DBR2_ARTAN
ID DBR2_ARTAN Reviewed; 388 AA.
AC C5H429; A0A2U1QC65; R4N2K9; S4V8I4; S4VAQ7;
DT 03-OCT-2012, integrated into UniProtKB/Swiss-Prot.
DT 18-SEP-2019, sequence version 2.
DT 03-AUG-2022, entry version 36.
DE RecName: Full=Artemisinic aldehyde Delta(11(13)) reductase {ECO:0000303|PubMed:18495659};
DE EC=1.3.1.92 {ECO:0000269|PubMed:18495659};
GN Name=DBR2 {ECO:0000303|PubMed:18495659, ECO:0000303|PubMed:23638869};
GN Synonyms=AAR {ECO:0000303|PubMed:19664791};
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], IDENTIFICATION BY MASS SPECTROMETRY, FUNCTION,
RP BIOPHYSICOCHEMICAL PROPERTIES, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION,
RP AND TISSUE SPECIFICITY.
RX PubMed=18495659; DOI=10.1074/jbc.m803090200;
RA Zhang Y., Teoh K.H., Reed D.W., Maes L., Goossens A., Olson D.J.,
RA Ross A.R., Covello P.S.;
RT "The molecular cloning of artemisinic aldehyde Delta11(13) reductase and
RT its role in glandular trichome-dependent biosynthesis of artemisinin in
RT Artemisia annua.";
RL J. Biol. Chem. 283:21501-21508(2008).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=23638869; DOI=10.1111/nph.12274;
RA Ting H.-M., Wang B., Ryden A.-M., Woittiez L., van Herpen T.,
RA Verstappen F.W.A., Ruyter-Spira C., Beekwilder J., Bouwmeester H.J.,
RA van der Krol A.;
RT "The metabolite chemotype of Nicotiana benthamiana transiently expressing
RT artemisinin biosynthetic pathway genes is a function of CYP71AV1 type and
RT relative gene dosage.";
RL New Phytol. 199:352-366(2013).
RN [3]
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 [4]
RP IDENTIFICATION.
RX PubMed=15678372; DOI=10.1055/s-2005-837749;
RA Bertea C.M., Freije J.R., van der Woude H., Verstappen F.W., Perk L.,
RA Marquez V., De Kraker J.W., Posthumus M.A., Jansen B.J., de Groot A.,
RA Franssen M.C., Bouwmeester H.J.;
RT "Identification of intermediates and enzymes involved in the early steps of
RT artemisinin biosynthesis in Artemisia annua.";
RL Planta Med. 71:40-47(2005).
RN [5]
RP TISSUE SPECIFICITY.
RX PubMed=19664791; DOI=10.1016/j.phytochem.2009.07.009;
RA Olsson M.E., Olofsson L.M., Lindahl A.-L., Lundgren A., Brodelius M.,
RA Brodelius P.E.;
RT "Localization of enzymes of artemisinin biosynthesis to the apical cells of
RT glandular secretory trichomes of Artemisia annua L.";
RL Phytochemistry 70:1123-1128(2009).
RN [6]
RP TISSUE SPECIFICITY.
RX PubMed=22195571; DOI=10.1016/j.plantsci.2011.10.019;
RA Olofsson L., Lundgren A., Brodelius P.E.;
RT "Trichome isolation with and without fixation using laser microdissection
RT and pressure catapulting followed by RNA amplification: expression of genes
RT of terpene metabolism in apical and sub-apical trichome cells of Artemisia
RT annua L.";
RL Plant Sci. 183:9-13(2012).
RN [7]
RP REVIEW ON ARTEMISININ ANTIMALARIAL PROPERTIES.
RX PubMed=27488942; DOI=10.1002/anie.201601967;
RA Tu Y.;
RT "Artemisinin-A Gift from Traditional Chinese Medicine to the World (Nobel
RT Lecture).";
RL Angew. Chem. Int. Ed. 55:10210-10226(2016).
RN [8]
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 [9]
RP PATHWAY, AND REVIEW.
RX PubMed=30468448; DOI=10.1039/c8np00077h;
RA Liu Y., Jing S.-X., Luo S.-H., Li S.-H.;
RT "Non-volatile natural products in plant glandular trichomes: chemistry,
RT biological activities and biosynthesis.";
RL Nat. Prod. Rep. 36:626-665(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).
RN [12]
RP X-RAY CRYSTALLOGRAPHY (1.45 ANGSTROMS) IN COMPLEX WITH FMN AND SUBSTRATE.
RA Li L.;
RT "The Crystal structure of Dbr2.";
RL Submitted (SEP-2015) to the PDB data bank.
CC -!- FUNCTION: Involved in the biosynthesis of the antimalarial endoperoxide
CC artemisinin (PubMed:18495659, PubMed:27488942). Catalyzes the double
CC bond reduction of artemisinic aldehyde to produce (11R)-
CC dihydroartemisinic aldehyde (PubMed:18495659). Also able to reduce 2-
CC cyclohexen-1-one into cyclohexanone to a lesser extent
CC (PubMed:18495659). {ECO:0000269|PubMed:18495659,
CC ECO:0000303|PubMed:27488942}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(11R)-dihydroartemisinic aldehyde + NADP(+) = (+)-artemisinic
CC aldehyde + H(+) + NADPH; Xref=Rhea:RHEA:32883, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:57783, ChEBI:CHEBI:58349, ChEBI:CHEBI:64688,
CC ChEBI:CHEBI:64691; EC=1.3.1.92;
CC Evidence={ECO:0000269|PubMed:18495659};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:32885;
CC Evidence={ECO:0000269|PubMed:18495659};
CC -!- COFACTOR:
CC Name=FMN; Xref=ChEBI:CHEBI:58210; Evidence={ECO:0000250};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=19 uM for artemisinic aldehyde {ECO:0000269|PubMed:18495659};
CC KM=790 uM for 2-cyclohexen-1-one {ECO:0000269|PubMed:18495659};
CC KM=650 uM for (+)-carvone {ECO:0000269|PubMed:18495659};
CC KM=95 uM for NADPH {ECO:0000269|PubMed:18495659};
CC KM=770 uM for NADH {ECO:0000269|PubMed:18495659};
CC Note=kcat is 2.6 sec(-1) with artemisinic aldehyde as substrate. kcat
CC is 1.8 sec(-1) with 2-cyclohexen-1-one as substrate. kcat is 0.86
CC sec(-1) with (+)-carvone as substrate. kcat is 1.3 sec(-1) for the
CC NADH-dependent reduction of artemisinic aldehyde.
CC {ECO:0000269|PubMed:18495659};
CC pH dependence:
CC Optimum pH is 7.5. {ECO:0000269|PubMed:18495659};
CC -!- PATHWAY: Sesquiterpene biosynthesis. {ECO:0000303|PubMed:30468448}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000269|PubMed:18495659}.
CC -!- TISSUE SPECIFICITY: Expression at relatively high level in glandular
CC trichomes, and at lower level in leaves and flower buds
CC (PubMed:18495659). Weakly expressed in roots (PubMed:18495659).
CC Expressed both in apical and sub-apical cells of glandular secretory
CC trichomes (PubMed:22195571, PubMed:19664791). Also present in non-
CC glandular trichome cells (PubMed:30851440).
CC {ECO:0000269|PubMed:18495659, ECO:0000269|PubMed:19664791,
CC ECO:0000269|PubMed:22195571, 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 -!- SIMILARITY: Belongs to the NADH:flavin oxidoreductase/NADH oxidase
CC family. {ECO:0000305}.
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DR EMBL; EU704257; ACH61780.1; -; mRNA.
DR EMBL; JX898526; AGO50599.1; -; mRNA.
DR EMBL; JX898527; AGO50600.1; -; mRNA.
DR EMBL; KC505370; AGL34708.1; -; mRNA.
DR EMBL; PKPP01000231; PWA95606.1; -; Genomic_DNA.
DR PDB; 5DXX; X-ray; 1.45 A; A=1-388.
DR PDB; 5DXY; X-ray; 1.77 A; A=1-388.
DR PDB; 5DY2; X-ray; 1.57 A; A=1-388.
DR PDB; 5DY3; X-ray; 1.82 A; A=1-388.
DR PDBsum; 5DXX; -.
DR PDBsum; 5DXY; -.
DR PDBsum; 5DY2; -.
DR PDBsum; 5DY3; -.
DR AlphaFoldDB; C5H429; -.
DR SMR; C5H429; -.
DR STRING; 35608.C5H429; -.
DR PRIDE; C5H429; -.
DR KEGG; ag:ACH61780; -.
DR BioCyc; MetaCyc:MON-12186; -.
DR BRENDA; 1.3.1.92; 7150.
DR Proteomes; UP000245207; Unassembled WGS sequence.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0010181; F:FMN binding; IEA:InterPro.
DR GO; GO:0016628; F:oxidoreductase activity, acting on the CH-CH group of donors, NAD or NADP as acceptor; IDA:UniProtKB.
DR Gene3D; 3.20.20.70; -; 1.
DR InterPro; IPR013785; Aldolase_TIM.
DR InterPro; IPR001155; OxRdtase_FMN_N.
DR InterPro; IPR045247; Oye-like.
DR PANTHER; PTHR22893; PTHR22893; 1.
DR Pfam; PF00724; Oxidored_FMN; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Cytoplasm; Flavoprotein; FMN; NADP; Oxidoreductase;
KW Reference proteome.
FT CHAIN 1..388
FT /note="Artemisinic aldehyde Delta(11(13)) reductase"
FT /id="PRO_0000419682"
FT MOTIF 386..388
FT /note="Microbody targeting signal"
FT /evidence="ECO:0000255"
FT ACT_SITE 186
FT /note="Proton donor"
FT /evidence="ECO:0000250|UniProtKB:P42593"
FT BINDING 27..29
FT /ligand="FMN"
FT /ligand_id="ChEBI:CHEBI:58210"
FT /evidence="ECO:0000269|Ref.12, ECO:0007744|PDB:5DXY,
FT ECO:0007744|PDB:5DY3"
FT BINDING 60
FT /ligand="FMN"
FT /ligand_id="ChEBI:CHEBI:58210"
FT /evidence="ECO:0000269|Ref.12, ECO:0007744|PDB:5DXY,
FT ECO:0007744|PDB:5DY3"
FT BINDING 102
FT /ligand="FMN"
FT /ligand_id="ChEBI:CHEBI:58210"
FT /evidence="ECO:0000269|Ref.12, ECO:0007744|PDB:5DXY,
FT ECO:0007744|PDB:5DY3"
FT BINDING 181..184
FT /ligand="substrate"
FT /evidence="ECO:0000269|Ref.12, ECO:0007744|PDB:5DXY"
FT BINDING 181
FT /ligand="FMN"
FT /ligand_id="ChEBI:CHEBI:58210"
FT /evidence="ECO:0000269|Ref.12, ECO:0007744|PDB:5DXY,
FT ECO:0007744|PDB:5DY3"
FT BINDING 233
FT /ligand="FMN"
FT /ligand_id="ChEBI:CHEBI:58210"
FT /evidence="ECO:0000269|Ref.12, ECO:0007744|PDB:5DXY,
FT ECO:0007744|PDB:5DY3"
FT BINDING 279
FT /ligand="substrate"
FT /evidence="ECO:0000269|Ref.12, ECO:0007744|PDB:5DXY"
FT BINDING 317..319
FT /ligand="FMN"
FT /ligand_id="ChEBI:CHEBI:58210"
FT /evidence="ECO:0000269|Ref.12, ECO:0007744|PDB:5DXY,
FT ECO:0007744|PDB:5DY3"
FT BINDING 340..341
FT /ligand="FMN"
FT /ligand_id="ChEBI:CHEBI:58210"
FT /evidence="ECO:0000269|Ref.12, ECO:0007744|PDB:5DXY,
FT ECO:0007744|PDB:5DY3"
FT BINDING 368
FT /ligand="substrate"
FT /evidence="ECO:0000269|Ref.12, ECO:0007744|PDB:5DXY,
FT ECO:0007744|PDB:5DY3"
FT CONFLICT 4..5
FT /note="NP -> K (in Ref. 1; ACH61780 and 2; AGL34708/
FT AGO50599/AGO50600)"
FT /evidence="ECO:0000305"
FT CONFLICT 16
FT /note="N -> K (in Ref. 1; ACH61780)"
FT /evidence="ECO:0000305"
FT CONFLICT 112
FT /note="Q -> K (in Ref. 2; AGL34708/AGO50600)"
FT /evidence="ECO:0000305"
FT CONFLICT 137
FT /note="L -> M (in Ref. 2; AGL34708)"
FT /evidence="ECO:0000305"
FT CONFLICT 226
FT /note="A -> G (in Ref. 2; AGO50600)"
FT /evidence="ECO:0000305"
FT CONFLICT 226
FT /note="A -> T (in Ref. 1; ACH61780 and 2; AGO50599/
FT AGL34708)"
FT /evidence="ECO:0000305"
FT CONFLICT 231
FT /note="L -> G (in Ref. 2; AGO50600)"
FT /evidence="ECO:0000305"
FT CONFLICT 231
FT /note="L -> I (in Ref. 1; ACH61780 and 2; AGO50599/
FT AGL34708)"
FT /evidence="ECO:0000305"
FT CONFLICT 295
FT /note="S -> SDH (in Ref. 2; AGO50600)"
FT /evidence="ECO:0000305"
FT CONFLICT 344
FT /note="V -> I (in Ref. 2; AGO50600)"
FT /evidence="ECO:0000305"
FT CONFLICT 384
FT /note="K -> Q (in Ref. 2; AGO50600)"
FT /evidence="ECO:0000305"
FT STRAND 12..14
FT /evidence="ECO:0007829|PDB:5DXX"
FT STRAND 17..25
FT /evidence="ECO:0007829|PDB:5DXX"
FT HELIX 34..36
FT /evidence="ECO:0007829|PDB:5DXX"
FT HELIX 40..49
FT /evidence="ECO:0007829|PDB:5DXX"
FT STRAND 55..64
FT /evidence="ECO:0007829|PDB:5DXX"
FT HELIX 65..67
FT /evidence="ECO:0007829|PDB:5DXX"
FT STRAND 75..78
FT /evidence="ECO:0007829|PDB:5DXY"
FT HELIX 79..94
FT /evidence="ECO:0007829|PDB:5DXX"
FT STRAND 98..104
FT /evidence="ECO:0007829|PDB:5DXX"
FT HELIX 112..114
FT /evidence="ECO:0007829|PDB:5DXX"
FT HELIX 116..118
FT /evidence="ECO:0007829|PDB:5DXX"
FT STRAND 122..126
FT /evidence="ECO:0007829|PDB:5DXX"
FT STRAND 133..136
FT /evidence="ECO:0007829|PDB:5DXX"
FT STRAND 142..144
FT /evidence="ECO:0007829|PDB:5DXX"
FT HELIX 153..172
FT /evidence="ECO:0007829|PDB:5DXX"
FT STRAND 176..182
FT /evidence="ECO:0007829|PDB:5DXX"
FT HELIX 187..192
FT /evidence="ECO:0007829|PDB:5DXX"
FT TURN 194..196
FT /evidence="ECO:0007829|PDB:5DXX"
FT STRAND 204..206
FT /evidence="ECO:0007829|PDB:5DXX"
FT HELIX 207..210
FT /evidence="ECO:0007829|PDB:5DXX"
FT HELIX 212..225
FT /evidence="ECO:0007829|PDB:5DXX"
FT HELIX 227..229
FT /evidence="ECO:0007829|PDB:5DXX"
FT STRAND 230..234
FT /evidence="ECO:0007829|PDB:5DXX"
FT TURN 240..242
FT /evidence="ECO:0007829|PDB:5DXX"
FT HELIX 248..266
FT /evidence="ECO:0007829|PDB:5DXX"
FT STRAND 271..276
FT /evidence="ECO:0007829|PDB:5DXX"
FT STRAND 281..286
FT /evidence="ECO:0007829|PDB:5DXX"
FT HELIX 297..309
FT /evidence="ECO:0007829|PDB:5DXX"
FT STRAND 310..312
FT /evidence="ECO:0007829|PDB:5DY2"
FT STRAND 314..319
FT /evidence="ECO:0007829|PDB:5DXX"
FT HELIX 322..330
FT /evidence="ECO:0007829|PDB:5DXX"
FT STRAND 335..340
FT /evidence="ECO:0007829|PDB:5DXX"
FT HELIX 341..345
FT /evidence="ECO:0007829|PDB:5DXX"
FT HELIX 349..355
FT /evidence="ECO:0007829|PDB:5DXX"
FT HELIX 364..366
FT /evidence="ECO:0007829|PDB:5DXX"
FT TURN 374..376
FT /evidence="ECO:0007829|PDB:5DXX"
SQ SEQUENCE 388 AA; 42585 MW; 1FA441BEA42027EE CRC64;
MSENPPTLFS AYKMGNFNLS HRVVLAPMTR CRAINAIPNE ALVEYYRQRS TAGGFLITEG
TMISPSSAGF PHVPGIFTKE QVEGWKKVVD AAHKEGAVIF CQLWHVGRAS HQVYQPGGAA
PISSTSKPIS KKWEILLPDA TYGTYPEPRP LAANEILEVV EDYRVAAINA IEAGFDGIEI
HGAHGYLLDQ FMKDGINDRT DEYGGSLENR CKFILQVVQA VSAAIATDRV LIRISPAIDH
TDAMDSDPRS LGLAVIERLN KLQFKLGSRL AYLHVTQPRY TADGHGQTEA GANGSEEEVA
QLMKTWRGAY VGTFICCGGY TRELGLQAVA QGDADLVAFG RYFVSNPDLV LRLKLNAPLN
RYDRATFYTH DPVVGYTDYP SLDKGSLL
