PTR1_LEIMA
ID PTR1_LEIMA Reviewed; 288 AA.
AC Q01782; Q4QBE7; Q9U1F8;
DT 01-FEB-1994, integrated into UniProtKB/Swiss-Prot.
DT 27-MAY-2002, sequence version 2.
DT 03-AUG-2022, entry version 147.
DE RecName: Full=Pteridine reductase 1;
DE EC=1.5.1.33;
DE AltName: Full=H region methotrexate resistance protein;
GN Name=PTR1; Synonyms=HMTXR; ORFNames=L1063.01, LmjF23.0270, LmjF_23_0270;
OS Leishmania major.
OC Eukaryota; Discoba; Euglenozoa; Kinetoplastea; Metakinetoplastina;
OC Trypanosomatida; Trypanosomatidae; Leishmaniinae; Leishmania.
OX NCBI_TaxID=5664;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC STRAIN=MHOM/IR/83/Lt252 / CC-1;
RX PubMed=1339441; DOI=10.1016/s0021-9258(18)35743-0;
RA Callahan H.L., Beverley S.M.;
RT "A member of the aldoketo reductase family confers methotrexate resistance
RT in Leishmania.";
RL J. Biol. Chem. 267:24165-24168(1992).
RN [2]
RP SEQUENCE REVISION TO 162-171.
RA Callahan H.L., Beverley S.M.;
RL Submitted (MAY-2001) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=MHOM/IL/81/Friedlin;
RX PubMed=16020728; DOI=10.1126/science.1112680;
RA Ivens A.C., Peacock C.S., Worthey E.A., Murphy L., Aggarwal G.,
RA Berriman M., Sisk E., Rajandream M.A., Adlem E., Aert R., Anupama A.,
RA Apostolou Z., Attipoe P., Bason N., Bauser C., Beck A., Beverley S.M.,
RA Bianchettin G., Borzym K., Bothe G., Bruschi C.V., Collins M., Cadag E.,
RA Ciarloni L., Clayton C., Coulson R.M.R., Cronin A., Cruz A.K., Davies R.M.,
RA De Gaudenzi J., Dobson D.E., Duesterhoeft A., Fazelina G., Fosker N.,
RA Frasch A.C., Fraser A., Fuchs M., Gabel C., Goble A., Goffeau A.,
RA Harris D., Hertz-Fowler C., Hilbert H., Horn D., Huang Y., Klages S.,
RA Knights A., Kube M., Larke N., Litvin L., Lord A., Louie T., Marra M.,
RA Masuy D., Matthews K., Michaeli S., Mottram J.C., Mueller-Auer S.,
RA Munden H., Nelson S., Norbertczak H., Oliver K., O'neil S., Pentony M.,
RA Pohl T.M., Price C., Purnelle B., Quail M.A., Rabbinowitsch E.,
RA Reinhardt R., Rieger M., Rinta J., Robben J., Robertson L., Ruiz J.C.,
RA Rutter S., Saunders D., Schaefer M., Schein J., Schwartz D.C., Seeger K.,
RA Seyler A., Sharp S., Shin H., Sivam D., Squares R., Squares S., Tosato V.,
RA Vogt C., Volckaert G., Wambutt R., Warren T., Wedler H., Woodward J.,
RA Zhou S., Zimmermann W., Smith D.F., Blackwell J.M., Stuart K.D.,
RA Barrell B.G., Myler P.J.;
RT "The genome of the kinetoplastid parasite, Leishmania major.";
RL Science 309:436-442(2005).
RN [4]
RP FUNCTION.
RX PubMed=7972081; DOI=10.1073/pnas.91.24.11442;
RA Bello A.R., Nare B., Freedman D., Hardy L.W., Beverley S.M.;
RT "PTR1: a reductase mediating salvage of oxidized pteridines and
RT methotrexate resistance in the protozoan parasite Leishmania major.";
RL Proc. Natl. Acad. Sci. U.S.A. 91:11442-11446(1994).
RN [5]
RP SUBUNIT.
RC STRAIN=MHOM/IR/83/Lt252;
RX PubMed=9153248; DOI=10.1074/jbc.272.21.13883;
RA Nare B., Hardy L.W., Beverley S.M.;
RT "The roles of pteridine reductase 1 and dihydrofolate reductase-thymidylate
RT synthase in pteridine metabolism in the protozoan parasite Leishmania
RT major.";
RL J. Biol. Chem. 272:13883-13891(1997).
RN [6]
RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) IN COMPLEX WITH NADP AND SUBSTRATE.
RX PubMed=11373620; DOI=10.1038/88584;
RA Gourley D.G., Schuettelkopf A.W., Leonard G.A., Luba J., Hardy L.W.,
RA Beverley S.M., Hunter W.N.;
RT "Pteridine reductase mechanism correlates pterin metabolism with drug
RT resistance in trypanosomatid parasites.";
RL Nat. Struct. Biol. 8:521-525(2001).
RN [7]
RP PATHWAY.
RX PubMed=9521731; DOI=10.1021/bi972693a;
RA Luba J., Nare B., Liang P.-H., Anderson K.S., Beverley S.M., Hardy L.W.;
RT "Leishmania major pteridine reductase 1 belongs to the short chain
RT dehydrogenase family: stereochemical and kinetic evidence.";
RL Biochemistry 37:4093-4104(1998).
CC -!- FUNCTION: Exhibits a NADPH-dependent biopterin reductase activity. Has
CC good activity with folate and significant activity with dihydrofolate
CC and dihydrobiopterin, but not with quinonoid dihydrobiopterin. Confers
CC resistance to methotrexate (MTX). {ECO:0000269|PubMed:7972081}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(6R)-L-erythro-5,6,7,8-tetrahydrobiopterin + 2 NADP(+) = 2
CC H(+) + L-erythro-biopterin + 2 NADPH; Xref=Rhea:RHEA:19509,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349,
CC ChEBI:CHEBI:59560, ChEBI:CHEBI:63931; EC=1.5.1.33;
CC -!- PATHWAY: Cofactor biosynthesis; tetrahydrobiopterin biosynthesis;
CC tetrahydrobiopterin from biopterin: step 1/1.
CC {ECO:0000269|PubMed:9521731}.
CC -!- SUBUNIT: Homotetramer. {ECO:0000269|PubMed:11373620,
CC ECO:0000269|PubMed:9153248}.
CC -!- SIMILARITY: Belongs to the short-chain dehydrogenases/reductases (SDR)
CC family. {ECO:0000305}.
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DR EMBL; L01699; AAA29249.2; -; Genomic_DNA.
DR EMBL; FR796419; CAJ03998.1; -; Genomic_DNA.
DR PIR; A45168; A45168.
DR RefSeq; XP_001683351.1; XM_001683299.1.
DR PDB; 1E7W; X-ray; 1.75 A; A/B=1-288.
DR PDB; 1E92; X-ray; 2.20 A; A/B/C/D=1-288.
DR PDB; 1W0C; X-ray; 2.60 A; A/B/C/D/E/F/G/H=1-288.
DR PDB; 2BF7; X-ray; 2.40 A; A/B/C/D=1-288.
DR PDB; 2BFA; X-ray; 2.70 A; A/B/C/D=1-288.
DR PDB; 2BFM; X-ray; 2.60 A; A/B/C/D=1-288.
DR PDB; 2BFO; X-ray; 2.60 A; A/B/C/D=1-288.
DR PDB; 2BFP; X-ray; 2.55 A; A/B/C/D=1-288.
DR PDB; 2QHX; X-ray; 2.61 A; A/B/C/D=1-288.
DR PDB; 3H4V; X-ray; 2.40 A; A/B/C/D/E/F/G/H=1-288.
DR PDB; 5L42; X-ray; 2.10 A; A/B/C/D=1-288.
DR PDB; 5L4N; X-ray; 2.35 A; A/B/C/D=1-288.
DR PDB; 6RXC; X-ray; 2.10 A; A/B/C/D=1-288.
DR PDB; 7PXX; X-ray; 1.81 A; A/B/C/D=1-288.
DR PDBsum; 1E7W; -.
DR PDBsum; 1E92; -.
DR PDBsum; 1W0C; -.
DR PDBsum; 2BF7; -.
DR PDBsum; 2BFA; -.
DR PDBsum; 2BFM; -.
DR PDBsum; 2BFO; -.
DR PDBsum; 2BFP; -.
DR PDBsum; 2QHX; -.
DR PDBsum; 3H4V; -.
DR PDBsum; 5L42; -.
DR PDBsum; 5L4N; -.
DR PDBsum; 6RXC; -.
DR PDBsum; 7PXX; -.
DR AlphaFoldDB; Q01782; -.
DR SMR; Q01782; -.
DR STRING; 5664.LmjF.23.0270; -.
DR BindingDB; Q01782; -.
DR ChEMBL; CHEMBL6194; -.
DR DrugBank; DB02532; 2,4,6-Triaminoquinazoline.
DR DrugBank; DB04400; L-erythro-7,8-dihydrobiopterin.
DR DrugBank; DB02338; NADPH.
DR DrugBank; DB03461; Nicotinamide adenine dinucleotide phosphate.
DR DrugCentral; Q01782; -.
DR EnsemblProtists; CAJ03998; CAJ03998; LMJF_23_0270.
DR GeneID; 5651987; -.
DR KEGG; lma:LMJF_23_0270; -.
DR VEuPathDB; TriTrypDB:LmjF.23.0270; -.
DR VEuPathDB; TriTrypDB:LMJLV39_230008000; -.
DR VEuPathDB; TriTrypDB:LMJSD75_230008200; -.
DR eggNOG; KOG0725; Eukaryota.
DR InParanoid; Q01782; -.
DR BRENDA; 1.5.1.33; 2950.
DR SABIO-RK; Q01782; -.
DR UniPathway; UPA00849; UER00822.
DR EvolutionaryTrace; Q01782; -.
DR PRO; PR:Q01782; -.
DR Proteomes; UP000000542; Chromosome 23.
DR GO; GO:0005829; C:cytosol; ISO:GeneDB.
DR GO; GO:0004155; F:6,7-dihydropteridine reductase activity; IDA:GeneDB.
DR GO; GO:0016491; F:oxidoreductase activity; ISM:GeneDB.
DR GO; GO:0047040; F:pteridine reductase activity; IDA:GeneDB.
DR GO; GO:0031427; P:response to methotrexate; IEA:UniProtKB-KW.
DR GO; GO:0006729; P:tetrahydrobiopterin biosynthetic process; IEA:UniProtKB-UniPathway.
DR InterPro; IPR036291; NAD(P)-bd_dom_sf.
DR InterPro; IPR014058; Pteridine_reductase.
DR InterPro; IPR020904; Sc_DH/Rdtase_CS.
DR InterPro; IPR002347; SDR_fam.
DR PRINTS; PR00081; GDHRDH.
DR PRINTS; PR00080; SDRFAMILY.
DR SUPFAM; SSF51735; SSF51735; 1.
DR TIGRFAMs; TIGR02685; pter_reduc_Leis; 1.
DR PROSITE; PS00061; ADH_SHORT; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Methotrexate resistance; NADP; Oxidoreductase;
KW Reference proteome.
FT CHAIN 1..288
FT /note="Pteridine reductase 1"
FT /id="PRO_0000054753"
FT ACT_SITE 194
FT /note="Proton acceptor"
FT BINDING 17..40
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250"
FT BINDING 175
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:11373620"
FT CONFLICT 162
FT /note="F -> V (in Ref. 3; CAJ03998)"
FT /evidence="ECO:0000305"
FT STRAND 8..11
FT /evidence="ECO:0007829|PDB:1E7W"
FT HELIX 17..28
FT /evidence="ECO:0007829|PDB:1E7W"
FT STRAND 32..39
FT /evidence="ECO:0007829|PDB:1E7W"
FT HELIX 41..54
FT /evidence="ECO:0007829|PDB:1E7W"
FT STRAND 59..63
FT /evidence="ECO:0007829|PDB:1E7W"
FT STRAND 67..69
FT /evidence="ECO:0007829|PDB:1E7W"
FT STRAND 75..77
FT /evidence="ECO:0007829|PDB:1W0C"
FT HELIX 85..100
FT /evidence="ECO:0007829|PDB:1E7W"
FT STRAND 105..108
FT /evidence="ECO:0007829|PDB:1E7W"
FT HELIX 134..147
FT /evidence="ECO:0007829|PDB:1E7W"
FT HELIX 149..163
FT /evidence="ECO:0007829|PDB:1E7W"
FT HELIX 167..169
FT /evidence="ECO:0007829|PDB:1E7W"
FT STRAND 174..179
FT /evidence="ECO:0007829|PDB:1E7W"
FT TURN 182..185
FT /evidence="ECO:0007829|PDB:1E7W"
FT HELIX 192..212
FT /evidence="ECO:0007829|PDB:1E7W"
FT HELIX 213..215
FT /evidence="ECO:0007829|PDB:1E7W"
FT STRAND 217..227
FT /evidence="ECO:0007829|PDB:1E7W"
FT HELIX 230..232
FT /evidence="ECO:0007829|PDB:1E7W"
FT HELIX 235..242
FT /evidence="ECO:0007829|PDB:1E7W"
FT TURN 246..249
FT /evidence="ECO:0007829|PDB:1E7W"
FT HELIX 254..265
FT /evidence="ECO:0007829|PDB:1E7W"
FT HELIX 267..269
FT /evidence="ECO:0007829|PDB:1E7W"
FT STRAND 276..280
FT /evidence="ECO:0007829|PDB:1E7W"
FT HELIX 283..285
FT /evidence="ECO:0007829|PDB:1E7W"
SQ SEQUENCE 288 AA; 30457 MW; B8F6FC23018367E0 CRC64;
MTAPTVPVAL VTGAAKRLGR SIAEGLHAEG YAVCLHYHRS AAEANALSAT LNARRPNSAI
TVQADLSNVA TAPVSGADGS APVTLFTRCA ELVAACYTHW GRCDVLVNNA SSFYPTPLLR
NDEDGHEPCV GDREAMETAT ADLFGSNAIA PYFLIKAFAH RFAGTPAKHR GTNYSIINMV
DAMTNQPLLG YTIYTMAKGA LEGLTRSAAL ELAPLQIRVN GVGPGLSVLV DDMPPAVWEG
HRSKVPLYQR DSSAAEVSDV VIFLCSSKAK YITGTCVKVD GGYSLTRA
