DYR_PNECA
ID DYR_PNECA Reviewed; 206 AA.
AC P16184;
DT 01-APR-1990, integrated into UniProtKB/Swiss-Prot.
DT 01-APR-1990, sequence version 1.
DT 03-AUG-2022, entry version 119.
DE RecName: Full=Dihydrofolate reductase;
DE EC=1.5.1.3;
OS Pneumocystis carinii.
OC Eukaryota; Fungi; Dikarya; Ascomycota; Taphrinomycotina;
OC Pneumocystidomycetes; Pneumocystidaceae; Pneumocystis.
OX NCBI_TaxID=4754;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
RX PubMed=2682653; DOI=10.1073/pnas.86.22.8625;
RA Edman J.C., Edman U., Cao M., Lundgren B., Kovacs J., Santi D.V.;
RT "Isolation and expression of the Pneumocystis carinii dihydrofolate
RT reductase gene.";
RL Proc. Natl. Acad. Sci. U.S.A. 86:8625-8629(1989).
RN [2]
RP X-RAY CRYSTALLOGRAPHY (1.86 ANGSTROMS).
RX PubMed=7866743; DOI=10.1016/s0969-2126(94)00093-x;
RA Champness J.N., Achari A., Ballantine S.P., Bryant P.K., Delves C.J.,
RA Stammers D.K.;
RT "The structure of Pneumocystis carinii dihydrofolate reductase to 1.9-A
RT resolution.";
RL Structure 2:915-924(1994).
RN [3]
RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) IN COMPLEX WITH FOLATE AND NADP.
RX PubMed=10194348; DOI=10.1021/bi982728m;
RA Cody V., Galitsky N., Rak D., Luft J.R., Pangborn W., Queener S.F.;
RT "Ligand-induced conformational changes in the crystal structures of
RT Pneumocystis carinii dihydrofolate reductase complexes with folate and
RT NADP+.";
RL Biochemistry 38:4303-4312(1999).
RN [4]
RP X-RAY CRYSTALLOGRAPHY (2.10 ANGSTROMS) IN COMPLEX WITH NADP AND THE
RP SYNTHETIC INHIBITOR TAB.
RX PubMed=10736154; DOI=10.1021/bi9924563;
RA Cody V., Chan D., Galitsky N., Rak D., Luft J.R., Pangborn W.,
RA Queener S.F., Laughton C.A., Stevens M.F.;
RT "Structural studies on bioactive compounds. 30. Crystal structure and
RT molecular modeling studies on the Pneumocystis carinii dihydrofolate
RT reductase cofactor complex with TAB, a highly selective antifolate.";
RL Biochemistry 39:3556-3564(2000).
RN [5]
RP X-RAY CRYSTALLOGRAPHY (2.30 ANGSTROMS) IN COMPLEX WITH PT653 AND NADPH.
RX PubMed=12037296; DOI=10.1107/s090744490200505x;
RA Cody V., Galitsky N., Luft J.R., Pangborn W., Rosowsky A., Queener S.F.;
RT "Structure-based enzyme inhibitor design: modeling studies and crystal
RT structure analysis of Pneumocystis carinii dihydrofolate reductase ternary
RT complex with PT653 and NADPH.";
RL Acta Crystallogr. D 58:946-954(2002).
RN [6]
RP X-RAY CRYSTALLOGRAPHY (1.90 ANGSTROMS) IN COMPLEX WITH INHIBITOR AND NADPH.
RX PubMed=12198294; DOI=10.1107/s0907444902010442;
RA Cody V., Galitsky N., Luft J.R., Pangborn W., Queener S.F., Gangjee A.;
RT "Analysis of quinazoline and pyrido[2,3-d]pyrimidine N9-C10 reversed-bridge
RT antifolates in complex with NADP+ and Pneumocystis carinii dihydrofolate
RT reductase.";
RL Acta Crystallogr. D 58:1393-1399(2002).
RN [7]
RP X-RAY CRYSTALLOGRAPHY (2.25 ANGSTROMS) IN COMPLEX WITH SYNTHETIC INHIBITOR.
RX PubMed=15039552; DOI=10.1107/s0907444904002094;
RA Cody V., Luft J.R., Pangborn W., Gangjee A., Queener S.F.;
RT "Structure determination of tetrahydroquinazoline antifolates in complex
RT with human and Pneumocystis carinii dihydrofolate reductase: correlations
RT between enzyme selectivity and stereochemistry.";
RL Acta Crystallogr. D 60:646-655(2004).
RN [8]
RP X-RAY CRYSTALLOGRAPHY (1.60 ANGSTROMS) IN COMPLEX WITH INHIBITOR AND NADPH.
RX PubMed=17019704; DOI=10.1002/prot.21131;
RA Cody V., Pace J., Chisum K., Rosowsky A.;
RT "New insights into DHFR interactions: analysis of Pneumocystis carinii and
RT mouse DHFR complexes with NADPH and two highly potent 5-(omega-
RT carboxy(alkyloxy) trimethoprim derivatives reveals conformational
RT correlations with activity and novel parallel ring stacking interactions.";
RL Proteins 65:959-969(2006).
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 -!- SIMILARITY: Belongs to the dihydrofolate reductase family.
CC {ECO:0000305}.
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DR EMBL; M26495; AAA33787.1; -; Genomic_DNA.
DR EMBL; M26496; AAA33788.1; -; mRNA.
DR PIR; A36177; A36177.
DR PDB; 1CD2; X-ray; 2.20 A; A=1-206.
DR PDB; 1DAJ; X-ray; 2.30 A; A=1-206.
DR PDB; 1DYR; X-ray; 1.86 A; A=1-206.
DR PDB; 1E26; X-ray; 2.00 A; A=1-206.
DR PDB; 1KLK; X-ray; 2.30 A; A=1-206.
DR PDB; 1LY3; X-ray; 1.90 A; A=1-206.
DR PDB; 1LY4; X-ray; 2.10 A; A=1-206.
DR PDB; 1S3Y; X-ray; 2.25 A; A=1-206.
DR PDB; 1VJ3; X-ray; 2.10 A; A=2-206.
DR PDB; 2CD2; X-ray; 1.90 A; A=1-206.
DR PDB; 2FZH; X-ray; 2.10 A; A=1-206.
DR PDB; 2FZI; X-ray; 1.60 A; A=1-206.
DR PDB; 3CD2; X-ray; 2.50 A; A=1-206.
DR PDB; 3NZ6; X-ray; 2.00 A; X=1-206.
DR PDB; 3NZ9; X-ray; 1.80 A; X=1-206.
DR PDB; 3NZA; X-ray; 1.90 A; X=1-206.
DR PDB; 3NZB; X-ray; 1.45 A; X=1-206.
DR PDB; 3NZC; X-ray; 2.00 A; X=1-206.
DR PDB; 3TD8; X-ray; 1.80 A; A=1-206.
DR PDB; 4CD2; X-ray; 2.00 A; A=1-206.
DR PDB; 4G8Z; X-ray; 1.75 A; X=3-206.
DR PDB; 4IXE; X-ray; 1.54 A; D=1-206.
DR PDB; 4IXF; X-ray; 1.70 A; X=1-206.
DR PDB; 4IXG; X-ray; 1.70 A; X=1-206.
DR PDB; 4QJZ; X-ray; 1.61 A; D=1-206.
DR PDBsum; 1CD2; -.
DR PDBsum; 1DAJ; -.
DR PDBsum; 1DYR; -.
DR PDBsum; 1E26; -.
DR PDBsum; 1KLK; -.
DR PDBsum; 1LY3; -.
DR PDBsum; 1LY4; -.
DR PDBsum; 1S3Y; -.
DR PDBsum; 1VJ3; -.
DR PDBsum; 2CD2; -.
DR PDBsum; 2FZH; -.
DR PDBsum; 2FZI; -.
DR PDBsum; 3CD2; -.
DR PDBsum; 3NZ6; -.
DR PDBsum; 3NZ9; -.
DR PDBsum; 3NZA; -.
DR PDBsum; 3NZB; -.
DR PDBsum; 3NZC; -.
DR PDBsum; 3TD8; -.
DR PDBsum; 4CD2; -.
DR PDBsum; 4G8Z; -.
DR PDBsum; 4IXE; -.
DR PDBsum; 4IXF; -.
DR PDBsum; 4IXG; -.
DR PDBsum; 4QJZ; -.
DR AlphaFoldDB; P16184; -.
DR SMR; P16184; -.
DR BindingDB; P16184; -.
DR ChEMBL; CHEMBL1926; -.
DR DrugBank; DB02427; 2,4-Diamino-6-[N-(2',5'-Dimethoxybenzyl)-N-Methylamino]Quinazoline.
DR DrugBank; DB03987; 2,4-Diamino-6-[N-(3',5'-Dimethoxybenzyl)-N-Methylamino]Pyrido[2,3-D]Pyrimidine.
DR DrugBank; DB02559; 6-(Octahydro-1h-Indol-1-Ylmethyl)Decahydroquinazoline-2,4-Diamine.
DR DrugBank; DB02026; Furo[2,3d]Pyrimidine Antifolate.
DR DrugBank; DB03461; Nicotinamide adenine dinucleotide phosphate.
DR DrugCentral; P16184; -.
DR BRENDA; 1.5.1.3; 4924.
DR SABIO-RK; P16184; -.
DR UniPathway; UPA00077; UER00158.
DR EvolutionaryTrace; P16184; -.
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 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; NADP; One-carbon metabolism; Oxidoreductase.
FT CHAIN 1..206
FT /note="Dihydrofolate reductase"
FT /id="PRO_0000186376"
FT DOMAIN 6..204
FT /note="DHFR"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00660"
FT BINDING 12
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:10194348,
FT ECO:0000269|PubMed:10736154, ECO:0000269|PubMed:12037296,
FT ECO:0000269|PubMed:12198294, ECO:0000269|PubMed:17019704"
FT BINDING 18..24
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:10194348,
FT ECO:0000269|PubMed:10736154, ECO:0000269|PubMed:12037296,
FT ECO:0000269|PubMed:12198294, ECO:0000269|PubMed:17019704"
FT BINDING 32..37
FT /ligand="substrate"
FT /evidence="ECO:0000305|PubMed:10194348"
FT BINDING 59..61
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:10194348,
FT ECO:0000269|PubMed:10736154, ECO:0000269|PubMed:12037296,
FT ECO:0000269|PubMed:12198294, ECO:0000269|PubMed:17019704"
FT BINDING 75
FT /ligand="substrate"
FT /evidence="ECO:0000305|PubMed:10194348"
FT BINDING 81..83
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:10194348,
FT ECO:0000269|PubMed:10736154, ECO:0000269|PubMed:12037296,
FT ECO:0000269|PubMed:12198294, ECO:0000269|PubMed:17019704"
FT BINDING 124..131
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:10194348,
FT ECO:0000269|PubMed:10736154, ECO:0000269|PubMed:12037296,
FT ECO:0000269|PubMed:12198294, ECO:0000269|PubMed:17019704"
FT STRAND 3..5
FT /evidence="ECO:0007829|PDB:2FZI"
FT STRAND 7..14
FT /evidence="ECO:0007829|PDB:3NZB"
FT STRAND 18..21
FT /evidence="ECO:0007829|PDB:3NZB"
FT HELIX 30..41
FT /evidence="ECO:0007829|PDB:3NZB"
FT HELIX 47..49
FT /evidence="ECO:0007829|PDB:3NZB"
FT STRAND 51..58
FT /evidence="ECO:0007829|PDB:3NZB"
FT HELIX 59..64
FT /evidence="ECO:0007829|PDB:3NZB"
FT HELIX 67..69
FT /evidence="ECO:0007829|PDB:3NZB"
FT STRAND 75..80
FT /evidence="ECO:0007829|PDB:3NZB"
FT STRAND 89..91
FT /evidence="ECO:0007829|PDB:4IXF"
FT STRAND 93..97
FT /evidence="ECO:0007829|PDB:3NZB"
FT HELIX 98..108
FT /evidence="ECO:0007829|PDB:3NZB"
FT STRAND 111..122
FT /evidence="ECO:0007829|PDB:3NZB"
FT HELIX 126..134
FT /evidence="ECO:0007829|PDB:3NZB"
FT STRAND 138..146
FT /evidence="ECO:0007829|PDB:3NZB"
FT STRAND 153..155
FT /evidence="ECO:0007829|PDB:3NZB"
FT HELIX 163..165
FT /evidence="ECO:0007829|PDB:3NZB"
FT TURN 166..168
FT /evidence="ECO:0007829|PDB:3NZB"
FT STRAND 169..171
FT /evidence="ECO:0007829|PDB:3TD8"
FT HELIX 174..181
FT /evidence="ECO:0007829|PDB:3NZB"
FT STRAND 190..192
FT /evidence="ECO:0007829|PDB:3NZB"
FT STRAND 195..203
FT /evidence="ECO:0007829|PDB:3NZB"
SQ SEQUENCE 206 AA; 23884 MW; 6BA64A7019911508 CRC64;
MNQQKSLTLI VALTTSYGIG RSNSLPWKLK KEISYFKRVT SFVPTFDSFE SMNVVLMGRK
TWESIPLQFR PLKGRINVVI TRNESLDLGN GIHSAKSLDH ALELLYRTYG SESSVQINRI
FVIGGAQLYK AAMDHPKLDR IMATIIYKDI HCDVFFPLKF RDKEWSSVWK KEKHSDLESW
VGTKVPHGKI NEDGFDYEFE MWTRDL
