DYR_LACCA
ID DYR_LACCA Reviewed; 163 AA.
AC P00381;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
DT 23-JAN-2007, sequence version 3.
DT 03-AUG-2022, entry version 125.
DE RecName: Full=Dihydrofolate reductase;
DE EC=1.5.1.3;
GN Name=folA; Synonyms=dhfR;
OS Lactobacillus casei.
OC Bacteria; Firmicutes; Bacilli; Lactobacillales; Lactobacillaceae;
OC Lacticaseibacillus.
OX NCBI_TaxID=1582;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=3928445; DOI=10.1016/0378-1119(85)90174-x;
RA Andrews J., Clore G.M., Davies R.W., Gronenborn A.M., Gronenborn B.,
RA Kalderon D., Papadopoulos P.C., Schaefer S., Sims P.F.G., Stancombe R.;
RT "Nucleotide sequence of the dihydrofolate reductase gene of methotrexate-
RT resistant Lactobacillus casei.";
RL Gene 35:217-222(1985).
RN [2]
RP PROTEIN SEQUENCE OF 2-163.
RX PubMed=98527; DOI=10.1016/s0021-9258(19)46952-4;
RA Freisheim J.H., Bitar K.G., Reddy A.V., Blankenship D.T.;
RT "Dihydrofolate reductase from amethopterin-resistant Lactobacillus casei.
RT Sequences of the cyanogen bromide peptides and complete sequences of the
RT enzyme.";
RL J. Biol. Chem. 253:6437-6444(1978).
RN [3]
RP PROTEIN SEQUENCE OF 2-52.
RX PubMed=405008; DOI=10.1016/0006-291x(77)91482-6;
RA Batley K.E., Morris H.R.;
RT "Dihydrofolate reductase from Lactobacillus casei: N-terminal sequence and
RT comparison with the substrate binding region of other reductases.";
RL Biochem. Biophys. Res. Commun. 75:1010-1014(1977).
RN [4]
RP X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) OF 2-163 IN COMPLEX WITH NADPH AND
RP METHOTREXATE.
RX PubMed=6815179; DOI=10.1016/s0021-9258(18)33498-7;
RA Filman D.J., Bolin J.T., Matthews D.A., Kraut J.;
RT "Crystal structures of Escherichia coli and Lactobacillus casei
RT dihydrofolate reductase refined at 1.7-A resolution. II. Environment of
RT bound NADPH and implications for catalysis.";
RL J. Biol. Chem. 257:13663-13672(1982).
RN [5]
RP STRUCTURE BY NMR.
RX PubMed=1905571; DOI=10.1021/bi00239a035;
RA Carr M.D., Birdsall B., Frenkiel T.A., Bauer C.J., Jimenez-Barbero J.,
RA Polshakov V.I., McCormick J.E., Roberts G.C.K., Feeney J.;
RT "Dihydrofolate reductase: sequential resonance assignments using 2D and 3D
RT NMR and secondary structure determination in solution.";
RL Biochemistry 30:6330-6341(1991).
RN [6]
RP STRUCTURE BY NMR.
RX PubMed=7547901; DOI=10.1021/bi00037a006;
RA Morgan W.D., Birdsall B., Polshakov V.I., Sali D., Kompis I., Feeney J.;
RT "Solution structure of a brodimoprim analogue in its complex with
RT Lactobacillus casei dihydrofolate reductase.";
RL Biochemistry 34:11690-11702(1995).
RN [7]
RP STRUCTURE BY NMR.
RX PubMed=9514736; DOI=10.1006/jmbi.1997.1560;
RA Gargaro A.R., Soteriou A., Frenkiel T.A., Bauer C.J., Birdsall B.,
RA Polshakov V.I., Barsukov I.L., Roberts G.C.K., Feeney J.;
RT "The solution structure of the complex of Lactobacillus casei dihydrofolate
RT reductase with methotrexate.";
RL J. Mol. Biol. 277:119-134(1998).
RN [8]
RP STRUCTURE BY NMR.
RX PubMed=10091649; DOI=10.1110/ps.8.3.467;
RA Polshakov V.I., Birdsall B., Frenkiel T.A., Gargaro A.R., Feeney J.;
RT "Structure and dynamics in solution of the complex of Lactobacillus casei
RT dihydrofolate reductase with the new lipophilic antifolate drug
RT trimetrexate.";
RL Protein Sci. 8:467-481(1999).
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 -!- SUBUNIT: Monomer. {ECO:0000269|PubMed:6815179}.
CC -!- MISCELLANEOUS: This bacterial strain is resistant to the folic acid
CC analog methotrexate (amethopterin).
CC -!- SIMILARITY: Belongs to the dihydrofolate reductase family.
CC {ECO:0000305}.
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DR EMBL; M10922; AAA25237.1; -; Genomic_DNA.
DR PIR; A24036; RDLBD.
DR PDB; 1AO8; NMR; -; A=2-163.
DR PDB; 1BZF; NMR; -; A=2-163.
DR PDB; 1DIS; NMR; -; A=2-163.
DR PDB; 1DIU; NMR; -; A=2-163.
DR PDB; 1LUD; NMR; -; A=2-163.
DR PDB; 2HM9; NMR; -; A=2-163.
DR PDB; 2HQP; NMR; -; A=2-163.
DR PDB; 2L28; NMR; -; A=2-163.
DR PDB; 2LF1; NMR; -; A=2-163.
DR PDB; 3DFR; X-ray; 1.70 A; A=2-163.
DR PDBsum; 1AO8; -.
DR PDBsum; 1BZF; -.
DR PDBsum; 1DIS; -.
DR PDBsum; 1DIU; -.
DR PDBsum; 1LUD; -.
DR PDBsum; 2HM9; -.
DR PDBsum; 2HQP; -.
DR PDBsum; 2L28; -.
DR PDBsum; 2LF1; -.
DR PDBsum; 3DFR; -.
DR AlphaFoldDB; P00381; -.
DR BMRB; P00381; -.
DR SMR; P00381; -.
DR BindingDB; P00381; -.
DR ChEMBL; CHEMBL2902; -.
DR DrugBank; DB03125; 2,4-Diamino-5-(3,4,5-Trimethoxy-Benzyl)-Pyrimidin-1-Ium.
DR DrugBank; DB02809; Brodimoprim-4,6-Dicarboxylate.
DR DrugCentral; P00381; -.
DR BRENDA; 1.5.1.3; 2854.
DR SABIO-RK; P00381; -.
DR UniPathway; UPA00077; UER00158.
DR EvolutionaryTrace; P00381; -.
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; -; 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; Antibiotic resistance; Direct protein sequencing;
KW Methotrexate resistance; NADP; One-carbon metabolism; Oxidoreductase.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000269|PubMed:405008,
FT ECO:0000269|PubMed:98527"
FT CHAIN 2..163
FT /note="Dihydrofolate reductase"
FT /id="PRO_0000186393"
FT DOMAIN 2..161
FT /note="DHFR"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00660"
FT BINDING 5..7
FT /ligand="substrate"
FT /evidence="ECO:0000305|PubMed:6815179"
FT BINDING 6..7
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:6815179"
FT BINDING 14..19
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:6815179"
FT BINDING 27
FT /ligand="methotrexate"
FT /ligand_id="ChEBI:CHEBI:50681"
FT /evidence="ECO:0000269|PubMed:6815179"
FT BINDING 27
FT /ligand="substrate"
FT /evidence="ECO:0000305|PubMed:6815179"
FT BINDING 32
FT /ligand="methotrexate"
FT /ligand_id="ChEBI:CHEBI:50681"
FT /evidence="ECO:0000269|PubMed:6815179"
FT BINDING 32
FT /ligand="substrate"
FT /evidence="ECO:0000305|PubMed:6815179"
FT BINDING 43..46
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:6815179"
FT BINDING 58
FT /ligand="methotrexate"
FT /ligand_id="ChEBI:CHEBI:50681"
FT /evidence="ECO:0000269|PubMed:6815179"
FT BINDING 58
FT /ligand="substrate"
FT /evidence="ECO:0000305|PubMed:6815179"
FT BINDING 63..66
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:6815179"
FT BINDING 80
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:6815179"
FT BINDING 98..103
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:6815179"
FT BINDING 117
FT /ligand="substrate"
FT /evidence="ECO:0000305|PubMed:6815179"
FT SITE 22
FT /note="May be important for enzyme function"
FT CONFLICT 9
FT /note="D -> N (in Ref. 2; AA sequence)"
FT /evidence="ECO:0000305"
FT CONFLICT 91
FT /note="P -> L (in Ref. 2; AA sequence)"
FT /evidence="ECO:0000305"
FT STRAND 3..8
FT /evidence="ECO:0007829|PDB:3DFR"
FT TURN 10..12
FT /evidence="ECO:0007829|PDB:1BZF"
FT STRAND 13..16
FT /evidence="ECO:0007829|PDB:3DFR"
FT HELIX 25..33
FT /evidence="ECO:0007829|PDB:3DFR"
FT TURN 34..37
FT /evidence="ECO:0007829|PDB:3DFR"
FT STRAND 38..43
FT /evidence="ECO:0007829|PDB:3DFR"
FT HELIX 44..49
FT /evidence="ECO:0007829|PDB:3DFR"
FT STRAND 50..54
FT /evidence="ECO:0007829|PDB:3DFR"
FT STRAND 58..63
FT /evidence="ECO:0007829|PDB:3DFR"
FT STRAND 67..69
FT /evidence="ECO:0007829|PDB:2HQP"
FT STRAND 74..79
FT /evidence="ECO:0007829|PDB:3DFR"
FT HELIX 80..89
FT /evidence="ECO:0007829|PDB:3DFR"
FT STRAND 91..93
FT /evidence="ECO:0007829|PDB:1BZF"
FT STRAND 95..97
FT /evidence="ECO:0007829|PDB:3DFR"
FT HELIX 101..106
FT /evidence="ECO:0007829|PDB:3DFR"
FT HELIX 108..110
FT /evidence="ECO:0007829|PDB:3DFR"
FT STRAND 113..121
FT /evidence="ECO:0007829|PDB:3DFR"
FT STRAND 126..128
FT /evidence="ECO:0007829|PDB:3DFR"
FT HELIX 134..136
FT /evidence="ECO:0007829|PDB:3DFR"
FT STRAND 137..145
FT /evidence="ECO:0007829|PDB:3DFR"
FT HELIX 150..152
FT /evidence="ECO:0007829|PDB:3DFR"
FT STRAND 154..161
FT /evidence="ECO:0007829|PDB:3DFR"
SQ SEQUENCE 163 AA; 18439 MW; 1E4B556ED7A750D1 CRC64;
MTAFLWAQDR DGLIGKDGHL PWHLPDDLHY FRAQTVGKIM VVGRRTYESF PKRPLPERTN
VVLTHQEDYQ AQGAVVVHDV AAVFAYAKQH PDQELVIAGG AQIFTAFKDD VDTLLVTRLA
GSFEGDTKMI PLNWDDFTKV SSRTVEDTNP ALTHTYEVWQ KKA
