NSRK_ASPN1
ID NSRK_ASPN1 Reviewed; 504 AA.
AC A0A2I1C3T9;
DT 29-SEP-2021, integrated into UniProtKB/Swiss-Prot.
DT 28-FEB-2018, sequence version 1.
DT 03-AUG-2022, entry version 13.
DE RecName: Full=FAD-dependent monooxygenase nsrK {ECO:0000303|PubMed:30394754};
DE Short=FMO nsrK {ECO:0000303|PubMed:30394754};
DE EC=1.-.-.- {ECO:0000269|PubMed:32105084, ECO:0000269|PubMed:33891392};
DE AltName: Full=Neosartorin biosynthesis cluster protein K {ECO:0000303|PubMed:30394754};
GN Name=nsrK {ECO:0000303|PubMed:30394754}; ORFNames=P174DRAFT_460883;
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, CATALYTIC ACTIVITY, 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, CATALYTIC ACTIVITY, AND PATHWAY.
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: FAD-dependent 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=FAD; Xref=ChEBI:CHEBI:57692; Evidence={ECO:0000305};
CC -!- PATHWAY: Secondary metabolite biosynthesis.
CC {ECO:0000269|PubMed:30394754, ECO:0000269|PubMed:32105084,
CC ECO:0000269|PubMed:33891392}.
CC -!- DISRUPTION PHENOTYPE: Impairs the production of neosartorin and
CC accumulates two isomeric metabolites, moniliphenone and 2,2',6'-
CC trihydroxy-4-methyl-6-methoxya-cyldiphenylmethanone.
CC {ECO:0000269|PubMed:30394754}.
CC -!- SIMILARITY: Belongs to the paxM FAD-dependent monooxygenase family.
CC {ECO:0000305}.
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DR EMBL; MSZS01000005; PKX92299.1; -; Genomic_DNA.
DR SMR; A0A2I1C3T9; -.
DR VEuPathDB; FungiDB:P174DRAFT_460883; -.
DR OrthoDB; 462247at2759; -.
DR Proteomes; UP000234474; Unassembled WGS sequence.
DR GO; GO:0071949; F:FAD binding; IEA:InterPro.
DR GO; GO:0004497; F:monooxygenase activity; IEA:UniProtKB-KW.
DR GO; GO:0044550; P:secondary metabolite biosynthetic process; IEA:UniProt.
DR Gene3D; 3.50.50.60; -; 1.
DR InterPro; IPR002938; FAD-bd.
DR InterPro; IPR036188; FAD/NAD-bd_sf.
DR Pfam; PF01494; FAD_binding_3; 1.
DR SUPFAM; SSF51905; SSF51905; 1.
PE 1: Evidence at protein level;
KW FAD; Flavoprotein; Monooxygenase; Oxidoreductase; Reference proteome.
FT CHAIN 1..504
FT /note="FAD-dependent monooxygenase nsrK"
FT /id="PRO_0000453481"
FT BINDING 62..63
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:A6T923"
FT BINDING 340
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:A6T923"
FT BINDING 350..354
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:A6T923"
SQ SEQUENCE 504 AA; 55808 MW; 50D459D2FD383415 CRC64;
MGSITESQEP LRFFATGDKH ESASSARPPT YVQVLIVGAG FAGLMAALEC WRKGHDVVGI
VERNQGPNYS GDLIIIQPSA LEIMKHWPQM RRELEEDKVT VGTYYYRHNG ELVDGPAHPN
YNAPEYVAER EARPGGFPYV GAVQIRKKFY RMLLRQVARL GFRVDYGQRV ESYFEDDSAG
VAGVRMTDGS IRKAHVVVAA DGFRSRSELL IADEYLPTQS SGMSVYRTAF PAKLALADEA
VRQRWGGKHT YEFWMGSGMH IGLYLSPELA AFGITPRDHL LAKDKVARES WDPDVSPDEV
IDVLRRAKVP GDSIIHWPLR WRNLRREWVS PGGRVVQIGD AAHSTVPSSA AGGTLALEDA
ITLATSLQIA SSPAAASGPG AGAGAGVPLG TRVYNLLRYE RASCTQKMAF VNAQVLGDTT
DWDAVRADPS KVRVRYPKWF FRHDPEGYVY EKYGQAFAHL VSGAEFHNTN IPPGHQFVHW
TLEGIHREMA AGKKVEDLLD GDWT
