NOTP_ASPVE
ID NOTP_ASPVE Reviewed; 292 AA.
AC L7WRR9;
DT 11-DEC-2019, integrated into UniProtKB/Swiss-Prot.
DT 03-APR-2013, sequence version 1.
DT 03-AUG-2022, entry version 26.
DE RecName: Full=Short chain dehydrogenases/reductase notP' {ECO:0000303|PubMed:23213353};
DE EC=1.1.1.- {ECO:0000305};
DE AltName: Full=Notoamide biosynthesis cluster protein P' {ECO:0000303|PubMed:23213353};
GN Name=notP' {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].
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: Short chain dehydrogenases/reductase; part of the gene
CC cluster that mediates the biosynthesis of notoamide, a fungal indole
CC alkaloid that belongs to a family of natural products containing a
CC characteristic bicyclo[2.2.2]diazaoctane core (PubMed:23213353). The
CC first step of notoamide biosynthesis involves coupling of L-proline and
CC L-tryptophan by the bimodular NRPS notE', to produce cyclo-L-
CC tryptophan-L-proline called brevianamide F (Probable). The reverse
CC prenyltransferase notF' then acts as a deoxybrevianamide E synthase and
CC converts brevianamide F to deoxybrevianamide E via reverse prenylation
CC at C-2 of the indole ring leading to the bicyclo[2.2.2]diazaoctane core
CC (PubMed:22660767) (Probable). Deoxybrevianamide E is further
CC hydroxylated at C-6 of the indole ring, likely catalyzed by the
CC cytochrome P450 monooxygenase notG', to yield 6-hydroxy-
CC deoxybrevianamide E (Probable). 6-hydroxy-deoxybrevianamide E is a
CC specific substrate of the prenyltransferase notC' for normal
CC prenylation at C-7 to produce 6-hydroxy-7-prenyl-deoxybrevianamide,
CC also called notoamide S (Probable). As the proposed pivotal branching
CC point in notoamide biosynthesis, notoamide S can be diverted to
CC notoamide E through an oxidative pyran ring closure putatively
CC catalyzed by either notH' cytochrome P450 monooxygenase or the notD'
CC FAD-linked oxidoreductase (Probable). This step would be followed by an
CC indole 2,3-epoxidation-initiated pinacol-like rearrangement catalyzed
CC by the notB' FAD-dependent monooxygenase leading to the formation of
CC notoamide C and notoamide D (Probable). On the other hand notoamide S
CC is converted to notoamide T by notH' (or notD'), a bifunctional oxidase
CC that also functions as the intramolecular Diels-Alderase responsible
CC for generation of (-)-notoamide T (Probable). To generate antipodal
CC (+)-notoaminide T, notH (or notD) in Aspergillus strain MF297-2 is
CC expected to catalyze a Diels-Alder reaction leading to the opposite
CC stereochemistry (Probable). The remaining oxidoreductase notD' (or
CC notH') 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). The fonction of notP' in the
CC notoamide biosynthesis has not been determined yet (Probable).
CC {ECO:0000269|PubMed:22660767, ECO:0000269|PubMed:23213353,
CC ECO:0000305|PubMed:23213353}.
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 short-chain dehydrogenases/reductases (SDR)
CC family. {ECO:0000305}.
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DR EMBL; JQ708194; AGC83587.1; -; Genomic_DNA.
DR AlphaFoldDB; L7WRR9; -.
DR SMR; L7WRR9; -.
DR VEuPathDB; FungiDB:ASPVEDRAFT_877678; -.
DR GO; GO:0016491; F:oxidoreductase activity; IEA:UniProtKB-KW.
DR InterPro; IPR036291; NAD(P)-bd_dom_sf.
DR InterPro; IPR020904; Sc_DH/Rdtase_CS.
DR InterPro; IPR002347; SDR_fam.
DR PRINTS; PR00081; GDHRDH.
DR SUPFAM; SSF51735; SSF51735; 1.
DR PROSITE; PS00061; ADH_SHORT; 1.
PE 1: Evidence at protein level;
KW NADP; Oxidoreductase.
FT CHAIN 1..292
FT /note="Short chain dehydrogenases/reductase notP'"
FT /id="PRO_0000448826"
FT REGION 1..25
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 178
FT /note="Proton donor"
FT /evidence="ECO:0000250|UniProtKB:O93868"
FT ACT_SITE 193
FT /note="Proton donor"
FT /evidence="ECO:0000250|UniProtKB:O93868"
FT ACT_SITE 197
FT /note="Lowers pKa of active site Tyr"
FT /evidence="ECO:0000250|UniProtKB:O93868"
FT BINDING 45..48
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:O93868"
FT BINDING 68..70
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:O93868"
FT BINDING 97..98
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:O93868"
FT BINDING 193
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:O93868"
FT BINDING 197
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:O93868"
SQ SEQUENCE 292 AA; 31222 MW; 637A3DEFB518F6A2 CRC64;
MPQTSDGNVH APQYREAKPS QGDPSLSVSQ LFRLDNRTII ITGATGFLGS TLAIAILESG
ADVVCLDLPP TPTAENWNDV KTTASRHEQQ LSYYQLDVTD EDAVADTFAK FLPTLRYPVR
GLVTCAGLSL NGPSSEFPAS AFRKVLDINV TGTFLVAKAT ARAMISANTT GSMVFVASMS
GYGANKGVDT AGYNSSKAAV HQLTRSLAAE WGSRVGLPLI RVNSLSPGYI RTAATAEALQ
KPGMEDQWTG DNMLYRLSRV DEFRAPVLFM LGDGSSFMTG ADLRVDGGHC SW
