ID   VIRF_HYPVG              Reviewed;         451 AA.
AC   G9N4A7;
DT   22-APR-2020, integrated into UniProtKB/Swiss-Prot.
DT   22-FEB-2012, sequence version 1.
DT   25-MAY-2022, entry version 42.
DE   RecName: Full=FAD-linked oxidoreductase virF {ECO:0000303|PubMed:31790246};
DE            EC=1.-.-.- {ECO:0000305|PubMed:31790246};
DE   AltName: Full=Trichoxide biosynthesis protein virF {ECO:0000303|PubMed:31790246};
DE   AltName: Full=Virensol biosynthesis cluster protein F {ECO:0000303|PubMed:31790246};
DE   Flags: Fragment;
GN   Name=virF {ECO:0000303|PubMed:31790246}; ORFNames=TRIVIDRAFT_134898;
OS   Hypocrea virens (strain Gv29-8 / FGSC 10586) (Gliocladium virens)
OS   (Trichoderma virens).
OC   Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Sordariomycetes;
OC   Hypocreomycetidae; Hypocreales; Hypocreaceae; Trichoderma.
OX   NCBI_TaxID=413071;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC   STRAIN=Gv29-8 / FGSC 10586;
RX   PubMed=21501500; DOI=10.1186/gb-2011-12-4-r40;
RA   Kubicek C.P., Herrera-Estrella A., Seidl-Seiboth V., Martinez D.A.,
RA   Druzhinina I.S., Thon M., Zeilinger S., Casas-Flores S., Horwitz B.A.,
RA   Mukherjee P.K., Mukherjee M., Kredics L., Alcaraz L.D., Aerts A., Antal Z.,
RA   Atanasova L., Cervantes-Badillo M.G., Challacombe J., Chertkov O.,
RA   McCluskey K., Coulpier F., Deshpande N., von Doehren H., Ebbole D.J.,
RA   Esquivel-Naranjo E.U., Fekete E., Flipphi M., Glaser F.,
RA   Gomez-Rodriguez E.Y., Gruber S., Han C., Henrissat B., Hermosa R.,
RA   Hernandez-Onate M., Karaffa L., Kosti I., Le Crom S., Lindquist E.,
RA   Lucas S., Luebeck M., Luebeck P.S., Margeot A., Metz B., Misra M.,
RA   Nevalainen H., Omann M., Packer N., Perrone G., Uresti-Rivera E.E.,
RA   Salamov A., Schmoll M., Seiboth B., Shapiro H., Sukno S.,
RA   Tamayo-Ramos J.A., Tisch D., Wiest A., Wilkinson H.H., Zhang M.,
RA   Coutinho P.M., Kenerley C.M., Monte E., Baker S.E., Grigoriev I.V.;
RT   "Comparative genome sequence analysis underscores mycoparasitism as the
RT   ancestral life style of Trichoderma.";
RL   Genome Biol. 12:R40.1-R40.15(2011).
RN   [2]
RP   FUNCTION, AND PATHWAY.
RX   PubMed=31790246; DOI=10.1021/jacs.9b09669;
RA   Liu L., Tang M.C., Tang Y.;
RT   "Fungal highly reducing polyketide synthases biosynthesize salicylaldehydes
RT   that are precursors to epoxycyclohexenol natural products.";
RL   J. Am. Chem. Soc. 141:19538-19541(2019).
CC   -!- FUNCTION: FAD-linked oxidoreductase; part of the gene cluster that
CC       mediates the biosynthesis of virensols and trichoxide, fungal natural
CC       products that contain or are derived from a salicylaldehyde core
CC       (PubMed:31790246). The pathway begins with the synthesis of the reduced
CC       chain in virensol C by the highly reducing polyketide synthase virA via
CC       condensation of one acetate and 8 malonate units (PubMed:31790246).
CC       VirA has interesting programming rules since the first 2 ketides are
CC       fully reduced, the 3 following ketides undergo beta-dehydration, and
CC       the last 3 ketides are only reduced to beta-hydroxys to yield the
CC       trihydroxy portion (PubMed:31790246). The production of aldehyde
CC       virensol C by virA alone is surprising, since virA does not contain a
CC       reductase (R) domain that is typically associated with reductive
CC       product release in HRPKS (PubMed:31790246). The cupin-domain enzyme
CC       virC is involved in enhancing virA product turnover (PubMed:31790246).
CC       The short-chain dehydrogenase virB then oxidizes the C-7 alcohol of
CC       virensol C to a ketone, yielding virensol D (PubMed:31790246). Virensol
CC       D is further transformed to salicylaldehyde 5-deoxyaurocitrin by the
CC       short-chain dehydrogenase virD (PubMed:31790246). VirD catalyzes the
CC       dehydrogenation of C-3 to form the beta-ketone aldehyde, which is
CC       followed by the generation of the nucleophilic C-2 that is required for
CC       the intramolecular aldol condensation between C-2 and C-7, itself
CC       followed by dehydration and aromatization which leads to
CC       salicylaldehyde 5-deoxyaurocitrin (PubMed:31790246). While the
CC       dehydrogenation of virensol D is definitely catalyzed by virD, the
CC       aldol condensation and dehydration may be uncatalyzed or assisted by
CC       virD (PubMed:31790246). The short chain dehydrogenase virG then
CC       converts salicylaldehyde 5-deoxyaurocitrin into virensol B which is
CC       further hydroxylated by the cytochrome P450 monooxygenase virE to yield
CC       the hydroquinone virensol A (PubMed:31790246). VirI then may oxidize
CC       virensol A to form the quinone, while virH performs the epoxidation
CC       (PubMed:31790246). Finally, the two remaining short-chain
CC       dehydrogenases, virK and virL, are probably responsible for reducing
CC       the ketones to the corresponding alcohols to furnish the
CC       epoxycyclohexanol structure in trichoxide (PubMed:31790246).
CC       {ECO:0000269|PubMed:31790246}.
CC   -!- COFACTOR:
CC       Name=FAD; Xref=ChEBI:CHEBI:57692;
CC         Evidence={ECO:0000250|UniProtKB:Q5BEJ5};
CC   -!- PATHWAY: Secondary metabolite biosynthesis.
CC       {ECO:0000269|PubMed:31790246}.
CC   -!- SIMILARITY: Belongs to the oxygen-dependent FAD-linked oxidoreductase
CC       family. {ECO:0000305}.
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DR   EMBL; ABDF02000086; EHK18433.1; -; Genomic_DNA.
DR   RefSeq; XP_013952633.1; XM_014097158.1.
DR   AlphaFoldDB; G9N4A7; -.
DR   SMR; G9N4A7; -.
DR   STRING; 413071.G9N4A7; -.
DR   EnsemblFungi; EHK18433; EHK18433; TRIVIDRAFT_134898.
DR   GeneID; 25787655; -.
DR   VEuPathDB; FungiDB:TRIVIDRAFT_134898; -.
DR   eggNOG; ENOG502SJ3M; Eukaryota.
DR   HOGENOM; CLU_018354_0_0_1; -.
DR   InParanoid; G9N4A7; -.
DR   OMA; DTINNGM; -.
DR   OrthoDB; 350817at2759; -.
DR   Proteomes; UP000007115; Unassembled WGS sequence.
DR   GO; GO:0071949; F:FAD binding; IEA:InterPro.
DR   GO; GO:0016491; F:oxidoreductase activity; IEA:UniProtKB-KW.
DR   Gene3D; 3.30.465.10; -; 1.
DR   InterPro; IPR012951; BBE.
DR   InterPro; IPR016166; FAD-bd_PCMH.
DR   InterPro; IPR036318; FAD-bd_PCMH-like_sf.
DR   InterPro; IPR016169; FAD-bd_PCMH_sub2.
DR   InterPro; IPR006094; Oxid_FAD_bind_N.
DR   Pfam; PF08031; BBE; 1.
DR   Pfam; PF01565; FAD_binding_4; 1.
DR   SUPFAM; SSF56176; SSF56176; 1.
DR   PROSITE; PS51387; FAD_PCMH; 1.
PE   3: Inferred from homology;
KW   FAD; Flavoprotein; Oxidoreductase; Reference proteome.
FT   CHAIN           <1..>451
FT                   /note="FAD-linked oxidoreductase virF"
FT                   /id="PRO_0000449285"
FT   DOMAIN          22..196
FT                   /note="FAD-binding PCMH-type"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00718"
FT   NON_TER         1
FT                   /evidence="ECO:0000305"
FT   NON_TER         451
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   451 AA;  49676 MW;  A6B2D598EAC1E8D3 CRC64;
     SLNTTVSFPN SPAFNASTER WTIADPPTYI AAIRPGTEED IGKVINLART KRFPFLTRGA
     GHGYSASLGA FQHGLSLDLS QWKTLKIDKK AQTLTVGPGV TFAEIFDPLF KAGFYIQTGS
     CSCPSMIGVT IGGGIGRLMG KYGLLMDALQ SVRMVGAGGK VMRVSATSHP DLWWGILGAG
     ANFGVITSAT YKVHPLVNNG NVFIADFYLP VERSREYFDI VEANYSNMSA NLAQIMVASW
     NRTTSSVQLG GNWVYYGPEK EARKELAPVF NLNATSSTRI VRWSEIISSA GFDEFICQPN
     QPRSLFSLNQ KIYSADGYQA GFEKIEKYFY DHPGGRDTTL VFENFPNQAV AAIPDASTAF
     PWRDFKGFIQ INFAWTAGDD ATAQASNKLG KELRNQFATT SGYSEKAIFV NYAHGDESIE
     NIYGRRKLPR LAQLKKKYDP SNLFAYNHPL P