DYR_MYCTU
ID DYR_MYCTU Reviewed; 161 AA.
AC P9WNX1; L0TDH5; O33305; P0A546;
DT 16-APR-2014, integrated into UniProtKB/Swiss-Prot.
DT 01-APR-2015, sequence version 2.
DT 03-AUG-2022, entry version 49.
DE RecName: Full=Dihydrofolate reductase;
DE EC=1.5.1.3;
GN Name=folA; Synonyms=dfrA; OrderedLocusNames=Rv2763c; ORFNames=MTV002.28c;
OS Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv).
OC Bacteria; Actinobacteria; Corynebacteriales; Mycobacteriaceae;
OC Mycobacterium; Mycobacterium tuberculosis complex.
OX NCBI_TaxID=83332;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=9634230; DOI=10.1038/31159;
RA Cole S.T., Brosch R., Parkhill J., Garnier T., Churcher C.M., Harris D.E.,
RA Gordon S.V., Eiglmeier K., Gas S., Barry C.E. III, Tekaia F., Badcock K.,
RA Basham D., Brown D., Chillingworth T., Connor R., Davies R.M., Devlin K.,
RA Feltwell T., Gentles S., Hamlin N., Holroyd S., Hornsby T., Jagels K.,
RA Krogh A., McLean J., Moule S., Murphy L.D., Oliver S., Osborne J.,
RA Quail M.A., Rajandream M.A., Rogers J., Rutter S., Seeger K., Skelton S.,
RA Squares S., Squares R., Sulston J.E., Taylor K., Whitehead S.,
RA Barrell B.G.;
RT "Deciphering the biology of Mycobacterium tuberculosis from the complete
RT genome sequence.";
RL Nature 393:537-544(1998).
RN [2]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=21969609; DOI=10.1074/mcp.m111.011627;
RA Kelkar D.S., Kumar D., Kumar P., Balakrishnan L., Muthusamy B., Yadav A.K.,
RA Shrivastava P., Marimuthu A., Anand S., Sundaram H., Kingsbury R.,
RA Harsha H.C., Nair B., Prasad T.S., Chauhan D.S., Katoch K., Katoch V.M.,
RA Kumar P., Chaerkady R., Ramachandran S., Dash D., Pandey A.;
RT "Proteogenomic analysis of Mycobacterium tuberculosis by high resolution
RT mass spectrometry.";
RL Mol. Cell. Proteomics 10:M111.011627-M111.011627(2011).
RN [3]
RP X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS).
RX PubMed=10623528; DOI=10.1006/jmbi.1999.3328;
RA Li R., Sirawaraporn R., Chitnumsub P., Sirawaraporn W., Wooden J.,
RA Athappilly F., Turley S., Hol W.G.J.;
RT "Three-dimensional structure of M. tuberculosis dihydrofolate reductase
RT reveals opportunities for the design of novel tuberculosis drugs.";
RL J. Mol. Biol. 295:307-323(2000).
RN [4]
RP X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) IN COMPLEX WITH ISONIAZID-NADP
RP ADDUCT, AND ACTIVITY REGULATION.
RX PubMed=16648861; DOI=10.1038/nsmb1089;
RA Argyrou A., Vetting M.W., Aladegbami B., Blanchard J.S.;
RT "Mycobacterium tuberculosis dihydrofolate reductase is a target for
RT isoniazid.";
RL Nat. Struct. Mol. Biol. 13:408-413(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 -!- ACTIVITY REGULATION: Inhibited by isoniazid metabolites. The prodrug
CC isoniazid is metabolized to isoniazid-NADP adducts that inhibit the
CC enzyme at subnanomolar concentration. {ECO:0000269|PubMed:16648861}.
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}.
CC -!- SEQUENCE CAUTION:
CC Sequence=CCP45562.1; Type=Erroneous initiation; Note=Truncated N-terminus.;
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DR EMBL; AL123456; CCP45562.1; ALT_INIT; Genomic_DNA.
DR PIR; B70881; B70881.
DR RefSeq; NP_217279.1; NC_000962.3.
DR PDB; 1DF7; X-ray; 1.70 A; A=3-161.
DR PDB; 1DG5; X-ray; 2.00 A; A=3-161.
DR PDB; 1DG7; X-ray; 1.80 A; A=3-161.
DR PDB; 1DG8; X-ray; 2.00 A; A=3-161.
DR PDB; 2CIG; X-ray; 1.90 A; A=3-161.
DR PDB; 4KL9; X-ray; 1.39 A; A=3-161.
DR PDB; 4KLX; X-ray; 1.23 A; A/B=3-161.
DR PDB; 4KM0; X-ray; 1.30 A; A/B=3-161.
DR PDB; 4KM2; X-ray; 1.40 A; A/B=3-161.
DR PDB; 4KNE; X-ray; 2.00 A; A/B=3-161.
DR PDB; 4M2X; X-ray; 2.26 A; A/C/E/G=3-161.
DR PDB; 5JA3; X-ray; 1.81 A; A/B/C/D=3-161.
DR PDB; 5SCM; X-ray; 1.65 A; A=3-161.
DR PDB; 5SCN; X-ray; 1.45 A; A=3-161.
DR PDB; 5SCO; X-ray; 1.30 A; A=3-161.
DR PDB; 5SCP; X-ray; 1.80 A; A/B=3-161.
DR PDB; 5SCQ; X-ray; 1.65 A; A=3-161.
DR PDB; 5SCR; X-ray; 1.95 A; A=3-161.
DR PDB; 5SCS; X-ray; 1.55 A; A=3-161.
DR PDB; 5SCT; X-ray; 1.55 A; A=3-161.
DR PDB; 5SCU; X-ray; 1.65 A; A=3-161.
DR PDB; 5SCV; X-ray; 1.55 A; A/B=3-161.
DR PDB; 5SCW; X-ray; 1.75 A; A=3-161.
DR PDB; 5SCX; X-ray; 1.30 A; A=3-161.
DR PDB; 5SCY; X-ray; 1.40 A; A=3-161.
DR PDB; 5SCZ; X-ray; 1.75 A; A=3-161.
DR PDB; 5SD0; X-ray; 1.75 A; A=3-161.
DR PDB; 5SD1; X-ray; 2.00 A; A=3-161.
DR PDB; 5SD2; X-ray; 2.00 A; A=3-161.
DR PDB; 5SD3; X-ray; 1.30 A; A=3-161.
DR PDB; 5SD4; X-ray; 1.25 A; A=3-161.
DR PDB; 5SD5; X-ray; 1.20 A; A=3-161.
DR PDB; 5U26; X-ray; 1.85 A; A=3-161.
DR PDB; 5U27; X-ray; 2.05 A; A=3-161.
DR PDB; 5UJF; X-ray; 2.30 A; A=3-161.
DR PDB; 6DDP; X-ray; 1.49 A; A/B/C/D=3-161.
DR PDB; 6DDS; X-ray; 1.72 A; A/B/C/D=3-161.
DR PDB; 6DDW; X-ray; 1.40 A; A=1-161.
DR PDB; 6NNC; X-ray; 1.80 A; A/B=3-161.
DR PDB; 6NND; X-ray; 1.70 A; A/B=3-161.
DR PDB; 6NNH; X-ray; 1.52 A; A/B=3-161.
DR PDB; 6NNI; X-ray; 1.56 A; A/B=3-161.
DR PDB; 6VS5; X-ray; 1.76 A; A/B=1-161.
DR PDB; 6VS6; X-ray; 1.85 A; A/B=1-161.
DR PDB; 6VS8; X-ray; 1.83 A; A/B=1-161.
DR PDB; 6VSD; X-ray; 1.69 A; A/B=1-161.
DR PDB; 6VSE; X-ray; 1.76 A; A/B=1-161.
DR PDB; 6VSF; X-ray; 2.01 A; A/B=1-161.
DR PDB; 6VSG; X-ray; 2.30 A; A/B=1-161.
DR PDB; 6VV6; X-ray; 2.23 A; A/B=1-161.
DR PDB; 6VVB; X-ray; 1.45 A; A=1-161.
DR PDBsum; 1DF7; -.
DR PDBsum; 1DG5; -.
DR PDBsum; 1DG7; -.
DR PDBsum; 1DG8; -.
DR PDBsum; 2CIG; -.
DR PDBsum; 4KL9; -.
DR PDBsum; 4KLX; -.
DR PDBsum; 4KM0; -.
DR PDBsum; 4KM2; -.
DR PDBsum; 4KNE; -.
DR PDBsum; 4M2X; -.
DR PDBsum; 5JA3; -.
DR PDBsum; 5SCM; -.
DR PDBsum; 5SCN; -.
DR PDBsum; 5SCO; -.
DR PDBsum; 5SCP; -.
DR PDBsum; 5SCQ; -.
DR PDBsum; 5SCR; -.
DR PDBsum; 5SCS; -.
DR PDBsum; 5SCT; -.
DR PDBsum; 5SCU; -.
DR PDBsum; 5SCV; -.
DR PDBsum; 5SCW; -.
DR PDBsum; 5SCX; -.
DR PDBsum; 5SCY; -.
DR PDBsum; 5SCZ; -.
DR PDBsum; 5SD0; -.
DR PDBsum; 5SD1; -.
DR PDBsum; 5SD2; -.
DR PDBsum; 5SD3; -.
DR PDBsum; 5SD4; -.
DR PDBsum; 5SD5; -.
DR PDBsum; 5U26; -.
DR PDBsum; 5U27; -.
DR PDBsum; 5UJF; -.
DR PDBsum; 6DDP; -.
DR PDBsum; 6DDS; -.
DR PDBsum; 6DDW; -.
DR PDBsum; 6NNC; -.
DR PDBsum; 6NND; -.
DR PDBsum; 6NNH; -.
DR PDBsum; 6NNI; -.
DR PDBsum; 6VS5; -.
DR PDBsum; 6VS6; -.
DR PDBsum; 6VS8; -.
DR PDBsum; 6VSD; -.
DR PDBsum; 6VSE; -.
DR PDBsum; 6VSF; -.
DR PDBsum; 6VSG; -.
DR PDBsum; 6VV6; -.
DR PDBsum; 6VVB; -.
DR AlphaFoldDB; P9WNX1; -.
DR SMR; P9WNX1; -.
DR STRING; 83332.Rv2763c; -.
DR BindingDB; P9WNX1; -.
DR ChEMBL; CHEMBL6065; -.
DR DrugBank; DB04007; Bromo-WR99210.
DR DrugBank; DB00951; Isoniazid.
DR DrugCentral; P9WNX1; -.
DR PaxDb; P9WNX1; -.
DR DNASU; 887777; -.
DR GeneID; 887777; -.
DR KEGG; mtu:Rv2763c; -.
DR PATRIC; fig|83332.12.peg.3080; -.
DR TubercuList; Rv2763c; -.
DR eggNOG; COG0262; Bacteria.
DR BRENDA; 1.5.1.3; 3445.
DR UniPathway; UPA00077; UER00158.
DR Proteomes; UP000001584; Chromosome.
DR GO; GO:0005829; C:cytosol; IBA:GO_Central.
DR GO; GO:0004146; F:dihydrofolate reductase activity; IDA:MTBBASE.
DR GO; GO:0050661; F:NADP binding; IBA:GO_Central.
DR GO; GO:0070401; F:NADP+ binding; IDA:MTBBASE.
DR GO; GO:0046452; P:dihydrofolate metabolic process; IBA:GO_Central.
DR GO; GO:0046655; P:folic acid metabolic process; IBA:GO_Central.
DR GO; GO:0006545; P:glycine biosynthetic process; IEA:InterPro.
DR GO; GO:0006730; P:one-carbon metabolic process; IDA:MTBBASE.
DR GO; GO:0046654; P:tetrahydrofolate biosynthetic process; IDA:MTBBASE.
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; NADP; One-carbon metabolism; Oxidoreductase;
KW Reference proteome.
FT CHAIN 1..161
FT /note="Dihydrofolate reductase"
FT /id="PRO_0000186400"
FT DOMAIN 1..160
FT /note="DHFR"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00660"
FT BINDING 7..9
FT /ligand="substrate"
FT BINDING 8..9
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT BINDING 16..21
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT BINDING 29
FT /ligand="substrate"
FT BINDING 34
FT /ligand="substrate"
FT BINDING 45..48
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT BINDING 62
FT /ligand="substrate"
FT BINDING 67..70
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT BINDING 82
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT BINDING 96..101
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT BINDING 102
FT /ligand="substrate"
FT BINDING 115
FT /ligand="substrate"
FT STRAND 3..11
FT /evidence="ECO:0007829|PDB:4KLX"
FT STRAND 14..18
FT /evidence="ECO:0007829|PDB:4KLX"
FT HELIX 27..37
FT /evidence="ECO:0007829|PDB:4KLX"
FT STRAND 40..45
FT /evidence="ECO:0007829|PDB:4KLX"
FT HELIX 46..51
FT /evidence="ECO:0007829|PDB:4KLX"
FT TURN 54..56
FT /evidence="ECO:0007829|PDB:4KLX"
FT STRAND 62..67
FT /evidence="ECO:0007829|PDB:4KLX"
FT STRAND 78..83
FT /evidence="ECO:0007829|PDB:4KLX"
FT HELIX 84..87
FT /evidence="ECO:0007829|PDB:4KLX"
FT STRAND 90..97
FT /evidence="ECO:0007829|PDB:4KLX"
FT HELIX 99..105
FT /evidence="ECO:0007829|PDB:4KLX"
FT HELIX 106..108
FT /evidence="ECO:0007829|PDB:4KLX"
FT STRAND 111..117
FT /evidence="ECO:0007829|PDB:4KLX"
FT STRAND 138..141
FT /evidence="ECO:0007829|PDB:4KLX"
FT STRAND 148..150
FT /evidence="ECO:0007829|PDB:6DDP"
FT STRAND 152..159
FT /evidence="ECO:0007829|PDB:4KLX"
SQ SEQUENCE 161 AA; 17872 MW; B8980922D2F18C44 CRC64;
MTMVGLIWAQ ATSGVIGRGG DIPWRLPEDQ AHFREITMGH TIVMGRRTWD SLPAKVRPLP
GRRNVVLSRQ ADFMASGAEV VGSLEEALTS PETWVIGGGQ VYALALPYAT RCEVTEVDIG
LPREAGDALA PVLDETWRGE TGEWRFSRSG LRYRLYSYHR S
