FTMF_ASPFU
ID FTMF_ASPFU Reviewed; 291 AA.
AC Q4WAW9;
DT 16-OCT-2013, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2005, sequence version 1.
DT 03-AUG-2022, entry version 91.
DE RecName: Full=Verruculogen synthase {ECO:0000303|PubMed:19763315};
DE EC=1.14.11.38 {ECO:0000269|PubMed:19763315, ECO:0000269|PubMed:31117657};
DE AltName: Full=Fumitremorgin biosynthesis protein F {ECO:0000303|PubMed:23649274};
GN Name=ftmOx1 {ECO:0000303|PubMed:19763315};
GN Synonyms=ftmF {ECO:0000303|PubMed:23649274}; ORFNames=AFUA_8G00230;
OS Neosartorya fumigata (strain ATCC MYA-4609 / Af293 / CBS 101355 / FGSC
OS A1100) (Aspergillus fumigatus).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Aspergillus;
OC Aspergillus subgen. Fumigati.
OX NCBI_TaxID=330879;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=ATCC MYA-4609 / Af293 / CBS 101355 / FGSC A1100;
RX PubMed=16372009; DOI=10.1038/nature04332;
RA Nierman W.C., Pain A., Anderson M.J., Wortman J.R., Kim H.S., Arroyo J.,
RA Berriman M., Abe K., Archer D.B., Bermejo C., Bennett J.W., Bowyer P.,
RA Chen D., Collins M., Coulsen R., Davies R., Dyer P.S., Farman M.L.,
RA Fedorova N., Fedorova N.D., Feldblyum T.V., Fischer R., Fosker N.,
RA Fraser A., Garcia J.L., Garcia M.J., Goble A., Goldman G.H., Gomi K.,
RA Griffith-Jones S., Gwilliam R., Haas B.J., Haas H., Harris D.E.,
RA Horiuchi H., Huang J., Humphray S., Jimenez J., Keller N., Khouri H.,
RA Kitamoto K., Kobayashi T., Konzack S., Kulkarni R., Kumagai T., Lafton A.,
RA Latge J.-P., Li W., Lord A., Lu C., Majoros W.H., May G.S., Miller B.L.,
RA Mohamoud Y., Molina M., Monod M., Mouyna I., Mulligan S., Murphy L.D.,
RA O'Neil S., Paulsen I., Penalva M.A., Pertea M., Price C., Pritchard B.L.,
RA Quail M.A., Rabbinowitsch E., Rawlins N., Rajandream M.A., Reichard U.,
RA Renauld H., Robson G.D., Rodriguez de Cordoba S., Rodriguez-Pena J.M.,
RA Ronning C.M., Rutter S., Salzberg S.L., Sanchez M., Sanchez-Ferrero J.C.,
RA Saunders D., Seeger K., Squares R., Squares S., Takeuchi M., Tekaia F.,
RA Turner G., Vazquez de Aldana C.R., Weidman J., White O., Woodward J.R.,
RA Yu J.-H., Fraser C.M., Galagan J.E., Asai K., Machida M., Hall N.,
RA Barrell B.G., Denning D.W.;
RT "Genomic sequence of the pathogenic and allergenic filamentous fungus
RT Aspergillus fumigatus.";
RL Nature 438:1151-1156(2005).
RN [2]
RP FUNCTION.
RX PubMed=16000710; DOI=10.1099/mic.0.27962-0;
RA Grundmann A., Li S.M.;
RT "Overproduction, purification and characterization of FtmPT1, a
RT brevianamide F prenyltransferase from Aspergillus fumigatus.";
RL Microbiology 151:2199-2207(2005).
RN [3]
RP FUNCTION.
RX PubMed=16755625; DOI=10.1002/cbic.200600003;
RA Maiya S., Grundmann A., Li S.M., Turner G.;
RT "The fumitremorgin gene cluster of Aspergillus fumigatus: identification of
RT a gene encoding brevianamide F synthetase.";
RL ChemBioChem 7:1062-1069(2006).
RN [4]
RP FUNCTION.
RX PubMed=18683158; DOI=10.1002/cbic.200800240;
RA Grundmann A., Kuznetsova T., Afiyatullov S.S., Li S.M.;
RT "FtmPT2, an N-prenyltransferase from Aspergillus fumigatus, catalyses the
RT last step in the biosynthesis of fumitremorgin B.";
RL ChemBioChem 9:2059-2063(2008).
RN [5]
RP FUNCTION.
RX PubMed=19226505; DOI=10.1002/cbic.200800787;
RA Kato N., Suzuki H., Takagi H., Asami Y., Kakeya H., Uramoto M., Usui T.,
RA Takahashi S., Sugimoto Y., Osada H.;
RT "Identification of cytochrome P450s required for fumitremorgin biosynthesis
RT in Aspergillus fumigatus.";
RL ChemBioChem 10:920-928(2009).
RN [6]
RP FUNCTION, CATALYTIC ACTIVITY, COFACTOR, SUBUNIT, AND PATHWAY.
RX PubMed=19763315; DOI=10.1039/b908392h;
RA Steffan N., Grundmann A., Afiyatullov S., Ruan H., Li S.M.;
RT "FtmOx1, a non-heme Fe(II) and alpha-ketoglutarate-dependent dioxygenase,
RT catalyses the endoperoxide formation of verruculogen in Aspergillus
RT fumigatus.";
RL Org. Biomol. Chem. 7:4082-4087(2009).
RN [7]
RP FUNCTION.
RX PubMed=21105662; DOI=10.1021/ja106817c;
RA Jost M., Zocher G., Tarcz S., Matuschek M., Xie X., Li S.M., Stehle T.;
RT "Structure-function analysis of an enzymatic prenyl transfer reaction
RT identifies a reaction chamber with modifiable specificity.";
RL J. Am. Chem. Soc. 132:17849-17858(2010).
RN [8]
RP FUNCTION.
RX PubMed=23090579; DOI=10.1039/c2ob26149a;
RA Wollinsky B., Ludwig L., Xie X., Li S.M.;
RT "Breaking the regioselectivity of indole prenyltransferases: identification
RT of regular C3-prenylated hexahydropyrrolo[2,3-b]indoles as side products of
RT the regular C2-prenyltransferase FtmPT1.";
RL Org. Biomol. Chem. 10:9262-9270(2012).
RN [9]
RP FUNCTION, AND PATHWAY.
RC STRAIN=ATCC MYA-4609 / Af293 / CBS 101355 / FGSC A1100;
RX PubMed=23649274; DOI=10.1271/bbb.130026;
RA Kato N., Suzuki H., Okumura H., Takahashi S., Osada H.;
RT "A point mutation in ftmD blocks the fumitremorgin biosynthetic pathway in
RT Aspergillus fumigatus strain Af293.";
RL Biosci. Biotechnol. Biochem. 77:1061-1067(2013).
RN [10]
RP RETRACTED PAPER.
RX PubMed=26524521; DOI=10.1038/nature15519;
RA Yan W., Song H., Song F., Guo Y., Wu C.H., Her A.S., Pu Y., Wang S.,
RA Naowarojna N., Weitz A., Hendrich M.P., Costello C.E., Zhang L., Liu P.,
RA Zhang Y.J.;
RT "Endoperoxide formation by an alpha-ketoglutarate-dependent mononuclear
RT non-haem iron enzyme.";
RL Nature 527:539-543(2015).
RN [11] {ECO:0007744|PDB:6OXH, ECO:0007744|PDB:6OXJ}
RP X-RAY CRYSTALLOGRAPHY (1.55 ANGSTROMS), FUNCTION, CATALYTIC ACTIVITY,
RP ACTIVE SITE, MUTAGENESIS OF TYR-68, AND PATHWAY.
RX PubMed=31117657; DOI=10.1021/jacs.9b03567;
RA Dunham N.P., Del Rio Pantoja J.M., Zhang B., Rajakovich L.J., Allen B.D.,
RA Krebs C., Boal A.K., Bollinger J.M. Jr.;
RT "Hydrogen Donation but not Abstraction by a Tyrosine (Y68) during
RT Endoperoxide Installation by Verruculogen Synthase (FtmOx1).";
RL J. Am. Chem. Soc. 141:9964-9979(2019).
CC -!- FUNCTION: Verruculogen synthase; part of the gene cluster that mediates
CC the biosynthesis of fumitremorgins, indole alkaloids that carry not
CC only intriguing chemical structures, but also interesting biological
CC and pharmacological activities (PubMed:19763315, PubMed:23649274,
CC PubMed:31117657). The biosynthesis of fumitremorgin-type alkaloids
CC begins by condensation of the two amino acids L-tryptophan and L-
CC proline to brevianamide F, catalyzed by the non-ribosomal peptide
CC synthetase ftmA (PubMed:16755625). Brevianamide F is then prenylated by
CC the prenyltransferase ftmPT1/ftmB in the presence of dimethylallyl
CC diphosphate, resulting in the formation of tryprostatin B
CC (PubMed:16000710, PubMed:21105662, PubMed:23090579). The three
CC cytochrome P450 monooxygenases, ftmP450-1/ftmC, ftmP450-2/ftmE and
CC ftmP450-3/FtmG, are responsible for the conversion of tryprostatin B to
CC 6-hydroxytryprostatin B, tryprostatin A to fumitremorgin C and
CC fumitremorgin C to 12,13-dihydroxyfumitremorgin C, respectively
CC (PubMed:19226505). The putative methyltransferase ftmMT/ftmD is
CC expected for the conversion of 6-hydroxytryprostatin B to tryprostatin
CC A (Probable). FtmPT2/FtmH catalyzes the prenylation of 12,13-
CC dihydroxyfumitre-morgin C in the presence of dimethylallyl diphosphate,
CC resulting in the formation of fumitremorgin B (PubMed:18683158).
CC Fumitremorgin B is further converted to verruculogen by ftmOx1/ftmF via
CC the insertion of an endoperoxide bond between the two prenyl moieties
CC (PubMed:19763315, PubMed:31117657). In some fungal species,
CC verruculogen is further converted to fumitremorgin A, but the enzymes
CC involved in this step have not been identified yet (Probable).
CC {ECO:0000269|PubMed:16000710, ECO:0000269|PubMed:16755625,
CC ECO:0000269|PubMed:18683158, ECO:0000269|PubMed:19226505,
CC ECO:0000269|PubMed:19763315, ECO:0000269|PubMed:21105662,
CC ECO:0000269|PubMed:23090579, ECO:0000269|PubMed:23649274,
CC ECO:0000269|PubMed:31117657, ECO:0000305, ECO:0000305|PubMed:16000710}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=2-oxoglutarate + AH2 + fumitremorgin B + 2 O2 = A + CO2 + H2O
CC + succinate + verruculogen; Xref=Rhea:RHEA:35975, ChEBI:CHEBI:13193,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15379, ChEBI:CHEBI:16526,
CC ChEBI:CHEBI:16810, ChEBI:CHEBI:17499, ChEBI:CHEBI:30031,
CC ChEBI:CHEBI:64531, ChEBI:CHEBI:72765; EC=1.14.11.38;
CC Evidence={ECO:0000269|PubMed:19763315, ECO:0000269|PubMed:31117657};
CC -!- COFACTOR:
CC Name=Fe cation; Xref=ChEBI:CHEBI:24875;
CC Evidence={ECO:0000269|PubMed:19763315};
CC -!- PATHWAY: Mycotoxin biosynthesis. {ECO:0000269|PubMed:19763315,
CC ECO:0000269|PubMed:23649274, ECO:0000269|PubMed:31117657}.
CC -!- SUBUNIT: Homodimer. {ECO:0000269|PubMed:19763315}.
CC -!- INTERACTION:
CC Q4WAW9; Q4WAW9: ftmOx1; NbExp=3; IntAct=EBI-16183015, EBI-16183015;
CC -!- SIMILARITY: Belongs to the PhyH family. {ECO:0000305}.
CC -!- CAUTION: Despite the presence of this enzyme, this enzyme may not be
CC involved in verruculogen synthesis in vivo. In contrast to other
CC A.fumigatus strains, strain ATCC MYA-4609 does not produce indole
CC alkaloids such as fumitremorgins and verruculogen. While the
CC biosynthetic pathway is complete, a variation in the O-
CC methyltransferase FtmD (AC Q4WAW6) abolishes production of the
CC tryprostatin A intermediate (PubMed:23649274).
CC {ECO:0000305|PubMed:23649274}.
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DR EMBL; AAHF01000014; EAL85143.1; -; Genomic_DNA.
DR RefSeq; XP_747181.1; XM_742088.1.
DR PDB; 4Y5S; X-ray; 2.54 A; A/B=2-291.
DR PDB; 4Y5T; X-ray; 1.95 A; A/B=2-291.
DR PDB; 6OXH; X-ray; 1.92 A; A/B=1-291.
DR PDB; 6OXJ; X-ray; 1.55 A; A/B=1-291.
DR PDB; 7DE0; X-ray; 2.40 A; A/B/C/D=1-291.
DR PDB; 7ETK; X-ray; 1.22 A; A/B=1-291.
DR PDB; 7ETL; X-ray; 1.99 A; A/B=1-291.
DR PDBsum; 4Y5S; -.
DR PDBsum; 4Y5T; -.
DR PDBsum; 6OXH; -.
DR PDBsum; 6OXJ; -.
DR PDBsum; 7DE0; -.
DR PDBsum; 7ETK; -.
DR PDBsum; 7ETL; -.
DR AlphaFoldDB; Q4WAW9; -.
DR SMR; Q4WAW9; -.
DR DIP; DIP-61797N; -.
DR STRING; 746128.CADAFUBP00008409; -.
DR EnsemblFungi; EAL85143; EAL85143; AFUA_8G00230.
DR GeneID; 3504528; -.
DR KEGG; afm:AFUA_8G00230; -.
DR VEuPathDB; FungiDB:Afu8g00230; -.
DR eggNOG; ENOG502S7ZW; Eukaryota.
DR HOGENOM; CLU_047725_1_0_1; -.
DR InParanoid; Q4WAW9; -.
DR OMA; VIHAICE; -.
DR OrthoDB; 623398at2759; -.
DR BioCyc; MetaCyc:MON-18769; -.
DR Proteomes; UP000002530; Chromosome 8.
DR GO; GO:0051213; F:dioxygenase activity; IDA:AspGD.
DR GO; GO:1902181; P:verruculogen biosynthetic process; IDA:AspGD.
DR InterPro; IPR008775; Phytyl_CoA_dOase.
DR Pfam; PF05721; PhyH; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Dioxygenase; Iron; Oxidoreductase; Reference proteome;
KW Virulence.
FT CHAIN 1..291
FT /note="Verruculogen synthase"
FT /id="PRO_0000424133"
FT ACT_SITE 68
FT /evidence="ECO:0000269|PubMed:31117657,
FT ECO:0007744|PDB:6OXJ"
FT MUTAGEN 68
FT /note="Y->F: Affects the catalytic activity."
FT /evidence="ECO:0000269|PubMed:31117657"
FT STRAND 11..13
FT /evidence="ECO:0007829|PDB:7ETK"
FT HELIX 18..27
FT /evidence="ECO:0007829|PDB:7ETK"
FT STRAND 29..35
FT /evidence="ECO:0007829|PDB:7ETK"
FT HELIX 39..53
FT /evidence="ECO:0007829|PDB:7ETK"
FT HELIX 65..67
FT /evidence="ECO:0007829|PDB:7ETK"
FT STRAND 70..75
FT /evidence="ECO:0007829|PDB:7ETK"
FT HELIX 78..81
FT /evidence="ECO:0007829|PDB:7ETK"
FT HELIX 83..87
FT /evidence="ECO:0007829|PDB:7ETK"
FT HELIX 89..91
FT /evidence="ECO:0007829|PDB:7ETK"
FT HELIX 93..102
FT /evidence="ECO:0007829|PDB:7ETK"
FT TURN 103..106
FT /evidence="ECO:0007829|PDB:7ETK"
FT STRAND 109..119
FT /evidence="ECO:0007829|PDB:7ETK"
FT HELIX 131..134
FT /evidence="ECO:0007829|PDB:7ETK"
FT HELIX 136..140
FT /evidence="ECO:0007829|PDB:7ETK"
FT STRAND 149..157
FT /evidence="ECO:0007829|PDB:7ETK"
FT TURN 161..164
FT /evidence="ECO:0007829|PDB:7ETK"
FT STRAND 166..168
FT /evidence="ECO:0007829|PDB:6OXJ"
FT HELIX 172..174
FT /evidence="ECO:0007829|PDB:7ETK"
FT STRAND 175..177
FT /evidence="ECO:0007829|PDB:6OXJ"
FT HELIX 183..185
FT /evidence="ECO:0007829|PDB:7ETK"
FT STRAND 187..189
FT /evidence="ECO:0007829|PDB:6OXJ"
FT STRAND 196..200
FT /evidence="ECO:0007829|PDB:7ETK"
FT STRAND 213..215
FT /evidence="ECO:0007829|PDB:7ETK"
FT STRAND 218..227
FT /evidence="ECO:0007829|PDB:7ETK"
FT HELIX 241..245
FT /evidence="ECO:0007829|PDB:7ETK"
FT HELIX 249..254
FT /evidence="ECO:0007829|PDB:7ETK"
FT STRAND 270..273
FT /evidence="ECO:0007829|PDB:7ETK"
FT HELIX 278..281
FT /evidence="ECO:0007829|PDB:7ETK"
FT TURN 287..291
FT /evidence="ECO:0007829|PDB:4Y5T"
SQ SEQUENCE 291 AA; 32667 MW; 7E4E41ABFA1525FD CRC64;
MTVDSKPQLQ RLAADADVDR MCRLLEEDGA FILKGLLPFD VVESFNRELD VQMAIPPPKG
ERLLADKYPP HFKYVPNVAT TCPTFRNTVL INPVIHAICE AYFQRTGDYW LSAAFLREIE
SGMPAQPFHR DDATHPLMHY QPLEAPPVSL SVIFPLTEFT EENGATEVIL GSHRWTEVGT
PERDQAVLAT MDPGDVLIVR QRVVHAGGGN RTTAGKPRRV VLAYFNSVQL TPFETYRTMP
REMVESMTVL GQRMLGWRTM KPSDPNIVGI NLIDDKRLEN VLQLKAADSP A
