EUPH_PHOSX
ID EUPH_PHOSX Reviewed; 430 AA.
AC A0A4P8GF19;
DT 26-FEB-2020, integrated into UniProtKB/Swiss-Prot.
DT 31-JUL-2019, sequence version 1.
DT 03-AUG-2022, entry version 9.
DE RecName: Full=Flavin-dependent monooxygenase eupH {ECO:0000303|PubMed:30980906};
DE EC=1.14.-.- {ECO:0000305|PubMed:30980906};
DE AltName: Full=Eupenifeldin biosynthesis cluster protein H {ECO:0000303|PubMed:30980906};
GN Name=eupH {ECO:0000303|PubMed:30980906}; ORFNames=gme12636;
OS Phoma sp.
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Dothideomycetes;
OC Pleosporomycetidae; Pleosporales; Pleosporineae; Didymellaceae; Phoma.
OX NCBI_TaxID=1707701;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, DISRUPTION PHENOTYPE, AND
RP PATHWAY.
RC STRAIN=XZ068 / CGMCC No. 10481;
RX PubMed=30980906; DOI=10.1016/j.fgb.2019.04.004;
RA Zhai Y., Li Y., Zhang J., Zhang Y., Ren F., Zhang X., Liu G., Liu X.,
RA Che Y.;
RT "Identification of the gene cluster for bistropolone-humulene meroterpenoid
RT biosynthesis in Phoma sp.";
RL Fungal Genet. Biol. 129:7-15(2019).
RN [2]
RP BIOTECHNOLOGY.
RX PubMed=8360103; DOI=10.7164/antibiotics.46.1082;
RA Mayerl F., Gao Q., Huang S., Klohr S.E., Matson J.A., Gustavson D.R.,
RA Pirnik D.M., Berry R.L., Fairchild C., Rose W.C.;
RT "Eupenifeldin, a novel cytotoxic bistropolone from Eupenicillium
RT brefeldianum.";
RL J. Antibiot. 46:1082-1088(1993).
RN [3]
RP BIOTECHNOLOGY.
RX PubMed=18095654; DOI=10.1021/np070513k;
RA Ayers S., Zink D.L., Powell J.S., Brown C.M., Grund A., Bills G.F.,
RA Platas G., Thompson D., Singh S.B.;
RT "Noreupenifeldin, a tropolone from an unidentified ascomycete.";
RL J. Nat. Prod. 71:457-459(2008).
RN [4]
RP BIOTECHNOLOGY.
RX DOI=10.1016/j.phytol.2008.09.008;
RA Bunyapaiboonsri T., Veeranondha S., Boonruangprapa T., Somrithipol S.;
RT "Ramiferin, a bisphenol-sesquiterpene from the fungus Kionochaeta ramifera
RT BCC 7585.";
RL Phytochem. Lett. 1:204-206(2008).
CC -!- FUNCTION: Flavin-dependent monooxygenase; part of the gene cluster that
CC mediates the biosynthesis of eupenifeldin, a bistropolone meroterpenoid
CC that acts as an antitumor agent (PubMed:30980906). The first step of
CC eupenifeldin biosynthesis is the biosynthesis of 3-methylorcinaldehyde
CC performed by the non-reducing polyketide synthase eupA
CC (PubMed:30980906). Oxidative dearomatization of 3-methylorcinaldehyde
CC likely catalyzed by the FAD-dependent monooxygenase eupB is followed by
CC oxidative ring expansion by the 2-oxoglutarate-dependent dioxygenase
CC eupC to provide the first tropolone metabolite, tropolone
CC stipitaldehyde (Probable). In parallel, generation of sesquiterpene
CC alpha-humulene from farnesylpyrophosphate (FPP) is catalyzed by the
CC terpene cyclase eupE (PubMed:30980906). The cytochrome P450
CC monooxygenase eupD then hydroxylates humulene to humulenol
CC (PubMed:30980906). The putative Diels-Alderase eupF probably catalyzes
CC the formation of the tropolone-humulene skeleton by linking humulenol
CC and the polyketide moiety (Probable). The short-chain
CC dehydrogenase/reductase eupG and the flavin-dependent monooxygenase
CC eupH are also essential for eupenifeldin biosynthesis and are likely
CC the additional decorating enzymes of the tropolone-humulene skeleton to
CC produce final eupenifeldin or derivatives (Probable).
CC {ECO:0000269|PubMed:30980906, ECO:0000305|PubMed:30980906}.
CC -!- COFACTOR:
CC Name=FAD; Xref=ChEBI:CHEBI:57692;
CC Evidence={ECO:0000250|UniProtKB:D3HKY4};
CC Note=Binds 1 FAD per subunit. {ECO:0000250|UniProtKB:D3HKY4};
CC -!- PATHWAY: Secondary metabolite biosynthesis; terpenoid biosynthesis.
CC {ECO:0000269|PubMed:30980906}.
CC -!- DOMAIN: Consists of an N-terminal FAD-binding domain with a Rossman
CC fold, a substrate-binding domain and a C-terminal helix that bridges
CC the 2 domains close to the antibiotic-binding site. This last helix is
CC flexible and may contribute to their different substrate specificities.
CC {ECO:0000250|UniProtKB:D3HKY4}.
CC -!- DISRUPTION PHENOTYPE: Abolishes the production of eupenifeldin.
CC {ECO:0000269|PubMed:30980906}.
CC -!- BIOTECHNOLOGY: Eupenifeldin is a bistropolone-humulene meroterpenoid
CC first discovered as an antitumor and anti-leukemia agent
CC (PubMed:8360103). This metabolite shows also anthelmintic activity
CC against the parasitic worm Hemonchus contortus, anti-malarial activity
CC as well as antifungal activity (PubMed:18095654, Ref.4).
CC {ECO:0000269|PubMed:18095654, ECO:0000269|PubMed:8360103,
CC ECO:0000269|Ref.4}.
CC -!- SIMILARITY: Belongs to the aromatic-ring hydroxylase family.
CC {ECO:0000305}.
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DR EMBL; MK400120; QCO93114.1; -; Genomic_DNA.
DR AlphaFoldDB; A0A4P8GF19; -.
DR SMR; A0A4P8GF19; -.
DR UniPathway; UPA00213; -.
DR GO; GO:0071949; F:FAD binding; IEA:InterPro.
DR GO; GO:0016491; F:oxidoreductase activity; IEA:UniProtKB-KW.
DR GO; GO:0044550; P:secondary metabolite biosynthetic process; IEA:UniProt.
DR GO; GO:0016114; P:terpenoid biosynthetic process; IEA:UniProtKB-UniPathway.
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; NADP; Nucleotide-binding; Oxidoreductase.
FT CHAIN 1..430
FT /note="Flavin-dependent monooxygenase eupH"
FT /id="PRO_0000449156"
FT BINDING 11..14
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:D3HKY4"
FT BINDING 33..34
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:D3HKY4"
FT BINDING 43
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:D3HKY4"
FT BINDING 107
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:D3HKY4"
FT BINDING 282
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:D3HKY4"
FT BINDING 306
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:D3HKY4"
SQ SEQUENCE 430 AA; 47161 MW; 7720064E27584D38 CRC64;
MTSLKVLIAG AGIGGPAAAF WLSRIGCEVT VVERSPRLRA TGQQVDLSGQ GIVVTRMMGI
EDDLRAVRCP ERGMRFVDHQ GVTKAFFPVD YSGKAVYSPT QEVEVMRGDL VRILYDATKT
LRGVKYVFDC HIKHFSQDDA PSGGKVHVAL SDGTQDSYDI LIGADGIASA TREMMLGTSF
PDLHRDLGVY MAYFTAPSQK DDTFDWSVCH ISGGKAIMTR RDQPENIRVY LATRVGFDVL
DAAKTLADQK AALISLFKGT QGWQVERFLN NLENSPEADD LYCQRMSQIR LPKGAWSKGR
AVLLGDAAFC PGAIGGGVGT TAALIGAYVL AGEIEKEWEG CGRKTEEFNA QNATKEYERI
VRPFITSRSD MSTWMVRLWL PESNFGVKTI QTIAGFAAGS QMSKYRGNSK PADETQKLEY
PDYFGLGPKP
