GLIT_ASPFU
ID GLIT_ASPFU Reviewed; 334 AA.
AC E9RAH5; Q4WMI9; Q5MBU7;
DT 02-NOV-2016, integrated into UniProtKB/Swiss-Prot.
DT 05-APR-2011, sequence version 1.
DT 03-AUG-2022, entry version 57.
DE RecName: Full=Thioredoxin reductase gliT {ECO:0000303|PubMed:15979823};
DE EC=1.8.1.- {ECO:0000269|PubMed:20548963};
DE AltName: Full=Gliotoxin biosynthesis protein T {ECO:0000303|PubMed:15979823};
GN Name=gliT {ECO:0000303|PubMed:15979823}; ORFNames=AFUA_6G09740;
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, CATALYTIC ACTIVITY, DISRUPTION PHENOTYPE, AND INDUCTION.
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 [5]
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 [6]
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 [7]
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 [8]
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 [9]
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 [10]
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 [11]
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 [12]
RP INDUCTION.
RX PubMed=23671611; DOI=10.1371/journal.pone.0062591;
RA Sekonyela R., Palmer J.M., Bok J.W., Jain S., Berthier E., Forseth R.,
RA Schroeder F., Keller N.P.;
RT "RsmA regulates Aspergillus fumigatus gliotoxin cluster metabolites
RT including cyclo(L-Phe-L-Ser), a potential new diagnostic marker for
RT invasive aspergillosis.";
RL PLoS ONE 8:E62591-E62591(2013).
RN [13]
RP DISRUPTION PHENOTYPE.
RX PubMed=25311525; DOI=10.1186/1471-2164-15-894;
RA O'Keeffe G., Hammel S., Owens R.A., Keane T.M., Fitzpatrick D.A.,
RA Jones G.W., Doyle S.;
RT "RNA-seq reveals the pan-transcriptomic impact of attenuating the gliotoxin
RT self-protection mechanism in Aspergillus fumigatus.";
RL BMC Genomics 15:894-894(2014).
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 INDUCTION.
RX PubMed=26032501; DOI=10.1016/j.bbrc.2015.05.090;
RA Shin K.S., Kim Y.H., Yu J.H.;
RT "Proteomic analyses reveal the key roles of BrlA and AbaA in biogenesis of
RT gliotoxin in Aspergillus fumigatus.";
RL Biochem. Biophys. Res. Commun. 463:428-433(2015).
RN [16]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
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).
RN [17]
RP X-RAY CRYSTALLOGRAPHY (1.90 ANGSTROMS) IN COMPLEX WITH FAD, SUBUNIT,
RP COFACTOR, AND DISULFIDE BOND.
RX PubMed=24446392; DOI=10.1002/anie.201309302;
RA Scharf D.H., Groll M., Habel A., Heinekamp T., Hertweck C., Brakhage A.A.,
RA Huber E.M.;
RT "Flavoenzyme-catalyzed formation of disulfide bonds in natural products.";
RL Angew. Chem. Int. Ed. 53:2221-2224(2014).
CC -!- FUNCTION: Thioredoxin reductase; part of the gene cluster that mediates
CC 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 GliT is required for self-protection against gliotoxin
CC (PubMed:20548963, PubMed:26150413). GliT plays a role in preventing
CC dysregulation of the methyl/methionine cycle to control intracellular
CC S-adenosylmethionine (SAM) depletion and S-adenosylhomocysteine (SAH)
CC homeostasis during gliotoxin biosynthesis and exposure
CC (PubMed:26150413). {ECO:0000269|PubMed:17154540,
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, ECO:0000269|PubMed:26150413}.
CC -!- COFACTOR:
CC Name=FAD; Xref=ChEBI:CHEBI:57692;
CC Evidence={ECO:0000269|PubMed:24446392};
CC Note=Binds 1 FAD per subunit. {ECO:0000269|PubMed:24446392};
CC -!- PATHWAY: Mycotoxin biosynthesis. {ECO:0000269|PubMed:20548963}.
CC -!- SUBUNIT: Homodimer (PubMed:24446392). {ECO:0000269|PubMed:24446392}.
CC -!- INDUCTION: Expression is induced by gliotoxin, but appears to be
CC independently regulated compared to all other cluster components
CC (PubMed:20548963). Expression is positively regulated by the brlA and
CC abaA transcription factors (PubMed:26032501). Expression is also
CC regulated by rsmA (PubMed:23671611). {ECO:0000269|PubMed:20548963,
CC ECO:0000269|PubMed:23671611, ECO:0000269|PubMed:26032501}.
CC -!- DISRUPTION PHENOTYPE: Impairs gliotoxin oxidation, leading to unchecked
CC methylation and subsequent significant S-adenosylmethionine (SAM)
CC depletion and S-adenosylhomocysteine (SAH) overproduction which in turn
CC significantly contributes to hypersensitivity to gliotoxin of gliT-
CC deficient A.fumigatus (PubMed:26150413). Results in altered expression
CC of over 200 genes involved in many functions (PubMed:25311525).
CC {ECO:0000269|PubMed:25311525, ECO:0000269|PubMed:26150413}.
CC -!- SIMILARITY: Belongs to the class-II pyridine nucleotide-disulfide
CC oxidoreductase family. {ECO:0000305}.
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DR EMBL; AY838877; AAW03299.1; -; Genomic_DNA.
DR EMBL; AAHF01000006; EAL88825.1; -; Genomic_DNA.
DR RefSeq; XP_750863.1; XM_745770.1.
DR PDB; 4NTC; X-ray; 1.90 A; A/B=1-334.
DR PDBsum; 4NTC; -.
DR AlphaFoldDB; E9RAH5; -.
DR SMR; E9RAH5; -.
DR STRING; 746128.CADAFUBP00007383; -.
DR EnsemblFungi; EAL88825; EAL88825; AFUA_6G09740.
DR GeneID; 3508168; -.
DR KEGG; afm:AFUA_6G09740; -.
DR VEuPathDB; FungiDB:Afu6g09740; -.
DR eggNOG; ENOG502QQDE; Eukaryota.
DR HOGENOM; CLU_031864_5_0_1; -.
DR InParanoid; E9RAH5; -.
DR OMA; ALMLPDW; -.
DR OrthoDB; 1133476at2759; -.
DR BioCyc; MetaCyc:MON-18853; -.
DR Proteomes; UP000002530; Chromosome 6.
DR GO; GO:0050660; F:flavin adenine dinucleotide binding; IDA:AspGD.
DR GO; GO:0016491; F:oxidoreductase activity; IEA:UniProtKB-KW.
DR GO; GO:0036146; P:cellular response to mycotoxin; IMP:AspGD.
DR GO; GO:2001310; P:gliotoxin biosynthetic process; IMP:AspGD.
DR GO; GO:0043386; P:mycotoxin biosynthetic process; IDA:AspGD.
DR Gene3D; 3.50.50.60; -; 2.
DR InterPro; IPR036188; FAD/NAD-bd_sf.
DR InterPro; IPR023753; FAD/NAD-binding_dom.
DR Pfam; PF07992; Pyr_redox_2; 1.
DR SUPFAM; SSF51905; SSF51905; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Disulfide bond; FAD; Flavoprotein; NADP; Oxidoreductase;
KW Redox-active center; Reference proteome; Virulence.
FT CHAIN 1..334
FT /note="Thioredoxin reductase gliT"
FT /id="PRO_0000437710"
FT BINDING 21..24
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000269|PubMed:24446392"
FT BINDING 43..48
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000269|PubMed:24446392"
FT BINDING 56
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000269|PubMed:24446392"
FT BINDING 91
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000269|PubMed:24446392"
FT BINDING 121
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000269|PubMed:24446392"
FT BINDING 294
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000269|PubMed:24446392"
FT BINDING 301..302
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000269|PubMed:24446392"
FT DISULFID 145..148
FT /note="Redox-active"
FT /evidence="ECO:0000269|PubMed:24446392"
FT STRAND 3..6
FT /evidence="ECO:0007829|PDB:4NTC"
FT STRAND 12..19
FT /evidence="ECO:0007829|PDB:4NTC"
FT HELIX 23..34
FT /evidence="ECO:0007829|PDB:4NTC"
FT STRAND 39..42
FT /evidence="ECO:0007829|PDB:4NTC"
FT TURN 48..51
FT /evidence="ECO:0007829|PDB:4NTC"
FT HELIX 66..79
FT /evidence="ECO:0007829|PDB:4NTC"
FT STRAND 83..87
FT /evidence="ECO:0007829|PDB:4NTC"
FT STRAND 91..98
FT /evidence="ECO:0007829|PDB:4NTC"
FT TURN 99..101
FT /evidence="ECO:0007829|PDB:4NTC"
FT STRAND 102..107
FT /evidence="ECO:0007829|PDB:4NTC"
FT STRAND 112..120
FT /evidence="ECO:0007829|PDB:4NTC"
FT STRAND 124..126
FT /evidence="ECO:0007829|PDB:4NTC"
FT STRAND 130..132
FT /evidence="ECO:0007829|PDB:4NTC"
FT HELIX 134..137
FT /evidence="ECO:0007829|PDB:4NTC"
FT TURN 139..141
FT /evidence="ECO:0007829|PDB:4NTC"
FT STRAND 142..144
FT /evidence="ECO:0007829|PDB:4NTC"
FT TURN 146..148
FT /evidence="ECO:0007829|PDB:4NTC"
FT HELIX 151..153
FT /evidence="ECO:0007829|PDB:4NTC"
FT STRAND 155..162
FT /evidence="ECO:0007829|PDB:4NTC"
FT HELIX 165..167
FT /evidence="ECO:0007829|PDB:4NTC"
FT HELIX 170..180
FT /evidence="ECO:0007829|PDB:4NTC"
FT TURN 181..183
FT /evidence="ECO:0007829|PDB:4NTC"
FT STRAND 184..190
FT /evidence="ECO:0007829|PDB:4NTC"
FT HELIX 195..207
FT /evidence="ECO:0007829|PDB:4NTC"
FT STRAND 208..210
FT /evidence="ECO:0007829|PDB:4NTC"
FT STRAND 215..218
FT /evidence="ECO:0007829|PDB:4NTC"
FT STRAND 222..227
FT /evidence="ECO:0007829|PDB:4NTC"
FT STRAND 234..238
FT /evidence="ECO:0007829|PDB:4NTC"
FT TURN 239..241
FT /evidence="ECO:0007829|PDB:4NTC"
FT STRAND 242..247
FT /evidence="ECO:0007829|PDB:4NTC"
FT STRAND 255..260
FT /evidence="ECO:0007829|PDB:4NTC"
FT HELIX 261..264
FT /evidence="ECO:0007829|PDB:4NTC"
FT TURN 279..282
FT /evidence="ECO:0007829|PDB:4NTC"
FT STRAND 289..291
FT /evidence="ECO:0007829|PDB:4NTC"
FT HELIX 293..296
FT /evidence="ECO:0007829|PDB:4NTC"
FT HELIX 302..322
FT /evidence="ECO:0007829|PDB:4NTC"
SQ SEQUENCE 334 AA; 36004 MW; 6744C7C4CF119B84 CRC64;
MSIGKLLSNG ALLVDVLIIG AGPAGLSTAT GLARQLHTAV VFDSGVYRNA KTQHMHNVLG
WDHRNPAELR AAGRADLTTR YSTIQFQNST IEAIRQVETN QLFEARDNEG HSWYGRKVVL
ATGVRDIPLD IEGYSECWAN GIYHCLFCDG YEERGQETVG VLALGPIANP ARALHLARMA
LRLSESVTIY TNGNEQLAKE IQQAAEESPV GASGLKFEAR PIRRFEKGDV AKTVIVHLGE
SESKTEGFLV YNPQTEVNGP FAKQLALNMT EGGDILTTPP FYETSVPGVF AVGDCATPLK
AVTPAVSMGS LAAGGLVAQL QAQALPEFRL DQEL
