NOTH_ASPVE
ID NOTH_ASPVE Reviewed; 499 AA.
AC L7WRY5;
DT 11-DEC-2019, integrated into UniProtKB/Swiss-Prot.
DT 03-APR-2013, sequence version 1.
DT 03-AUG-2022, entry version 28.
DE RecName: Full=Cytochrome P450 monooxygenase notH' {ECO:0000303|PubMed:23213353};
DE EC=1.-.-.- {ECO:0000305|PubMed:23213353};
DE AltName: Full=Notoamide biosynthesis cluster protein H' {ECO:0000303|PubMed:23213353};
GN Name=notH' {ECO:0000303|PubMed:23213353};
OS Aspergillus versicolor.
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Aspergillus;
OC Aspergillus subgen. Nidulantes.
OX NCBI_TaxID=46472;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, AND PATHWAY.
RC STRAIN=NRRL 35600;
RX PubMed=23213353; DOI=10.1039/c2md20029e;
RA Li S., Anand K., Tran H., Yu F., Finefield J.M., Sunderhaus J.D.,
RA McAfoos T.J., Tsukamoto S., Williams R.M., Sherman D.H.;
RT "Comparative analysis of the biosynthetic systems for fungal
RT bicyclo[2.2.2]diazaoctane indole alkaloids: the (+)/(-)-notoamide,
RT paraherquamide and malbrancheamide pathways.";
RL Med. Chem. Commun. 3:987-996(2012).
RN [2]
RP BIOTECHNOLOGY.
RX PubMed=17304611; DOI=10.1002/anie.200604381;
RA Kato H., Yoshida T., Tokue T., Nojiri Y., Hirota H., Ohta T.,
RA Williams R.M., Tsukamoto S.;
RT "Notoamides A-D: prenylated indole alkaloids isolated from a marine-derived
RT fungus, Aspergillus sp.";
RL Angew. Chem. Int. Ed. 46:2254-2256(2007).
RN [3]
RP FUNCTION.
RX PubMed=22660767; DOI=10.1007/s00253-012-4130-0;
RA Yin S., Yu X., Wang Q., Liu X.Q., Li S.M.;
RT "Identification of a brevianamide F reverse prenyltransferase BrePT from
RT Aspergillus versicolor with a broad substrate specificity towards
RT tryptophan-containing cyclic dipeptides.";
RL Appl. Microbiol. Biotechnol. 97:1649-1660(2013).
CC -!- FUNCTION: Cytochrome P450 monooxygenase; part of the gene cluster that
CC mediates the biosynthesis of notoamide, a fungal indole alkaloid that
CC belongs to a family of natural products containing a characteristic
CC bicyclo[2.2.2]diazaoctane core (PubMed:23213353). The first step of
CC notoamide biosynthesis involves coupling of L-proline and L-tryptophan
CC by the bimodular NRPS notE', to produce cyclo-L-tryptophan-L-proline
CC called brevianamide F (Probable). The reverse prenyltransferase notF'
CC then acts as a deoxybrevianamide E synthase and converts brevianamide F
CC to deoxybrevianamide E via reverse prenylation at C-2 of the indole
CC ring leading to the bicyclo[2.2.2]diazaoctane core (PubMed:22660767)
CC (Probable). Deoxybrevianamide E is further hydroxylated at C-6 of the
CC indole ring, likely catalyzed by the cytochrome P450 monooxygenase
CC notG', to yield 6-hydroxy-deoxybrevianamide E (Probable). 6-hydroxy-
CC deoxybrevianamide E is a specific substrate of the prenyltransferase
CC notC' for normal prenylation at C-7 to produce 6-hydroxy-7-prenyl-
CC deoxybrevianamide, also called notoamide S (Probable). As the proposed
CC pivotal branching point in notoamide biosynthesis, notoamide S can be
CC diverted to notoamide E through an oxidative pyran ring closure
CC putatively catalyzed by either notH' cytochrome P450 monooxygenase or
CC the notD' FAD-linked oxidoreductase (Probable). This step would be
CC followed by an indole 2,3-epoxidation-initiated pinacol-like
CC rearrangement catalyzed by the notB' FAD-dependent monooxygenase
CC leading to the formation of notoamide C and notoamide D (Probable). On
CC the other hand notoamide S is converted to notoamide T by notH' (or
CC notD'), a bifunctional oxidase that also functions as the
CC intramolecular Diels-Alderase responsible for generation of (-)-
CC notoamide T (Probable). To generate antipodal (+)-notoaminide T, notH
CC (or notD) in Aspergillus strain MF297-2 is expected to catalyze a
CC Diels-Alder reaction leading to the opposite stereochemistry
CC (Probable). The remaining oxidoreductase notD' (or notH') likely
CC catalyzes the oxidative pyran ring formation to yield (-)-stephacidin A
CC (Probable). The FAD-dependent monooxygenase notI' is highly similar to
CC notB' and is predicted to catalyze a similar conversion from (-)-
CC stephacidin A to (+)-notoamide B via the 2,3-epoxidation of (-)-
CC stephacidin A followed by a pinacol-type rearrangement (Probable).
CC Finally, it remains unclear which enzyme could be responsible for the
CC final hydroxylation steps leading to notoamide A and sclerotiamide
CC (Probable). {ECO:0000269|PubMed:22660767, ECO:0000269|PubMed:23213353,
CC ECO:0000305|PubMed:23213353}.
CC -!- COFACTOR:
CC Name=heme; Xref=ChEBI:CHEBI:30413;
CC Evidence={ECO:0000250|UniProtKB:P04798};
CC -!- PATHWAY: Alkaloid biosynthesis. {ECO:0000305|PubMed:23213353}.
CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000255}; Single-pass membrane
CC protein {ECO:0000255}.
CC -!- BIOTECHNOLOGY: Notoamides have been shown to exhibit antitumoral
CC activities (PubMed:17304611). Notoamides A-C show moderate cytotoxicity
CC against HeLa and L1210 cells with IC(50) values in the range of 22-52
CC mg/ml, but the IC(50) value of notoamide D is greater than 100 mg/ml
CC (PubMed:17304611). Moreover, notoamide C induces G2/M-cell cycle arrest
CC at a concentration of 6.3 mg/ml (PubMed:17304611).
CC {ECO:0000269|PubMed:17304611}.
CC -!- SIMILARITY: Belongs to the cytochrome P450 family. {ECO:0000305}.
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DR EMBL; JQ708194; AGC83579.1; -; Genomic_DNA.
DR AlphaFoldDB; L7WRY5; -.
DR SMR; L7WRY5; -.
DR VEuPathDB; FungiDB:ASPVEDRAFT_872263; -.
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:0009820; P:alkaloid metabolic process; IEA:UniProtKB-KW.
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 1: Evidence at protein level;
KW Alkaloid metabolism; Glycoprotein; Heme; Iron; Membrane; Metal-binding;
KW Monooxygenase; Oxidoreductase; Transmembrane; Transmembrane helix.
FT CHAIN 1..499
FT /note="Cytochrome P450 monooxygenase notH'"
FT /id="PRO_0000448807"
FT TRANSMEM 11..31
FT /note="Helical"
FT /evidence="ECO:0000255"
FT BINDING 440
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 296
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 427
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
SQ SEQUENCE 499 AA; 56650 MW; 8431CE803E115410 CRC64;
MAQDTALHLP LGLEPAGWAL ALLTSSIIYL FLSPKSKSPR FPVVNKYWWD FFQAKAKRDF
EAGAEDLIKL GLSKARTKPR REYPRLVLSD QLADAVGMDN RFDQDKGIAP VNLVTLKGFE
SMYAGALHDS VPRPATSATS KRLVHLTRPF SEETTDFLQR EWTESPDWHD IEVYPVISRL
TAQVLSRAFV GPRLCRDTRW LEIATTYISN RLTAVVAVQK WGAVLHPIVH WFLPSCRRLR
AQNKRARELL QPELDRIKES PLEDETFTSL AWIHGYGQGY IYDPGLAQLR LSAVANHTTS
DMMTKTLIRI CENPELIQPL REEAIEAVRG GGLRVAALQK MFLMESVMQE SQRLEPFILL
SMFRYATETV TLPEGTTIPK GTLLAIANPS RLDPAIYPDP HKFDGYRFVR MREDPRHAHL
APFTKTNSTN LNFGHGKQAC PGRFIAVNQI KIALCHMLLK YDIELVEECP SQLVRSGLVT
VRNPGAKIRV RRRQEEVCL
