NCPR1_ARTAN
ID NCPR1_ARTAN Reviewed; 704 AA.
AC A0A2U1LIM9; A1E3K2; A2TEY9; K7PQG7; Q001P5; Q1PQK4;
DT 02-DEC-2020, integrated into UniProtKB/Swiss-Prot.
DT 02-DEC-2020, sequence version 2.
DT 03-AUG-2022, entry version 17.
DE RecName: Full=NADPH--cytochrome P450 reductase 1 {ECO:0000255|HAMAP-Rule:MF_03212, ECO:0000303|PubMed:30851440};
DE Short=CPR 1 {ECO:0000255|HAMAP-Rule:MF_03212};
DE Short=P450R 1 {ECO:0000255|HAMAP-Rule:MF_03212};
DE EC=1.6.2.4 {ECO:0000255|HAMAP-Rule:MF_03212, ECO:0000269|PubMed:16612385};
GN Name=CPR1 {ECO:0000303|PubMed:30851440};
GN Synonyms=CPR {ECO:0000303|PubMed:16612385, ECO:0000303|PubMed:18816428};
GN ORFNames=CTI12_AA484860 {ECO:0000312|EMBL:PWA48849.1};
OS Artemisia annua (Sweet wormwood).
OC Eukaryota; Viridiplantae; Streptophyta; Embryophyta; Tracheophyta;
OC Spermatophyta; Magnoliopsida; eudicotyledons; Gunneridae; Pentapetalae;
OC asterids; campanulids; Asterales; Asteraceae; Asteroideae; Anthemideae;
OC Artemisiinae; Artemisia.
OX NCBI_TaxID=35608;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, CATALYTIC ACTIVITY,
RP BIOPHYSICOCHEMICAL PROPERTIES, AND BIOTECHNOLOGY.
RX PubMed=16612385; DOI=10.1038/nature04640;
RA Ro D.-K., Paradise E.M., Ouellet M., Fisher K.J., Newman K.L., Ndungu J.M.,
RA Ho K.A., Eachus R.A., Ham T.S., Kirby J., Chang M.C.Y., Withers S.T.,
RA Shiba Y., Sarpong R., Keasling J.D.;
RT "Production of the antimalarial drug precursor artemisinic acid in
RT engineered yeast.";
RL Nature 440:940-943(2006).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC TISSUE=Leaf;
RA Yin L.L., Yang R.Y., Zeng Q.P.;
RT "Induced expression and quantitation of artemisinin-related genes in
RT Artemisia annua L.";
RL Submitted (NOV-2006) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Kong J., Wang W., Cheng K.;
RT "Production of artemisinic acid by engineered yeast.";
RL Submitted (DEC-2006) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=cv. Feng-shun No.1; TISSUE=Leaf;
RX PubMed=18816428; DOI=10.1055/s-2008-1081333;
RA Yang R.-Y., Feng L.-L., Yang X.-Q., Yin L.-L., Xu X.-L., Zeng Q.-P.;
RT "Quantitative transcript profiling reveals down-regulation of A sterol
RT pathway relevant gene and overexpression of artemisinin biogenetic genes in
RT transgenic Artemisia annua plants.";
RL Planta Med. 74:1510-1516(2008).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=cv. CIM-Arogya;
RX PubMed=22986332; DOI=10.1016/j.gene.2012.09.015;
RA Misra A., Chanotiya C.S., Gupta M.M., Dwivedi U.N., Shasany A.K.;
RT "Characterization of cytochrome P450 monooxygenases isolated from trichome
RT enriched fraction of Artemisia annua L. leaf.";
RL Gene 510:193-201(2012).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=cv. Huhao1; TISSUE=Leaf;
RX PubMed=29703587; DOI=10.1016/j.molp.2018.03.015;
RA Shen Q., Zhang L., Liao Z., Wang S., Yan T., Shi P., Liu M., Fu X., Pan Q.,
RA Wang Y., Lv Z., Lu X., Zhang F., Jiang W., Ma Y., Chen M., Hao X., Li L.,
RA Tang Y., Lv G., Zhou Y., Sun X., Brodelius P.E., Rose J.K.C., Tang K.;
RT "The genome of Artemisia annua provides insight into the evolution of
RT Asteraceae family and artemisinin biosynthesis.";
RL Mol. Plant 11:776-788(2018).
RN [7]
RP BIOTECHNOLOGY.
RX PubMed=22247290; DOI=10.1073/pnas.1110740109;
RA Westfall P.J., Pitera D.J., Lenihan J.R., Eng D., Woolard F.X.,
RA Regentin R., Horning T., Tsuruta H., Melis D.J., Owens A., Fickes S.,
RA Diola D., Benjamin K.R., Keasling J.D., Leavell M.D., McPhee D.J.,
RA Renninger N.S., Newman J.D., Paddon C.J.;
RT "Production of amorphadiene in yeast, and its conversion to
RT dihydroartemisinic acid, precursor to the antimalarial agent artemisinin.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:E111-E118(2012).
RN [8]
RP BIOTECHNOLOGY.
RX PubMed=23575629; DOI=10.1038/nature12051;
RA Paddon C.J., Westfall P.J., Pitera D.J., Benjamin K., Fisher K., McPhee D.,
RA Leavell M.D., Tai A., Main A., Eng D., Polichuk D.R., Teoh K.H., Reed D.W.,
RA Treynor T., Lenihan J., Fleck M., Bajad S., Dang G., Diola D., Dorin G.,
RA Ellens K.W., Fickes S., Galazzo J., Gaucher S.P., Geistlinger T., Henry R.,
RA Hepp M., Horning T., Iqbal T., Jiang H., Kizer L., Lieu B., Melis D.,
RA Moss N., Regentin R., Secrest S., Tsuruta H., Vazquez R., Westblade L.F.,
RA Xu L., Yu M., Zhang Y., Zhao L., Lievense J., Covello P.S., Keasling J.D.,
RA Reiling K.K., Renninger N.S., Newman J.D.;
RT "High-level semi-synthetic production of the potent antimalarial
RT artemisinin.";
RL Nature 496:528-532(2013).
RN [9]
RP TISSUE SPECIFICITY.
RX PubMed=30851440; DOI=10.1016/j.molp.2019.02.011;
RA Judd R., Bagley M.C., Li M., Zhu Y., Lei C., Yuzuak S., Ekeloef M., Pu G.,
RA Zhao X., Muddiman D.C., Xie D.-Y.;
RT "Artemisinin biosynthesis in non-glandular trichome cells of Artemisia
RT annua.";
RL Mol. Plant 12:704-714(2019).
RN [10]
RP BIOTECHNOLOGY.
RX PubMed=32514287; DOI=10.1186/s13020-020-00336-8;
RA Uzun T., Toptas O.;
RT "Artesunate: could be an alternative drug to chloroquine in COVID-19
RT treatment?";
RL Chin. Med. J. 15:54-54(2020).
RN [11]
RP BIOTECHNOLOGY, AND REVIEW.
RX PubMed=32405226; DOI=10.1016/j.phrs.2020.104901;
RA Cheong D.H.J., Tan D.W.S., Wong F.W.S., Tran T.;
RT "Anti-malarial drug, artemisinin and its derivatives for the treatment of
RT respiratory diseases.";
RL Pharmacol. Res. 158:104901-104901(2020).
CC -!- FUNCTION: This enzyme is required for electron transfer from NADP to
CC cytochrome P450 in microsomes (By similarity). It can also provide
CC electron transfer to heme oxygenase and cytochrome B5 (By similarity).
CC Involved in the biosynthesis of the antimalarial endoperoxide
CC artemisinin (PubMed:16612385). Acts as a redox partner for CYP71AV1
CC which catalyzes the conversion of amorphadiene to more oxygenated
CC products (PubMed:16612385). {ECO:0000255|HAMAP-Rule:MF_03212,
CC ECO:0000269|PubMed:16612385}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=NADPH + 2 oxidized [cytochrome P450] = H(+) + NADP(+) + 2
CC reduced [cytochrome P450]; Xref=Rhea:RHEA:24040, Rhea:RHEA-
CC COMP:14627, Rhea:RHEA-COMP:14628, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:55376, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349,
CC ChEBI:CHEBI:60344; EC=1.6.2.4; Evidence={ECO:0000255|HAMAP-
CC Rule:MF_03212, ECO:0000269|PubMed:16612385};
CC -!- COFACTOR:
CC Name=FAD; Xref=ChEBI:CHEBI:57692;
CC Evidence={ECO:0000255|HAMAP-Rule:MF_03212};
CC Note=Binds 1 FAD per monomer. {ECO:0000255|HAMAP-Rule:MF_03212};
CC -!- COFACTOR:
CC Name=FMN; Xref=ChEBI:CHEBI:58210;
CC Evidence={ECO:0000255|HAMAP-Rule:MF_03212};
CC Note=Binds 1 FMN per monomer. {ECO:0000255|HAMAP-Rule:MF_03212};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=4.3 uM for cytochrome P450 {ECO:0000269|PubMed:16612385};
CC KM=23.0 uM for NADPH {ECO:0000269|PubMed:16612385};
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC {ECO:0000255|HAMAP-Rule:MF_03212}; Single-pass membrane protein
CC {ECO:0000255|HAMAP-Rule:MF_03212}; Cytoplasmic side {ECO:0000255|HAMAP-
CC Rule:MF_03212}.
CC -!- TISSUE SPECIFICITY: Present in non-glandular trichome cells.
CC {ECO:0000269|PubMed:30851440}.
CC -!- BIOTECHNOLOGY: Artemisinin and derivatives (e.g. artesunate), are
CC antimalarial drugs due to their endoperoxidase properties; they also
CC display multiple pharmacological actions against inflammation,viral
CC infections, and cell and tumor proliferation (PubMed:32514287,
CC PubMed:32405226). Artesunate may be a promising treatment for COVID-19
CC mediated by the severe acute respiratory syndrome coronavirus 2 (2019-
CC nCoV) (SARS-CoV-2) because of its anti-inflammatory activity, NF-kappaB
CC (nuclear factor kappa B)-coronavirus effect and chloroquine-like
CC endocytosis inhibition mechanism (PubMed:32514287, PubMed:32405226).
CC {ECO:0000303|PubMed:32405226, ECO:0000303|PubMed:32514287}.
CC -!- BIOTECHNOLOGY: Yeast (S.cerevisiae) has been engineered to produce
CC artemisinic-acid, a precursor of the antimalarial artemisinin compound,
CC by expressing AMS1/ADS, CYP71AV1, ADH1 and ALDH1 in conjunction with
CC CYB5 and CPR1. {ECO:0000269|PubMed:16612385,
CC ECO:0000269|PubMed:22247290, ECO:0000269|PubMed:23575629}.
CC -!- SIMILARITY: Belongs to the NADPH--cytochrome P450 reductase family.
CC {ECO:0000255|HAMAP-Rule:MF_03212}.
CC -!- SIMILARITY: In the N-terminal section; belongs to the flavodoxin
CC family. {ECO:0000255|HAMAP-Rule:MF_03212}.
CC -!- SIMILARITY: In the C-terminal section; belongs to the flavoprotein
CC pyridine nucleotide cytochrome reductase family. {ECO:0000255|HAMAP-
CC Rule:MF_03212}.
CC -!- SEQUENCE CAUTION:
CC Sequence=PWA48849.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
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DR EMBL; DQ318192; ABC47946.1; -; mRNA.
DR EMBL; EF104642; ABL09938.1; -; Genomic_DNA.
DR EMBL; EF197890; ABM88789.1; -; mRNA.
DR EMBL; DQ984181; ABI98819.1; -; mRNA.
DR EMBL; JN594507; AFO64618.1; -; mRNA.
DR EMBL; PKPP01009187; PWA48849.1; ALT_INIT; Genomic_DNA.
DR AlphaFoldDB; A0A2U1LIM9; -.
DR SMR; A0A2U1LIM9; -.
DR Proteomes; UP000245207; Unassembled WGS sequence.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0050660; F:flavin adenine dinucleotide binding; IEA:UniProtKB-UniRule.
DR GO; GO:0010181; F:FMN binding; IEA:UniProtKB-UniRule.
DR GO; GO:0050661; F:NADP binding; IEA:UniProtKB-UniRule.
DR GO; GO:0003958; F:NADPH-hemoprotein reductase activity; IDA:UniProtKB.
DR GO; GO:0016491; F:oxidoreductase activity; IDA:UniProtKB.
DR GO; GO:0051762; P:sesquiterpene biosynthetic process; IDA:UniProtKB.
DR Gene3D; 1.20.990.10; -; 1.
DR Gene3D; 3.40.50.360; -; 1.
DR Gene3D; 3.40.50.80; -; 1.
DR HAMAP; MF_03212; NCPR; 1.
DR InterPro; IPR003097; CysJ-like_FAD-binding.
DR InterPro; IPR017927; FAD-bd_FR_type.
DR InterPro; IPR001094; Flavdoxin-like.
DR InterPro; IPR008254; Flavodoxin/NO_synth.
DR InterPro; IPR001709; Flavoprot_Pyr_Nucl_cyt_Rdtase.
DR InterPro; IPR029039; Flavoprotein-like_sf.
DR InterPro; IPR039261; FNR_nucleotide-bd.
DR InterPro; IPR023173; NADPH_Cyt_P450_Rdtase_alpha.
DR InterPro; IPR001433; OxRdtase_FAD/NAD-bd.
DR InterPro; IPR023208; P450R.
DR InterPro; IPR017938; Riboflavin_synthase-like_b-brl.
DR Pfam; PF00667; FAD_binding_1; 1.
DR Pfam; PF00258; Flavodoxin_1; 1.
DR Pfam; PF00175; NAD_binding_1; 1.
DR PIRSF; PIRSF000208; P450R; 1.
DR PRINTS; PR00369; FLAVODOXIN.
DR PRINTS; PR00371; FPNCR.
DR SUPFAM; SSF52218; SSF52218; 1.
DR SUPFAM; SSF52343; SSF52343; 1.
DR SUPFAM; SSF63380; SSF63380; 1.
DR PROSITE; PS51384; FAD_FR; 1.
DR PROSITE; PS50902; FLAVODOXIN_LIKE; 1.
PE 1: Evidence at protein level;
KW Endoplasmic reticulum; FAD; Flavoprotein; FMN; Glycoprotein; Membrane;
KW NADP; Oxidoreductase; Reference proteome; Transmembrane;
KW Transmembrane helix.
FT CHAIN 1..704
FT /note="NADPH--cytochrome P450 reductase 1"
FT /id="PRO_0000451732"
FT TOPO_DOM 1..45
FT /note="Lumenal"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03212"
FT TRANSMEM 46..66
FT /note="Helical"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03212"
FT TOPO_DOM 67..704
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03212"
FT DOMAIN 100..250
FT /note="Flavodoxin-like"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03212"
FT DOMAIN 302..549
FT /note="FAD-binding FR-type"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03212"
FT BINDING 106..111
FT /ligand="FMN"
FT /ligand_id="ChEBI:CHEBI:58210"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03212"
FT BINDING 161..164
FT /ligand="FMN"
FT /ligand_id="ChEBI:CHEBI:58210"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03212"
FT BINDING 199..208
FT /ligand="FMN"
FT /ligand_id="ChEBI:CHEBI:58210"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03212"
FT BINDING 234
FT /ligand="FMN"
FT /ligand_id="ChEBI:CHEBI:58210"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03212"
FT BINDING 322
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03212"
FT BINDING 482..485
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03212"
FT BINDING 500..502
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03212"
FT BINDING 516..519
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03212"
FT BINDING 563
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03212"
FT BINDING 624..625
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03212"
FT BINDING 630..634
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03212"
FT BINDING 666
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03212"
FT BINDING 704
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03212"
FT CARBOHYD 29
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CONFLICT 33
FT /note="T -> S (in Ref. 3; ABM88789)"
FT /evidence="ECO:0000305"
FT CONFLICT 75
FT /note="K -> R (in Ref. 5; AFO64618)"
FT /evidence="ECO:0000305"
FT CONFLICT 190
FT /note="E -> D (in Ref. 4; ABI98819, 3; ABM88789 and 1;
FT ABC47946)"
FT /evidence="ECO:0000305"
FT CONFLICT 219
FT /note="V -> T (in Ref. 5; AFO64618)"
FT /evidence="ECO:0000305"
FT CONFLICT 274
FT /note="A -> G (in Ref. 1; ABC47946)"
FT /evidence="ECO:0000305"
FT CONFLICT 353
FT /note="E -> D (in Ref. 3; ABM88789)"
FT /evidence="ECO:0000305"
FT CONFLICT 372..374
FT /note="VHT -> IHA (in Ref. 5; AFO64618)"
FT /evidence="ECO:0000305"
FT CONFLICT 374
FT /note="T -> A (in Ref. 2; ABL09938, 4; ABI98819 and 3;
FT ABM88789)"
FT /evidence="ECO:0000305"
FT CONFLICT 434
FT /note="L -> F (in Ref. 1; ABC47946)"
FT /evidence="ECO:0000305"
FT CONFLICT 491
FT /note="K -> R (in Ref. 2; ABL09938 and 4; ABI98819)"
FT /evidence="ECO:0000305"
FT CONFLICT 501
FT /note="C -> S (in Ref. 2; ABL09938)"
FT /evidence="ECO:0000305"
FT CONFLICT 641
FT /note="A -> T (in Ref. 5; AFO64618)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 704 AA; 78182 MW; 1454F638AD677526 CRC64;
MQSTTSVKLS PFDLMTALLN GKVSFDTSNT SDTNIPLAVF MENRELLMIL TTSVAVLIGC
VVVLVWRRSS SAAKKAAESP VIVVPKKVTE DEVDDGRKKV TVFFGTQTGT AEGFAKALVE
EAKARYEKAV FKVIDLDDYA AEDDEYEEKL KKESLAFFFL ATYGDGEPTD NAARFYKWFT
EGEEKGEWLE KLQYAVFGLG NRQYEHFNKI AKVVDEKLVE QGAKRLVPVG MGDDDQCIED
DFTAWKELVW PELDQLLRDE DDTSVATPYT AAVAEYRVVF HDKPETYDQD QLTNGHAVHD
AQHPCRSNVA VKKELHSPLS DRSCTHLEFD ISNTGLSYET GDHVGVYVEN LSEVVDEAEK
LIGLPPHTYF SVHTDNEDGT PLGGASLPPP FPPCTLRKAL ASYADVLSSP KKSALLALAA
HATDSTEADR LKFLASPAGK DEYAQWIVAS HRSLLEVMEA FPSAKPPLGV FFASVAPRLQ
PRYYSISSSP KFAPNRIHVT CALVYEQTPS GRVHKGVCST WMKNAVPMTE SQDCSWAPIY
VRTSNFRLPS DPKVPVIMIG PGTGLAPFRG FLQERLAQKE AGTELGTAIL FFGCRNRKVD
FIYEDELNNF VETGALSELV TAFSREGATK EYVQHKMTQK ASDIWNLLSE GAYLYVCGDA
KGMAKDVHRT LHTIVQEQGS LDSSKAELYV KNLQMAGRYL RDVW
