ID   AFOD_EMENI              Reviewed;         440 AA.
AC   Q5BEJ7; C8VTY0;
DT   08-JUN-2016, integrated into UniProtKB/Swiss-Prot.
DT   26-APR-2005, sequence version 1.
DT   03-AUG-2022, entry version 105.
DE   RecName: Full=FAD-dependent monooxygenase afoD {ECO:0000305};
DE            EC=1.-.-.- {ECO:0000305|PubMed:19199437};
DE   AltName: Full=Asperfuranone biosynthesis protein D {ECO:0000303|PubMed:19199437};
GN   Name=afoD {ECO:0000303|PubMed:19199437}; ORFNames=AN1033;
OS   Emericella nidulans (strain FGSC A4 / ATCC 38163 / CBS 112.46 / NRRL 194 /
OS   M139) (Aspergillus nidulans).
OC   Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC   Eurotiomycetidae; Eurotiales; Aspergillaceae; Aspergillus;
OC   Aspergillus subgen. Nidulantes.
OX   NCBI_TaxID=227321;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC   STRAIN=FGSC A4 / ATCC 38163 / CBS 112.46 / NRRL 194 / M139;
RX   PubMed=16372000; DOI=10.1038/nature04341;
RA   Galagan J.E., Calvo S.E., Cuomo C., Ma L.-J., Wortman J.R., Batzoglou S.,
RA   Lee S.-I., Bastuerkmen M., Spevak C.C., Clutterbuck J., Kapitonov V.,
RA   Jurka J., Scazzocchio C., Farman M.L., Butler J., Purcell S., Harris S.,
RA   Braus G.H., Draht O., Busch S., D'Enfert C., Bouchier C., Goldman G.H.,
RA   Bell-Pedersen D., Griffiths-Jones S., Doonan J.H., Yu J., Vienken K.,
RA   Pain A., Freitag M., Selker E.U., Archer D.B., Penalva M.A., Oakley B.R.,
RA   Momany M., Tanaka T., Kumagai T., Asai K., Machida M., Nierman W.C.,
RA   Denning D.W., Caddick M.X., Hynes M., Paoletti M., Fischer R., Miller B.L.,
RA   Dyer P.S., Sachs M.S., Osmani S.A., Birren B.W.;
RT   "Sequencing of Aspergillus nidulans and comparative analysis with A.
RT   fumigatus and A. oryzae.";
RL   Nature 438:1105-1115(2005).
RN   [2]
RP   GENOME REANNOTATION.
RC   STRAIN=FGSC A4 / ATCC 38163 / CBS 112.46 / NRRL 194 / M139;
RX   PubMed=19146970; DOI=10.1016/j.fgb.2008.12.003;
RA   Wortman J.R., Gilsenan J.M., Joardar V., Deegan J., Clutterbuck J.,
RA   Andersen M.R., Archer D., Bencina M., Braus G., Coutinho P., von Dohren H.,
RA   Doonan J., Driessen A.J., Durek P., Espeso E., Fekete E., Flipphi M.,
RA   Estrada C.G., Geysens S., Goldman G., de Groot P.W., Hansen K.,
RA   Harris S.D., Heinekamp T., Helmstaedt K., Henrissat B., Hofmann G.,
RA   Homan T., Horio T., Horiuchi H., James S., Jones M., Karaffa L.,
RA   Karanyi Z., Kato M., Keller N., Kelly D.E., Kiel J.A., Kim J.M.,
RA   van der Klei I.J., Klis F.M., Kovalchuk A., Krasevec N., Kubicek C.P.,
RA   Liu B., Maccabe A., Meyer V., Mirabito P., Miskei M., Mos M., Mullins J.,
RA   Nelson D.R., Nielsen J., Oakley B.R., Osmani S.A., Pakula T., Paszewski A.,
RA   Paulsen I., Pilsyk S., Pocsi I., Punt P.J., Ram A.F., Ren Q., Robellet X.,
RA   Robson G., Seiboth B., van Solingen P., Specht T., Sun J.,
RA   Taheri-Talesh N., Takeshita N., Ussery D., vanKuyk P.A., Visser H.,
RA   van de Vondervoort P.J., de Vries R.P., Walton J., Xiang X., Xiong Y.,
RA   Zeng A.P., Brandt B.W., Cornell M.J., van den Hondel C.A., Visser J.,
RA   Oliver S.G., Turner G.;
RT   "The 2008 update of the Aspergillus nidulans genome annotation: a community
RT   effort.";
RL   Fungal Genet. Biol. 46:S2-13(2009).
RN   [3]
RP   FUNCTION, AND DISRUPTION PHENOTYPE.
RX   PubMed=19199437; DOI=10.1021/ja8088185;
RA   Chiang Y.M., Szewczyk E., Davidson A.D., Keller N., Oakley B.R., Wang C.C.;
RT   "A gene cluster containing two fungal polyketide synthases encodes the
RT   biosynthetic pathway for a polyketide, asperfuranone, in Aspergillus
RT   nidulans.";
RL   J. Am. Chem. Soc. 131:2965-2970(2009).
RN   [4]
RP   BIOTECHNOLOGY.
RX   PubMed=20148857; DOI=10.1111/j.1742-7843.2010.00545.x;
RA   Wang C.C., Chiang Y.M., Praseuth M.B., Kuo P.L., Liang H.L., Hsu Y.L.;
RT   "Asperfuranone from Aspergillus nidulans inhibits proliferation of human
RT   non-small cell lung cancer A549 cells via blocking cell cycle progression
RT   and inducing apoptosis.";
RL   Basic Clin. Pharmacol. Toxicol. 107:583-589(2010).
CC   -!- FUNCTION: FAD-dependent monooxygenase; part of the gene cluster that
CC       mediates the biosynthesis of asperfuranone, a probable antitumor agent
CC       (PubMed:19199437). The polyketide synthase afoG is responsible for
CC       producing the 3,5-dimethyloctadienone moiety from acetyl-CoA, three
CC       malonyl-CoA, and two S-adenosyl methionines (SAM) (PubMed:19199437).
CC       The 3,5-dimethyloctadienone moiety is then loaded onto the SAT domain
CC       of afoE and extended with four malonyl-CoA and one SAM, which leads to
CC       the formation of 2,4-dihydroxy-6-(5,7-dimethyl-2-oxo-trans-3-trans-5-
CC       nonadienyl)-3-methylbenzaldehyde (compound 2) after reductive release
CC       and aldol condensation (PubMed:19199437). AfoD is the next enzyme in
CC       the biosynthesis sequence and hydroxylates the side chain at the
CC       benzylic position of compound 2 (PubMed:19199437). After benzylic
CC       hydroxylation, a furan ring is formed after five-member ring hemiacetal
CC       formation and water elimination (PubMed:19199437). AfoF and afoC are
CC       proposed to oxidize the R-diketone proton and to reduce the
CC       unconjugated carbonyl group, respectively, to generate asperfuranone
CC       (PubMed:19199437). Since no intermediates could be isolated from afoF
CC       and afoC deletants, the sequence of these two enzymes is not fully
CC       understood (PubMed:19199437). Moreover, since afoC deletant still
CC       produces a small amount of asperfuranone, other endogenous
CC       oxidoreductases might catalyze the same reaction with much less
CC       efficiency (PubMed:19199437). {ECO:0000269|PubMed:19199437}.
CC   -!- COFACTOR:
CC       Name=FAD; Xref=ChEBI:CHEBI:57692; Evidence={ECO:0000305};
CC   -!- SUBCELLULAR LOCATION: Membrane {ECO:0000255}; Single-pass membrane
CC       protein {ECO:0000255}.
CC   -!- INDUCTION: Expression is regulated by the asperfuranone cluster
CC       transcription factor afoA (PubMed:19199437).
CC       {ECO:0000269|PubMed:19199437}.
CC   -!- DISRUPTION PHENOTYPE: Completely abolishes the production of
CC       asperfuranone (PubMed:19199437). Produces a large amount of
CC       intermediates including 2,4-dihydroxy-6-(5,7-dimethyl-2-oxo-trans-3-
CC       trans-5-nonadienyl)-3-methylbenzaldehyde (PubMed:19199437).
CC       {ECO:0000269|PubMed:19199437}.
CC   -!- BIOTECHNOLOGY: Asperfuranone provides anti-proliferative activity in
CC       human non-small cell lung cancer cells (PubMed:20148857).
CC       {ECO:0000269|PubMed:20148857}.
CC   -!- SIMILARITY: Belongs to the paxM FAD-dependent monooxygenase family.
CC       {ECO:0000305}.
CC   ---------------------------------------------------------------------------
CC   Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC   Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC   ---------------------------------------------------------------------------
DR   EMBL; BN001308; CBF88297.1; -; Genomic_DNA.
DR   EMBL; AACD01000015; EAA65601.1; -; Genomic_DNA.
DR   RefSeq; XP_658637.1; XM_653545.1.
DR   AlphaFoldDB; Q5BEJ7; -.
DR   SMR; Q5BEJ7; -.
DR   STRING; 162425.CADANIAP00001614; -.
DR   PRIDE; Q5BEJ7; -.
DR   EnsemblFungi; CBF88297; CBF88297; ANIA_01033.
DR   EnsemblFungi; EAA65601; EAA65601; AN1033.2.
DR   GeneID; 2876813; -.
DR   KEGG; ani:AN1033.2; -.
DR   VEuPathDB; FungiDB:AN1033; -.
DR   eggNOG; KOG2614; Eukaryota.
DR   HOGENOM; CLU_009665_6_3_1; -.
DR   InParanoid; Q5BEJ7; -.
DR   OMA; WSCLRSH; -.
DR   OrthoDB; 521070at2759; -.
DR   Proteomes; UP000000560; Chromosome VIII.
DR   Proteomes; UP000005890; Unassembled WGS sequence.
DR   GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR   GO; GO:0071949; F:FAD binding; IEA:InterPro.
DR   GO; GO:0004497; F:monooxygenase activity; IEA:UniProtKB-KW.
DR   GO; GO:1900554; P:asperfuranone biosynthetic process; IMP:AspGD.
DR   GO; GO:0044550; P:secondary metabolite biosynthetic process; IBA:GO_Central.
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; Glycoprotein; Membrane; Monooxygenase; Oxidoreductase;
KW   Reference proteome; Transmembrane; Transmembrane helix.
FT   CHAIN           1..440
FT                   /note="FAD-dependent monooxygenase afoD"
FT                   /id="PRO_0000436372"
FT   TRANSMEM        10..30
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   BINDING         41..42
FT                   /ligand="FAD"
FT                   /ligand_id="ChEBI:CHEBI:57692"
FT                   /evidence="ECO:0000250|UniProtKB:A6T923"
FT   BINDING         245..247
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250|UniProtKB:A6T923"
FT   BINDING         320
FT                   /ligand="FAD"
FT                   /ligand_id="ChEBI:CHEBI:57692"
FT                   /evidence="ECO:0000250|UniProtKB:A6T923"
FT   BINDING         330..334
FT                   /ligand="FAD"
FT                   /ligand_id="ChEBI:CHEBI:57692"
FT                   /evidence="ECO:0000250|UniProtKB:A6T923"
FT   CARBOHYD        352
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
SQ   SEQUENCE   440 AA;  49022 MW;  F1DB03E30B52E604 CRC64;
     MADHEQEQEP LSIAIIGGGI IGLMTALGLL HRNIGKVTIY ERASAWPDIG AAFAFTGIAR
     ECMQRLDPAI LSALSKVAQR NPHDKVRYWD GFHPKSKEEA QDPEKSVLFE IEEKNMAYWA
     CLRGVFHAEM ARLLPERVVR FGKRLVAYED GGDQKVVLRF EDGEVEEADI VIACDGVHST
     ARRVLLGAEH PAANARYSRK AVYRALVPMP AAIDALGTEK AHVQIAHCGP DAHIVSFPVN
     NAQIYNVFLF THDSNEWTHG HTMTVPSSKE EILSAVENWG PHIKELASLF PEQLSKYAIF
     DQADHPLPYY AAGRVALAGD AAHASSPFHG AGACMGVEDA LVLAELLEKV QNGSAFKEKK
     SNIELALKTY SDVRIERSQW LVKSSREMGD LYEWRYEDIG GDGVKCKAEW ERRSRVIWDF
     DVQGMVDQAR EAYERAVVKV