GLIF_ASPFU
ID GLIF_ASPFU Reviewed; 504 AA.
AC Q4WMJ0; Q5MBU6;
DT 02-NOV-2016, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2005, sequence version 1.
DT 03-AUG-2022, entry version 107.
DE RecName: Full=Cytochrome P450 monooxygenase gliF {ECO:0000303|PubMed:15979823};
DE EC=1.-.-.- {ECO:0000305|PubMed:15979823};
DE AltName: Full=Gliotoxin biosynthesis protein F {ECO:0000303|PubMed:15979823};
GN Name=gliF {ECO:0000303|PubMed:15979823}; ORFNames=AFUA_6G09730;
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 [GENOMIC DNA], AND FUNCTION.
RC STRAIN=ATCC MYA-4609 / Af293 / CBS 101355 / FGSC A1100;
RX PubMed=15979823; DOI=10.1016/j.femsle.2005.05.046;
RA Gardiner D.M., Howlett B.J.;
RT "Bioinformatic and expression analysis of the putative gliotoxin
RT biosynthetic gene cluster of Aspergillus fumigatus.";
RL FEMS Microbiol. Lett. 248:241-248(2005).
RN [2]
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 [3]
RP FUNCTION.
RX PubMed=17154540; DOI=10.1021/bi061845b;
RA Balibar C.J., Walsh C.T.;
RT "GliP, a multimodular nonribosomal peptide synthetase in Aspergillus
RT fumigatus, makes the diketopiperazine scaffold of gliotoxin.";
RL Biochemistry 45:15029-15038(2006).
RN [4]
RP FUNCTION.
RX PubMed=17601876; DOI=10.1128/ec.00141-07;
RA Sugui J.A., Pardo J., Chang Y.C., Zarember K.A., Nardone G., Galvez E.M.,
RA Mullbacher A., Gallin J.I., Simon M.M., Kwon-Chung K.J.;
RT "Gliotoxin is a virulence factor of Aspergillus fumigatus: gliP deletion
RT attenuates virulence in mice immunosuppressed with hydrocortisone.";
RL Eukaryot. Cell 6:1562-1569(2007).
RN [5]
RP FUNCTION.
RX PubMed=18199036; DOI=10.1086/525044;
RA Spikes S., Xu R., Nguyen C.K., Chamilos G., Kontoyiannis D.P.,
RA Jacobson R.H., Ejzykowicz D.E., Chiang L.Y., Filler S.G., May G.S.;
RT "Gliotoxin production in Aspergillus fumigatus contributes to host-specific
RT differences in virulence.";
RL J. Infect. Dis. 197:479-486(2008).
RN [6]
RP FUNCTION.
RX PubMed=20548963; DOI=10.1371/journal.ppat.1000952;
RA Schrettl M., Carberry S., Kavanagh K., Haas H., Jones G.W., O'Brien J.,
RA Nolan A., Stephens J., Fenelon O., Doyle S.;
RT "Self-protection against gliotoxin--a component of the gliotoxin
RT biosynthetic cluster, GliT, completely protects Aspergillus fumigatus
RT against exogenous gliotoxin.";
RL PLoS Pathog. 6:E1000952-E1000952(2010).
RN [7]
RP FUNCTION.
RX PubMed=21513890; DOI=10.1016/j.chembiol.2010.12.022;
RA Davis C., Carberry S., Schrettl M., Singh I., Stephens J.C., Barry S.M.,
RA Kavanagh K., Challis G.L., Brougham D., Doyle S.;
RT "The role of glutathione S-transferase GliG in gliotoxin biosynthesis in
RT Aspergillus fumigatus.";
RL Chem. Biol. 18:542-552(2011).
RN [8]
RP FUNCTION.
RX PubMed=21612254; DOI=10.1021/ja2029987;
RA Forseth R.R., Fox E.M., Chung D., Howlett B.J., Keller N.P.,
RA Schroeder F.C.;
RT "Identification of cryptic products of the gliotoxin gene cluster using
RT NMR-based comparative metabolomics and a model for gliotoxin
RT biosynthesis.";
RL J. Am. Chem. Soc. 133:9678-9681(2011).
RN [9]
RP FUNCTION.
RX PubMed=21749092; DOI=10.1021/ja201311d;
RA Scharf D.H., Remme N., Habel A., Chankhamjon P., Scherlach K.,
RA Heinekamp T., Hortschansky P., Brakhage A.A., Hertweck C.;
RT "A dedicated glutathione S-transferase mediates carbon-sulfur bond
RT formation in gliotoxin biosynthesis.";
RL J. Am. Chem. Soc. 133:12322-12325(2011).
RN [10]
RP FUNCTION.
RX PubMed=22936680; DOI=10.1002/anie.201205041;
RA Scharf D.H., Chankhamjon P., Scherlach K., Heinekamp T., Roth M.,
RA Brakhage A.A., Hertweck C.;
RT "Epidithiol formation by an unprecedented twin carbon-sulfur lyase in the
RT gliotoxin pathway.";
RL Angew. Chem. Int. Ed. 51:10064-10068(2012).
RN [11]
RP FUNCTION.
RX PubMed=22903976; DOI=10.1128/ec.00113-12;
RA Gallagher L., Owens R.A., Dolan S.K., O'Keeffe G., Schrettl M.,
RA Kavanagh K., Jones G.W., Doyle S.;
RT "The Aspergillus fumigatus protein GliK protects against oxidative stress
RT and is essential for gliotoxin biosynthesis.";
RL Eukaryot. Cell 11:1226-1238(2012).
RN [12]
RP FUNCTION.
RX PubMed=24039048; DOI=10.1002/anie.201305059;
RA Scharf D.H., Chankhamjon P., Scherlach K., Heinekamp T., Willing K.,
RA Brakhage A.A., Hertweck C.;
RT "Epidithiodiketopiperazine biosynthesis: a four-enzyme cascade converts
RT glutathione conjugates into transannular disulfide bridges.";
RL Angew. Chem. Int. Ed. 52:11092-11095(2013).
RN [13]
RP FUNCTION.
RX PubMed=23434416; DOI=10.1016/j.bmcl.2013.01.099;
RA Chang S.L., Chiang Y.M., Yeh H.H., Wu T.K., Wang C.C.;
RT "Reconstitution of the early steps of gliotoxin biosynthesis in Aspergillus
RT nidulans reveals the role of the monooxygenase GliC.";
RL Bioorg. Med. Chem. Lett. 23:2155-2157(2013).
RN [14]
RP FUNCTION.
RX PubMed=25062268; DOI=10.1021/ja5033106;
RA Scharf D.H., Habel A., Heinekamp T., Brakhage A.A., Hertweck C.;
RT "Opposed effects of enzymatic gliotoxin N- and S-methylations.";
RL J. Am. Chem. Soc. 136:11674-11679(2014).
RN [15]
RP FUNCTION.
RX PubMed=26150413; DOI=10.1128/ec.00055-15;
RA Owens R.A., O'Keeffe G., Smith E.B., Dolan S.K., Hammel S., Sheridan K.J.,
RA Fitzpatrick D.A., Keane T.M., Jones G.W., Doyle S.;
RT "Interplay between gliotoxin resistance, secretion, and the
RT methyl/methionine cycle in Aspergillus fumigatus.";
RL Eukaryot. Cell 14:941-957(2015).
CC -!- FUNCTION: Cytochrome P450 monooxygenase; part of the gene cluster that
CC mediates the biosynthesis of gliotoxin, a member of the
CC epipolythiodioxopiperazine (ETP) class of toxins characterized by a
CC disulfide bridged cyclic dipeptide (PubMed:15979823, PubMed:21612254).
CC The first step in gliotoxin biosynthesis is the condensation of serine
CC and phenylalanine to form the cyclo-L-phenylalanyl-L-serine
CC diketopiperazine (DKP) by the NRPS gliP (PubMed:17154540,
CC PubMed:21612254). GliP is also able to produce the DKP cyclo-L-
CC tryptophanyl-L-serine, suggesting that the substrate specificity of the
CC first adenylation (A) domain in gliP is sufficiently relaxed to
CC accommodate both L-Phe and L-Trp (PubMed:23434416). The cytochrome P450
CC monooxygenase gliC has been shown to catalyze the subsequent
CC hydroxylation of the alpha-carbon of L-Phe in cyclo-L-phenylalanyl-L-
CC serine whereas the second cytochrome P450 enzyme, gliF, is presumably
CC involved in the modification of the DKP side chain (PubMed:24039048,
CC PubMed:23434416). The glutathione S-transferase (GST) gliG then forms a
CC bis-glutathionylated biosynthetic intermediate which is responsible for
CC the sulfurization of gliotoxin (PubMed:21513890, PubMed:21749092). This
CC bis-glutathionylated intermediate is subsequently processed by the
CC gamma-glutamyl cyclotransferase gliK to remove both gamma-glutamyl
CC moieties (PubMed:22903976, PubMed:24039048). Subsequent processing via
CC gliI yields a biosynthetic intermediate, which is N-methylated via the
CC N-methyltransferase gliN, before the gliotoxin oxidoreductase gliT-
CC mediated disulfide bridge closure (PubMed:20548963, PubMed:22936680,
CC PubMed:24039048, PubMed:25062268). GliN-mediated amide methylation
CC confers stability to ETP, damping the spontaneous formation of tri- and
CC tetrasulfides (PubMed:25062268). Intracellular dithiol gliotoxin
CC oxidized by gliT is subsequently effluxed by gliA (PubMed:26150413).
CC Gliotoxin contributes to pathogenesis during invasive aspergillosis
CC (PubMed:17601876, PubMed:18199036). In macrophages and neutrophils,
CC gliotoxin showed inhibition of various different cell functions
CC including cytokine production, antigen presentation, phagocytosis, and
CC production of reactive oxygen species (PubMed:17601876).
CC {ECO:0000269|PubMed:17154540, ECO:0000269|PubMed:18199036,
CC ECO:0000269|PubMed:20548963, ECO:0000269|PubMed:21513890,
CC ECO:0000269|PubMed:21612254, ECO:0000269|PubMed:21749092,
CC ECO:0000269|PubMed:22903976, ECO:0000269|PubMed:22936680,
CC ECO:0000269|PubMed:23434416, ECO:0000269|PubMed:24039048,
CC ECO:0000269|PubMed:25062268}.
CC -!- COFACTOR:
CC Name=heme; Xref=ChEBI:CHEBI:30413;
CC Evidence={ECO:0000250|UniProtKB:P04798};
CC -!- PATHWAY: Mycotoxin biosynthesis. {ECO:0000305|PubMed:15979823}.
CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000255}; Single-pass membrane
CC protein {ECO:0000255}.
CC -!- SIMILARITY: Belongs to the cytochrome P450 family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAW03300.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305};
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DR EMBL; AY838877; AAW03300.1; ALT_SEQ; Genomic_DNA.
DR EMBL; AAHF01000006; EAL88824.1; -; Genomic_DNA.
DR RefSeq; XP_750862.1; XM_745769.1.
DR AlphaFoldDB; Q4WMJ0; -.
DR SMR; Q4WMJ0; -.
DR STRING; 746128.CADAFUBP00007382; -.
DR EnsemblFungi; EAL88824; EAL88824; AFUA_6G09730.
DR GeneID; 3508167; -.
DR KEGG; afm:AFUA_6G09730; -.
DR VEuPathDB; FungiDB:Afu6g09730; -.
DR eggNOG; KOG0156; Eukaryota.
DR HOGENOM; CLU_022195_0_2_1; -.
DR InParanoid; Q4WMJ0; -.
DR OMA; GEYSYMG; -.
DR OrthoDB; 574756at2759; -.
DR Proteomes; UP000002530; Chromosome 6.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0020037; F:heme binding; IEA:InterPro.
DR GO; GO:0005506; F:iron ion binding; IEA:InterPro.
DR GO; GO:0004497; F:monooxygenase activity; IEA:UniProtKB-KW.
DR GO; GO:0016705; F:oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen; IEA:InterPro.
DR GO; GO:0043386; P:mycotoxin biosynthetic process; IEP:AspGD.
DR Gene3D; 1.10.630.10; -; 1.
DR InterPro; IPR001128; Cyt_P450.
DR InterPro; IPR002403; Cyt_P450_E_grp-IV.
DR InterPro; IPR036396; Cyt_P450_sf.
DR Pfam; PF00067; p450; 1.
DR PRINTS; PR00465; EP450IV.
DR SUPFAM; SSF48264; SSF48264; 1.
PE 3: Inferred from homology;
KW Glycoprotein; Heme; Iron; Membrane; Metal-binding; Monooxygenase;
KW Oxidoreductase; Reference proteome; Transmembrane; Transmembrane helix;
KW Virulence.
FT CHAIN 1..504
FT /note="Cytochrome P450 monooxygenase gliF"
FT /id="PRO_0000437705"
FT TRANSMEM 13..31
FT /note="Helical"
FT /evidence="ECO:0000255"
FT BINDING 449
FT /ligand="heme"
FT /ligand_id="ChEBI:CHEBI:30413"
FT /ligand_part="Fe"
FT /ligand_part_id="ChEBI:CHEBI:18248"
FT /note="axial binding residue"
FT /evidence="ECO:0000250|UniProtKB:P04798"
FT CARBOHYD 197
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 299
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
SQ SEQUENCE 504 AA; 56513 MW; 73E99F869A4BDA50 CRC64;
MDQVYLPQSV RTAVAVSFGV GLLYWVYRLL LQKTKSLKAL DLPVLQSVGD QDIVKTLEEG
HAKYPDTPFA LGVPGQQLVV LPVSEIDTVK ALPENQLSIK KHHYNQFLGE YSYMGTKADE
FDDAMRYLLV RNTPAVLASF TAEIDYAMST VLQVPPNSWT RVKPRSIMPK VATILSGRAF
VGLPLSREPD WIESNVNYTQ DVSRAWMVLR FYPHWIRPLV APFLREVKTL EQNKALIGRK
IAKLLADQEA QKLSPAQEKI PGGDMIDWFK SRYQAQGKTA TAQQLTRDQL LATFASIYNL
SNALTYVMFD LAANPAAVDE LREELDQVLG PNVGAESIDK TALPRLIKLD SFVRESQRLS
PTSLVNIPRI VTDPNGLRLK TGHVIPPGYL VMVRAQPINQ SPTLYPNPER FDAFRFARLR
QQGGANENRW QHTSTGADNI NFGHGIWACP GRFFASAEIK VVVAYVIRHY DLRLIEGRPH
PKPKYGGLAI FPDAGAEVEL KPRV
