ID   GLIG_ASPFU              Reviewed;         240 AA.
AC   A4GYZ0; Q5MBU2;
DT   02-NOV-2016, integrated into UniProtKB/Swiss-Prot.
DT   17-APR-2007, sequence version 1.
DT   24-JAN-2024, entry version 86.
DE   RecName: Full=Glutathione S-transferase gliG {ECO:0000303|PubMed:15979823};
DE            EC=2.5.1.18 {ECO:0000269|PubMed:21513890, ECO:0000269|PubMed:21749092};
DE   AltName: Full=Gliotoxin biosynthesis protein G {ECO:0000303|PubMed:15979823};
GN   Name=gliG {ECO:0000303|PubMed:15979823}; ORFNames=AFUA_6G09690;
OS   Aspergillus fumigatus (strain ATCC MYA-4609 / CBS 101355 / FGSC A1100 /
OS   Af293) (Neosartorya fumigata).
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 / CBS 101355 / FGSC A1100 / Af293;
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 / CBS 101355 / FGSC A1100 / Af293;
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, CATALYTIC ACTIVITY, AND DISRUPTION PHENOTYPE.
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, AND CATALYTIC ACTIVITY.
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: Glutathione S-transferase; 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   -!- CATALYTIC ACTIVITY:
CC       Reaction=glutathione + RX = a halide anion + an S-substituted
CC         glutathione + H(+); Xref=Rhea:RHEA:16437, ChEBI:CHEBI:15378,
CC         ChEBI:CHEBI:16042, ChEBI:CHEBI:17792, ChEBI:CHEBI:57925,
CC         ChEBI:CHEBI:90779; EC=2.5.1.18;
CC         Evidence={ECO:0000269|PubMed:21513890, ECO:0000269|PubMed:21749092};
CC   -!- PATHWAY: Mycotoxin biosynthesis. {ECO:0000269|PubMed:21513890,
CC       ECO:0000269|PubMed:21749092}.
CC   -!- DISRUPTION PHENOTYPE: Abrogates gliotoxin biosynthesis and leads to the
CC       accumulation of the shunt metabolite 6-benzyl-6-hydroxy-1-methoxy-3-
CC       methylene-piperazine-2,5-dione (PubMed:21513890).
CC       {ECO:0000269|PubMed:21513890}.
CC   -!- SIMILARITY: Belongs to the GST superfamily. {ECO:0000305}.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=AAW03304.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305};
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DR   EMBL; AY838877; AAW03304.1; ALT_SEQ; Genomic_DNA.
DR   EMBL; AAHF01000006; EAL88820.2; -; Genomic_DNA.
DR   RefSeq; XP_750858.2; XM_745765.2.
DR   AlphaFoldDB; A4GYZ0; -.
DR   SMR; A4GYZ0; -.
DR   STRING; 330879.A4GYZ0; -.
DR   EnsemblFungi; EAL88820; EAL88820; AFUA_6G09690.
DR   GeneID; 3508163; -.
DR   KEGG; afm:AFUA_6G09690; -.
DR   VEuPathDB; FungiDB:Afu6g09690; -.
DR   eggNOG; KOG0867; Eukaryota.
DR   HOGENOM; CLU_011226_14_2_1; -.
DR   InParanoid; A4GYZ0; -.
DR   OMA; THNTVKP; -.
DR   OrthoDB; 1928199at2759; -.
DR   BioCyc; MetaCyc:MONOMER-18849; -.
DR   Proteomes; UP000002530; Chromosome 6.
DR   GO; GO:0004364; F:glutathione transferase activity; IDA:AspGD.
DR   GO; GO:2001310; P:gliotoxin biosynthetic process; IMP:AspGD.
DR   GO; GO:0043386; P:mycotoxin biosynthetic process; IMP:AspGD.
DR   Gene3D; 1.20.1050.130; -; 1.
DR   InterPro; IPR010987; Glutathione-S-Trfase_C-like.
DR   InterPro; IPR036282; Glutathione-S-Trfase_C_sf.
DR   InterPro; IPR040079; Glutathione_S-Trfase.
DR   InterPro; IPR004045; Glutathione_S-Trfase_N.
DR   InterPro; IPR004046; GST_C.
DR   InterPro; IPR036249; Thioredoxin-like_sf.
DR   PANTHER; PTHR44051; GLUTATHIONE S-TRANSFERASE-RELATED; 1.
DR   PANTHER; PTHR44051:SF8; GLUTATHIONE S-TRANSFERASE-RELATED; 1.
DR   Pfam; PF00043; GST_C; 1.
DR   Pfam; PF13409; GST_N_2; 1.
DR   SFLD; SFLDS00019; Glutathione_Transferase_(cytos; 1.
DR   SFLD; SFLDG00358; Main_(cytGST); 1.
DR   SUPFAM; SSF47616; GST C-terminal domain-like; 1.
DR   SUPFAM; SSF52833; Thioredoxin-like; 1.
DR   PROSITE; PS50405; GST_CTER; 1.
DR   PROSITE; PS50404; GST_NTER; 1.
PE   1: Evidence at protein level;
KW   Reference proteome; Transferase; Virulence.
FT   CHAIN           1..240
FT                   /note="Glutathione S-transferase gliG"
FT                   /id="PRO_0000437724"
FT   DOMAIN          15..98
FT                   /note="GST N-terminal"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00684"
FT   DOMAIN          104..237
FT                   /note="GST C-terminal"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00685"
SQ   SEQUENCE   240 AA;  27470 MW;  5352BD3FFD7D1A4B CRC64;
     MSERPSDLVV NRLVLFVVKG TATSTHNTVK PLILLEELGV PHDIYVVEKV SAPWFSEINP
     HKMVPAILDR SPDGRDTLRA WESTSTLMYI ADAYDKDGTL GGRNVQERSE INNWLTLHTA
     ALGPTAKYWL YFYKLHPEKL PKTIEKLRSN ITVQYDILER RLNEPGQQYL ALKDRPTIAD
     IATLPFAMKS TAELFGLEFE KWPKLQEWSV RMGEREAVKR AWQRVAGFGH GEKEYGMLEA
//