=1-162. DR PDB; 3S9U; X-ray; 1.90 A; A/B=1-162. DR PDB; 3SA1; X-ray; 2.50 A; A/B=1-162. DR PDB; 3SA2; X-ray; 2.25 A; A/B=1-162. DR PDB; 3SAI; X-ray; 2.25 A; A/B=1-162. DR PDB; 4ELB; X-ray; 2.60 A; A/B/C/D/E/F/G/H=1-162. DR PDB; 4ELE; X-ray; 2.35 A; A/B/C/D/E/F/G/H=1-162. DR PDB; 4ELF; X-ray; 2.30 A; A/B/C/D/E/F/G/H=1-162. DR PDB; 4ELG; X-ray; 2.10 A; A/B/C/D/E/F/G/H=1-162. DR PDB; 4ELH; X-ray; 2.10 A; A/B/C/D/E/F/G/H=1-162. DR PDB; 8SSX; X-ray; 1.65 A; A=1-162. DR PDBsum; 2KGK; -. DR PDBsum; 2QK8; -. DR PDBsum; 3DAT; -. DR PDBsum; 3E0B; -. DR PDBsum; 3FL8; -. DR PDBsum; 3FL9; -. DR PDBsum; 3JVX; -. DR PDBsum; 3JW3; -. DR PDBsum; 3JW5; -. DR PDBsum; 3JWC; -. DR PDBsum; 3JWF; -. DR PDBsum; 3JWK; -. DR PDBsum; 3JWM; -. DR PDBsum; 3S9U; -. DR PDBsum; 3SA1; -. DR PDBsum; 3SA2; -. DR PDBsum; 3SAI; -. DR PDBsum; 4ELB; -. DR PDBsum; 4ELE; -. DR PDBsum; 4ELF; -. DR PDBsum; 4ELG; -. DR PDBsum; 4ELH; -. DR ChEMBL; CHEMBL5270; -. DR DrugBank; DB08234; 5-[3-(2,5-dimethoxyphenyl)prop-1-yn-1-yl]-6-ethylpyrimidine-2,4-diamine. DR DNASU; 1085515; -. DR GeneID; 75085420; -. DR KEGG; banh:HYU01_11160; -. DR KEGG; bar:GBAA_2237; -. DR PATRIC; fig|1392.230.peg.2198; -. DR HOGENOM; CLU_043966_5_2_9; -. DR OMA; MISFIFA; -. DR OrthoDB; 9804315at2; -. DR BRENDA; 1.5.1.3; 634. DR UniPathway; UPA00077; UER00158. DR Proteomes; UP000000594; Chromosome. DR GO; GO:0004146; F:dihydrofolate reductase activity; IEA:UniProtKB-EC. DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW. 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; 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 {ECO:0007829|PDB:2KGK, ECO:0007829|PDB:2QK8}; KW Calcium {ECO:0007829|PDB:3FL8, ECO:0007829|PDB:3FL9}; KW Metal-binding {ECO:0007829|PDB:3FL8, ECO:0007829|PDB:3FL9}; KW NADP {ECO:0000256|ARBA:ARBA00022857, ECO:0000256|PIRNR:PIRNR000194}; KW Nucleotide-binding {ECO:0007829|PDB:3DAT, ECO:0007829|PDB:3E0B}; KW One-carbon metabolism {ECO:0000256|PIRNR:PIRNR000194}; KW Oxidoreductase {ECO:0000256|ARBA:ARBA00023002, KW ECO:0000256|PIRNR:PIRNR000194}; KW Reference proteome {ECO:0000313|Proteomes:UP000000594}. FT DOMAIN 2..160 FT /note="DHFR" FT /evidence="ECO:0000259|PROSITE:PS51330" FT BINDING 8 FT /ligand="NADP(+)" FT /ligand_id="ChEBI:CHEBI:58349" FT /evidence="ECO:0007829|PDB:3S9U, ECO:0007829|PDB:3SA1" FT BINDING 8 FT /ligand="NADPH" FT /ligand_id="ChEBI:CHEBI:57783" FT /evidence="ECO:0007829|PDB:3DAT, ECO:0007829|PDB:3E0B" FT BINDING 15 FT /ligand="NADP(+)" FT /ligand_id="ChEBI:CHEBI:58349" FT /evidence="ECO:0007829|PDB:3S9U, ECO:0007829|PDB:3SA1" FT BINDING 15 FT /ligand="NADPH" FT /ligand_id="ChEBI:CHEBI:57783" FT /evidence="ECO:0007829|PDB:3DAT, ECO:0007829|PDB:3E0B" FT BINDING 19 FT /ligand="NADPH" FT /ligand_id="ChEBI:CHEBI:57783" FT /evidence="ECO:0007829|PDB:3JW3" FT BINDING 20 FT /ligand="NADP(+)" FT /ligand_id="ChEBI:CHEBI:58349" FT /evidence="ECO:0007829|PDB:3S9U, ECO:0007829|PDB:3SA1" FT BINDING 20 FT /ligand="NADPH" FT /ligand_id="ChEBI:CHEBI:57783" FT /evidence="ECO:0007829|PDB:3DAT, ECO:0007829|PDB:3E0B" FT BINDING 45 FT /ligand="NADP(+)" FT /ligand_id="ChEBI:CHEBI:58349" FT /evidence="ECO:0007829|PDB:3S9U, ECO:0007829|PDB:3SA1" FT BINDING 45 FT /ligand="NADPH" FT /ligand_id="ChEBI:CHEBI:57783" FT /evidence="ECO:0007829|PDB:3DAT, ECO:0007829|PDB:3E0B" FT BINDING 46 FT /ligand="NADP(+)" FT /ligand_id="ChEBI:CHEBI:58349" FT /evidence="ECO:0007829|PDB:3S9U, ECO:0007829|PDB:3SA1" FT BINDING 46 FT /ligand="NADPH" FT /ligand_id="ChEBI:CHEBI:57783" FT /evidence="ECO:0007829|PDB:3DAT, ECO:0007829|PDB:3E0B" FT BINDING 47 FT /ligand="NADP(+)" FT /ligand_id="ChEBI:CHEBI:58349" FT /evidence="ECO:0007829|PDB:3S9U, ECO:0007829|PDB:3SA1" FT BINDING 47 FT /ligand="NADPH" FT /ligand_id="ChEBI:CHEBI:57783" FT /evidence="ECO:0007829|PDB:3DAT, ECO:0007829|PDB:3E0B" FT BINDING 64 FT /ligand="NADP(+)" FT /ligand_id="ChEBI:CHEBI:58349" FT /evidence="ECO:0007829|PDB:3S9U, ECO:0007829|PDB:3SA1" FT BINDING 64 FT /ligand="NADPH" FT /ligand_id="ChEBI:CHEBI:57783" FT /evidence="ECO:0007829|PDB:3E0B, ECO:0007829|PDB:3JVX" FT BINDING 65 FT /ligand="NADP(+)" FT /ligand_id="ChEBI:CHEBI:58349" FT /evidence="ECO:0007829|PDB:3S9U, ECO:0007829|PDB:3SA1" FT BINDING 65 FT /ligand="NADPH" FT /ligand_id="ChEBI:CHEBI:57783" FT /evidence="ECO:0007829|PDB:3DAT, ECO:0007829|PDB:3E0B" FT BINDING 66 FT /ligand="NADPH" FT /ligand_id="ChEBI:CHEBI:57783" FT /evidence="ECO:0007829|PDB:3JW5" FT BINDING 98 FT /ligand="NADP(+)" FT /ligand_id="ChEBI:CHEBI:58349" FT /evidence="ECO:0007829|PDB:3S9U, ECO:0007829|PDB:3SA1" FT BINDING 98 FT /ligand="NADPH" FT /ligand_id="ChEBI:CHEBI:57783" FT /evidence="ECO:0007829|PDB:3E0B, ECO:0007829|PDB:3JVX" FT BINDING 99 FT /ligand="NADP(+)" FT /ligand_id="ChEBI:CHEBI:58349" FT /evidence="ECO:0007829|PDB:3S9U, ECO:0007829|PDB:3SA1" FT BINDING 99 FT /ligand="NADPH" FT /ligand_id="ChEBI:CHEBI:57783" FT /evidence="ECO:0007829|PDB:3DAT, ECO:0007829|PDB:3E0B" FT BINDING 100 FT /ligand="NADP(+)" FT /ligand_id="ChEBI:CHEBI:58349" FT /evidence="ECO:0007829|PDB:3S9U, ECO:0007829|PDB:3SA1" FT BINDING 100 FT /ligand="NADPH" FT /ligand_id="ChEBI:CHEBI:57783" FT /evidence="ECO:0007829|PDB:3DAT, ECO:0007829|PDB:3E0B" FT BINDING 101 FT /ligand="NADP(+)" FT /ligand_id="ChEBI:CHEBI:58349" FT /evidence="ECO:0007829|PDB:3S9U, ECO:0007829|PDB:3SA1" FT BINDING 101 FT /ligand="NADPH" FT /ligand_id="ChEBI:CHEBI:57783" FT /evidence="ECO:0007829|PDB:3DAT, ECO:0007829|PDB:3E0B" FT BINDING 108 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="1" FT /evidence="ECO:0007829|PDB:3FL8, ECO:0007829|PDB:4ELE" FT BINDING 110 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="2" FT /evidence="ECO:0007829|PDB:3FL9" FT BINDING 110 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="1" FT /evidence="ECO:0007829|PDB:3FL8, ECO:0007829|PDB:4ELE" FT BINDING 125 FT /ligand="NADPH" FT /ligand_id="ChEBI:CHEBI:57783" FT /evidence="ECO:0007829|PDB:3DAT" SQ SEQUENCE 162 AA; 19125 MW; 4259925DD9A1365A CRC64; MIVSFMVAMD ENRVIGKDNN LPWRLPSELQ YVKKTTMGHP LIMGRKNYEA IGRPLPGRRN IIVTRNEGYH VEGCEVAHSV EEVFELCKNE EEIFIFGGAQ IYDLFLPYVD KLYITKIHHA FEGDTFFPEM DMTNWKEVFV EKGLTDEKNP YTYYYHVYEK QQ //