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   08-NOV-2023, entry version 123.
DE   RecName: Full=Dihydrofolate reductase;
DE            EC=1.5.1.3;
OS   Pneumocystis carinii.
OC   Eukaryota; Fungi; Dikarya; Ascomycota; Taphrinomycotina;
OC   Pneumocystomycetes; Pneumocystaceae; 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   VEuPathDB; FungiDB:T552_01177; -.
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; 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   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; 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
//