NOTH_ASPSM
ID NOTH_ASPSM Reviewed; 501 AA.
AC E1ACQ3;
DT 11-DEC-2019, integrated into UniProtKB/Swiss-Prot.
DT 02-NOV-2010, sequence version 1.
DT 03-AUG-2022, entry version 33.
DE RecName: Full=Cytochrome P450 monooxygenase notH {ECO:0000303|PubMed:20722388};
DE EC=1.-.-.- {ECO:0000305|PubMed:23213353};
DE AltName: Full=Notoamide biosynthesis cluster protein H {ECO:0000303|PubMed:20722388};
GN Name=notH {ECO:0000303|PubMed:20722388};
OS Aspergillus sp. (strain MF297-2).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Aspergillus.
OX NCBI_TaxID=877550;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND FUNCTION.
RC STRAIN=MF297-2;
RX PubMed=20722388; DOI=10.1021/ja1049302;
RA Ding Y., de Wet J.R., Cavalcoli J., Li S., Greshock T.J., Miller K.A.,
RA Finefield J.M., Sunderhaus J.D., McAfoos T.J., Tsukamoto S., Williams R.M.,
RA Sherman D.H.;
RT "Genome-based characterization of two prenylation steps in the assembly of
RT the stephacidin and notoamide anticancer agents in a marine-derived
RT Aspergillus sp.";
RL J. Am. Chem. Soc. 132:12733-12740(2010).
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=22188465; DOI=10.1021/ja2093212;
RA Li S., Finefield J.M., Sunderhaus J.D., McAfoos T.J., Williams R.M.,
RA Sherman D.H.;
RT "Biochemical characterization of NotB as an FAD-dependent oxidase in the
RT biosynthesis of notoamide indole alkaloids.";
RL J. Am. Chem. Soc. 134:788-791(2012).
RN [4]
RP FUNCTION, AND PATHWAY.
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).
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:20722388). 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 (PubMed:20722388). The reverse prenyltransferase
CC notF then acts as a deoxybrevianamide E synthase and converts
CC brevianamide F to deoxybrevianamide E via reverse prenylation at C-2 of
CC the indole ring leading to the bicyclo[2.2.2]diazaoctane core
CC (PubMed:20722388). Deoxybrevianamide E is further hydroxylated at C-6
CC of the indole ring, likely catalyzed by the cytochrome P450
CC monooxygenase notG, to yield 6-hydroxy-deoxybrevianamide E (Probable).
CC 6-hydroxy-deoxybrevianamide E is a specific substrate of the
CC prenyltransferase notC for normal prenylation at C-7 to produce 6-
CC hydroxy-7-prenyl-deoxybrevianamide, also called notoamide S
CC (PubMed:20722388). As the proposed pivotal branching point in notoamide
CC biosynthesis, notoamide S can be diverted to notoamide E through an
CC oxidative pyran ring closure putatively catalyzed by either notH
CC cytochrome P450 monooxygenase or the notD FAD-linked oxidoreductase
CC (Probable). This step would be followed by an indole 2,3-epoxidation-
CC initiated pinacol-like rearrangement catalyzed by the notB FAD-
CC dependent monooxygenase leading to the formation of notoamide C and
CC notoamide D (PubMed:22188465). On the other hand notoamide S is
CC converted to notoamide T by notH (or notD), a bifunctional oxidase that
CC also functions as the intramolecular Diels-Alderase responsible for
CC generation of (+)-notoamide T (Probable). To generate antipodal (-)-
CC notoaminide T, notH' (or notD') in Aspergillus versicolor is expected
CC to catalyze a Diels-Alder reaction leading to the opposite
CC stereochemistry (Probable). The remaining oxidoreductase notD (or notH)
CC likely catalyzes the oxidative pyran ring formation to yield (+)-
CC stephacidin A (Probable). The FAD-dependent monooxygenase notI is
CC highly similar to notB and is predicted to catalyze a similar
CC conversion from (+)-stephacidin A to (-)-notoamide B via the 2,3-
CC epoxidation of (+)-stephacidin A followed by a pinacol-type
CC rearrangement (Probable). Finally, it remains unclear which enzyme
CC could be responsible for the final hydroxylation steps leading to
CC notoamide A and sclerotiamide (Probable). {ECO:0000269|PubMed:20722388,
CC ECO:0000269|PubMed:22188465, 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; HM622670; ADM34141.1; -; Genomic_DNA.
DR AlphaFoldDB; E1ACQ3; -.
DR SMR; E1ACQ3; -.
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..501
FT /note="Cytochrome P450 monooxygenase notH"
FT /id="PRO_0000448806"
FT TRANSMEM 11..31
FT /note="Helical"
FT /evidence="ECO:0000255"
FT BINDING 442
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 298
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
SQ SEQUENCE 501 AA; 56926 MW; 9120493A2EEA68A0 CRC64;
MAKDTALHLP LGLESVGWVL GLLTTSILYL FLSPRSQIPR PPVVNKYWWD FFQIKAKRDF
DARAEDLIKL GLSKARAKNT ERRFGPRLVL SDKLADAVGM DNRFDQNKGI APVNLVELRG
FESMFSAALH DSVPRPATSA TSKRLVHLTQ PFSEETTDFL QREWTESPDW HEIVVYPVMS
RLTAQVLSRA FVGPKLCRDA RWLDIATTYV SHRMTAAVAV QKWGTVLQPI VHWFLPSCRR
LRAHIQRARE LIQPELDRIK ENPLEDETFT SLAWIHGFAQ GYIYDAGLAQ LRLTAVANHT
TSDMVTKILI RICENPELIQ PLRDEAIEAV RGGRLRVAAL QKMFLMESVM KESQRLEPFF
LLSMFRYATE TVILPGGTAI PQGTLLTVAN PSRLDPAIYP DPEKFDGYRF VRMREDPENA
HLAPFTKTNP TNLNFGHGKQ ACPGRFIAVN QIKIALCHIL LKYDVELVEE CPSQLIRSGL
LTVRNPGAKI RVRRRQEEVS L
