NSRP_ASPN1
ID NSRP_ASPN1 Reviewed; 515 AA.
AC A0A2I1C3T4;
DT 29-SEP-2021, integrated into UniProtKB/Swiss-Prot.
DT 28-FEB-2018, sequence version 1.
DT 03-AUG-2022, entry version 15.
DE RecName: Full=Cytochrome P450 monooxygenase nsrP {ECO:0000303|PubMed:30394754};
DE EC=1.14.13.- {ECO:0000305|PubMed:30394754};
DE AltName: Full=Neosartorin biosynthesis cluster protein P {ECO:0000303|PubMed:30394754};
GN Name=nsrP {ECO:0000303|PubMed:30394754}; ORFNames=P174DRAFT_372675;
OS Aspergillus novofumigatus (strain IBT 16806).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Aspergillus.
OX NCBI_TaxID=1392255;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=IBT 16806;
RX PubMed=29317534; DOI=10.1073/pnas.1715954115;
RA Kjaerboelling I., Vesth T.C., Frisvad J.C., Nybo J.L., Theobald S., Kuo A.,
RA Bowyer P., Matsuda Y., Mondo S., Lyhne E.K., Kogle M.E., Clum A.,
RA Lipzen A., Salamov A., Ngan C.Y., Daum C., Chiniquy J., Barry K.,
RA LaButti K., Haridas S., Simmons B.A., Magnuson J.K., Mortensen U.H.,
RA Larsen T.O., Grigoriev I.V., Baker S.E., Andersen M.R.;
RT "Linking secondary metabolites to gene clusters through genome sequencing
RT of six diverse Aspergillus species.";
RL Proc. Natl. Acad. Sci. U.S.A. 115:E753-E761(2018).
RN [2]
RP FUNCTION, DISRUPTION PHENOTYPE, AND PATHWAY.
RX PubMed=30394754; DOI=10.1021/acs.orglett.8b03123;
RA Matsuda Y., Gotfredsen C.H., Larsen T.O.;
RT "Genetic characterization of neosartorin biosynthesis provides insight into
RT heterodimeric natural product generation.";
RL Org. Lett. 20:7197-7200(2018).
RN [3]
RP FUNCTION, AND PATHWAY.
RX PubMed=32105084; DOI=10.1021/acs.orglett.0c00285;
RA Wei X., Matsuda Y.;
RT "Unraveling the fungal strategy for tetrahydroxanthone biosynthesis and
RT diversification.";
RL Org. Lett. 22:1919-1923(2020).
RN [4]
RP FUNCTION.
RX PubMed=33891392; DOI=10.1021/acs.jnatprod.1c00022;
RA Wei X., Chen X., Chen L., Yan D., Wang W.G., Matsuda Y.;
RT "Heterologous biosynthesis of tetrahydroxanthone dimers: determination of
RT key factors for selective or divergent synthesis.";
RL J. Nat. Prod. 84:1544-1549(2021).
CC -!- FUNCTION: Cytochrome P450 monooxygenase; part of the gene cluster that
CC mediates the biosynthesis of the tetrahydroxanthone dimer neosartorin,
CC which exhibits antibacterial activity (PubMed:30394754,
CC PubMed:32105084, PubMed:33891392). The two different monomeric units
CC appear to be synthesized by the same set of enzymes, among which the
CC Baeyer-Villiger monooxygenase nsrF is the key enzyme for the divergence
CC of the biosynthetic routes (PubMed:32105084). The pathway begins with
CC the synthesis of atrochrysone thioester by the polyketide synthase nsrB
CC (PubMed:32105084). The atrochrysone carboxyl ACP thioesterase nsrC then
CC breaks the thioester bond and releases the atrochrysone carboxylic acid
CC from AacuL (PubMed:32105084). Atrochrysone carboxylic acid is
CC decarboxylated by the decarboxylase nsrE, and oxidized by the anthrone
CC oxygenase nsrD to yield emodin (PubMed:32105084). Emodin is then
CC reduced to emodin hydroquinone by the oxidoreductase nsrR
CC (PubMed:32105084). A-ring reduction by the short chain dehydrogenase
CC nsrJ, dehydration by the scytalone dehydratase-like protein nsrI and
CC probable spontaneous re-oxidation, results in overall deoxygenation to
CC chrysophanol (PubMed:32105084). The Baeyer-Villiger monooxygenase nsrF
CC accepts chrysophanol as a substrate to insert one oxygen atom at two
CC different positions to yield the precursors of both monomric units
CC (PubMed:30394754, PubMed:32105084, PubMed:33891392). NsrF is
CC promiscuous/flexible in interacting with the 2 (non methylated and
CC methylated) aromatic rings of chrysophanol, thus diverging the
CC biosynthetic pathway at this point (PubMed:30394754, PubMed:32105084,
CC PubMed:33891392). After the hydrolysis of the lactones,
CC methylesterification by the methyltransferase nsrG yields respectively
CC moniliphenone and 2,2',6'-trihydroxy-4-methyl-6-methoxya-
CC cyldiphenylmethanone (PubMed:30394754, PubMed:32105084). The next steps
CC are the hydroxylation by the FAD-dependent monooxygenase nsrK, followed
CC by isomerization by the monooxygenase nsrQ (PubMed:32105084). The short
CC chain dehydrogenase/reductase nsrO then catalyzes the C-5 ketoreduction
CC to give the xanthone skeleton of blennolide C and 5-acetylblennolide A
CC (PubMed:32105084). The acetyltransferase nsrL has a strict substrate
CC specificity and uses only blennolide A but not blennolide C to yield 5-
CC acetylblennolide A as the single-acetylated product (PubMed:30394754).
CC In the final step of the biosynthesis, the heterodimerization of the 2
CC xanthones, blennolide C and 5-acetylblennolide A, is catalyzed by the
CC cytochrome P450 monooxygenase nsrP (PubMed:30394754). NsrP can utilize
CC at least three different xanthones as its substrates to perform the
CC dimerization reaction (PubMed:30394754). {ECO:0000269|PubMed:30394754,
CC ECO:0000269|PubMed:32105084, ECO:0000269|PubMed:33891392}.
CC -!- COFACTOR:
CC Name=heme; Xref=ChEBI:CHEBI:30413;
CC Evidence={ECO:0000250|UniProtKB:P04798};
CC -!- PATHWAY: Secondary metabolite biosynthesis.
CC {ECO:0000269|PubMed:30394754}.
CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000255}; Single-pass membrane
CC protein {ECO:0000255}.
CC -!- DISRUPTION PHENOTYPE: Impairs the production of neosartorin and
CC accumulates blennolide C and 5-acetylblennolide A.
CC {ECO:0000269|PubMed:30394754}.
CC -!- SIMILARITY: Belongs to the cytochrome P450 family. {ECO:0000305}.
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DR EMBL; MSZS01000005; PKX92294.1; -; Genomic_DNA.
DR SMR; A0A2I1C3T4; -.
DR VEuPathDB; FungiDB:P174DRAFT_372675; -.
DR OrthoDB; 825914at2759; -.
DR Proteomes; UP000234474; Unassembled WGS sequence.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0020037; F:heme binding; IEA:InterPro.
DR GO; GO:0005506; F:iron ion binding; IEA:InterPro.
DR GO; GO:0004497; F:monooxygenase activity; IEA:UniProtKB-KW.
DR GO; GO:0016705; F:oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen; IEA:InterPro.
DR GO; GO:0008152; P:metabolic process; IEA:UniProt.
DR Gene3D; 1.10.630.10; -; 1.
DR InterPro; IPR001128; Cyt_P450.
DR InterPro; IPR002403; Cyt_P450_E_grp-IV.
DR InterPro; IPR036396; Cyt_P450_sf.
DR Pfam; PF00067; p450; 1.
DR PRINTS; PR00465; EP450IV.
DR SUPFAM; SSF48264; SSF48264; 1.
PE 3: Inferred from homology;
KW Glycoprotein; Heme; Iron; Membrane; Metal-binding; Monooxygenase;
KW Oxidoreductase; Reference proteome; Transmembrane; Transmembrane helix.
FT CHAIN 1..515
FT /note="Cytochrome P450 monooxygenase nsrP"
FT /id="PRO_0000453477"
FT TRANSMEM 20..40
FT /note="Helical"
FT /evidence="ECO:0000255"
FT BINDING 452
FT /ligand="heme"
FT /ligand_id="ChEBI:CHEBI:30413"
FT /ligand_part="Fe"
FT /ligand_part_id="ChEBI:CHEBI:18248"
FT /note="axial binding residue"
FT /evidence="ECO:0000250|UniProtKB:P04798"
FT CARBOHYD 84
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 406
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 411
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
SQ SEQUENCE 515 AA; 58780 MW; 1046FFB314B92A4C CRC64;
MDFQIISRFT DGGDFQWTKF GTAAFLAVLL SALAFLSYTP RVHQKSPAFT SHKLPFIGSL
GFTTEQWKAR NWWKRATAES KTGNFSFWLG QRHVVGVTGE AARKMFFTHE ALDFVSGALI
RPINIHFWPP IHDIFRPDSK SRSKNTYFLR RLYELQSTEQ LNHYLPQLLK DARVGMAGLS
RVTKPSVSCW ETVFTQDVRL LCTDEIVADS KLLATFGRQV ETLLFTFSHY NVCFPWLPSP
SYYKRRQARY ALYNLMEDIV NKRLKNGARG PNDPVQILLD YNDKVDHIIE FFISVLFIAP
ANSRIIGGQM LNIMSIYRDW QEKVYADIKA AAAAHSPDKN APLVDQLAFI PLHAWENSFP
SIDLCLQETI RMWTSFSMAR LNLSPNPIPI PGSDEVIPGN TFVCYNSTEV NFSDSLYPDP
KKFDPARFLD GREEFRNEAY GFLGWGRGRH PCPGMRWAKL QQNIIIAYAV AMYDWSSCDE
TGKPTPQAVH VKELNAARGT VLPSAYCKLV PREKV
