GLIJ_ASPFU
ID GLIJ_ASPFU Reviewed; 388 AA.
AC Q4WMJ8; Q5MBT8;
DT 02-NOV-2016, integrated into UniProtKB/Swiss-Prot.
DT 17-APR-2007, sequence version 2.
DT 03-AUG-2022, entry version 93.
DE RecName: Full=Dipeptidase gliJ {ECO:0000305};
DE EC=3.4.13.19 {ECO:0000255|PROSITE-ProRule:PRU10073};
DE AltName: Full=Gliotoxin biosynthesis protein J {ECO:0000303|PubMed:15979823};
GN Name=gliJ {ECO:0000303|PubMed:15979823}; ORFNames=AFUA_6G09650;
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: Dipeptidase; part of the gene cluster that mediates the
CC biosynthesis of gliotoxin, a member of the epipolythiodioxopiperazine
CC (ETP) class of toxins characterized by a disulfide bridged cyclic
CC dipeptide (PubMed:15979823, PubMed:21612254). The first step in
CC gliotoxin biosynthesis is the condensation of serine and phenylalanine
CC to form the cyclo-L-phenylalanyl-L-serine diketopiperazine (DKP) by the
CC NRPS gliP (PubMed:17154540, PubMed:21612254). GliP is also able to
CC produce the DKP cyclo-L-tryptophanyl-L-serine, suggesting that the
CC substrate specificity of the first adenylation (A) domain in gliP is
CC sufficiently relaxed to accommodate both L-Phe and L-Trp
CC (PubMed:23434416). The cytochrome P450 monooxygenase gliC has been
CC shown to catalyze the subsequent hydroxylation of the alpha-carbon of
CC L-Phe in cyclo-L-phenylalanyl-L-serine whereas the second cytochrome
CC P450 enzyme, gliF, is presumably involved in the modification of the
CC DKP side chain (PubMed:24039048, PubMed:23434416). The glutathione S-
CC transferase (GST) gliG then forms a bis-glutathionylated biosynthetic
CC intermediate which is responsible for the sulfurization of gliotoxin
CC (PubMed:21513890, PubMed:21749092). This bis-glutathionylated
CC intermediate is subsequently processed by the gamma-glutamyl
CC cyclotransferase gliK to remove both gamma-glutamyl moieties
CC (PubMed:22903976, PubMed:24039048). Subsequent processing via gliI
CC yields a biosynthetic intermediate, which is N-methylated via the N-
CC 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=an L-aminoacyl-L-amino acid + H2O = 2 an L-alpha-amino acid;
CC Xref=Rhea:RHEA:48940, ChEBI:CHEBI:15377, ChEBI:CHEBI:59869,
CC ChEBI:CHEBI:77460; EC=3.4.13.19; Evidence={ECO:0000255|PROSITE-
CC ProRule:PRU10073};
CC -!- COFACTOR:
CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC Evidence={ECO:0000255|PROSITE-ProRule:PRU10073};
CC -!- PATHWAY: Mycotoxin biosynthesis. {ECO:0000305|PubMed:15979823}.
CC -!- SIMILARITY: Belongs to the metallo-dependent hydrolases superfamily.
CC Peptidase M19 family. {ECO:0000255|PROSITE-ProRule:PRU10073}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAW03308.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305};
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DR EMBL; AY838877; AAW03308.1; ALT_SEQ; Genomic_DNA.
DR EMBL; AAHF01000006; EAL88816.2; -; Genomic_DNA.
DR RefSeq; XP_750854.2; XM_745761.2.
DR PDB; 5LWZ; X-ray; 2.10 A; A/B/C=1-388.
DR PDB; 5LX0; X-ray; 2.40 A; A=1-387.
DR PDB; 5LX1; X-ray; 2.70 A; A=1-388.
DR PDB; 5LX4; X-ray; 1.90 A; A=1-388.
DR PDB; 5LX7; X-ray; 1.95 A; A=1-388.
DR PDB; 5NRT; X-ray; 2.20 A; A=1-388.
DR PDB; 5NRU; X-ray; 2.15 A; A=1-388.
DR PDB; 5NRX; X-ray; 2.35 A; A=1-388.
DR PDB; 5NRY; X-ray; 1.85 A; A=1-388.
DR PDB; 5NRZ; X-ray; 2.05 A; A=1-388.
DR PDB; 5NS1; X-ray; 2.40 A; A=1-388.
DR PDB; 5NS2; X-ray; 2.20 A; A=1-388.
DR PDB; 5NS5; X-ray; 2.20 A; A=1-388.
DR PDBsum; 5LWZ; -.
DR PDBsum; 5LX0; -.
DR PDBsum; 5LX1; -.
DR PDBsum; 5LX4; -.
DR PDBsum; 5LX7; -.
DR PDBsum; 5NRT; -.
DR PDBsum; 5NRU; -.
DR PDBsum; 5NRX; -.
DR PDBsum; 5NRY; -.
DR PDBsum; 5NRZ; -.
DR PDBsum; 5NS1; -.
DR PDBsum; 5NS2; -.
DR PDBsum; 5NS5; -.
DR AlphaFoldDB; Q4WMJ8; -.
DR SMR; Q4WMJ8; -.
DR STRING; 746128.CADAFUBP00007374; -.
DR MEROPS; M19.013; -.
DR EnsemblFungi; EAL88816; EAL88816; AFUA_6G09650.
DR GeneID; 3508159; -.
DR KEGG; afm:AFUA_6G09650; -.
DR VEuPathDB; FungiDB:Afu6g09650; -.
DR eggNOG; KOG4127; Eukaryota.
DR HOGENOM; CLU_031404_4_2_1; -.
DR InParanoid; Q4WMJ8; -.
DR OMA; EEVQNSC; -.
DR OrthoDB; 1272387at2759; -.
DR BioCyc; MetaCyc:MON-18851; -.
DR Proteomes; UP000002530; Chromosome 6.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0070573; F:metallodipeptidase activity; IEA:InterPro.
DR GO; GO:0043386; P:mycotoxin biosynthetic process; IEP:AspGD.
DR GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW.
DR CDD; cd01301; rDP_like; 1.
DR InterPro; IPR032466; Metal_Hydrolase.
DR InterPro; IPR008257; Pept_M19.
DR PANTHER; PTHR10443; PTHR10443; 1.
DR Pfam; PF01244; Peptidase_M19; 1.
DR SUPFAM; SSF51556; SSF51556; 1.
DR PROSITE; PS51365; RENAL_DIPEPTIDASE_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Dipeptidase; Disulfide bond; Hydrolase; Metal-binding;
KW Metalloprotease; Protease; Reference proteome; Virulence; Zinc.
FT CHAIN 1..388
FT /note="Dipeptidase gliJ"
FT /id="PRO_0000437702"
FT BINDING 23
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10073"
FT BINDING 25
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10073"
FT BINDING 134
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10073"
FT BINDING 161
FT /ligand="substrate"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10073"
FT BINDING 235
FT /ligand="substrate"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10073"
FT BINDING 294
FT /ligand="substrate"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10073"
FT DISULFID 74..163
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10073"
FT HELIX 5..16
FT /evidence="ECO:0007829|PDB:5NRY"
FT STRAND 20..24
FT /evidence="ECO:0007829|PDB:5NRY"
FT HELIX 26..33
FT /evidence="ECO:0007829|PDB:5NRY"
FT STRAND 34..36
FT /evidence="ECO:0007829|PDB:5NS1"
FT HELIX 42..46
FT /evidence="ECO:0007829|PDB:5NRY"
FT STRAND 49..52
FT /evidence="ECO:0007829|PDB:5NRY"
FT HELIX 55..60
FT /evidence="ECO:0007829|PDB:5NRY"
FT STRAND 65..69
FT /evidence="ECO:0007829|PDB:5NRY"
FT HELIX 80..104
FT /evidence="ECO:0007829|PDB:5NRY"
FT TURN 106..108
FT /evidence="ECO:0007829|PDB:5NRY"
FT STRAND 109..111
FT /evidence="ECO:0007829|PDB:5NRY"
FT HELIX 115..123
FT /evidence="ECO:0007829|PDB:5NRY"
FT STRAND 127..134
FT /evidence="ECO:0007829|PDB:5NRY"
FT HELIX 136..139
FT /evidence="ECO:0007829|PDB:5NRY"
FT HELIX 143..151
FT /evidence="ECO:0007829|PDB:5NRY"
FT STRAND 154..159
FT /evidence="ECO:0007829|PDB:5NRY"
FT STRAND 161..163
FT /evidence="ECO:0007829|PDB:5NRY"
FT STRAND 166..168
FT /evidence="ECO:0007829|PDB:5NRY"
FT STRAND 170..172
FT /evidence="ECO:0007829|PDB:5NRY"
FT STRAND 177..181
FT /evidence="ECO:0007829|PDB:5NRY"
FT HELIX 183..195
FT /evidence="ECO:0007829|PDB:5NRY"
FT STRAND 198..200
FT /evidence="ECO:0007829|PDB:5NRY"
FT HELIX 206..215
FT /evidence="ECO:0007829|PDB:5NRY"
FT STRAND 221..224
FT /evidence="ECO:0007829|PDB:5NRY"
FT TURN 228..230
FT /evidence="ECO:0007829|PDB:5NRY"
FT HELIX 239..248
FT /evidence="ECO:0007829|PDB:5NRY"
FT STRAND 251..254
FT /evidence="ECO:0007829|PDB:5NRY"
FT HELIX 258..261
FT /evidence="ECO:0007829|PDB:5NRY"
FT HELIX 265..267
FT /evidence="ECO:0007829|PDB:5NRY"
FT HELIX 270..284
FT /evidence="ECO:0007829|PDB:5NRY"
FT HELIX 286..288
FT /evidence="ECO:0007829|PDB:5NRY"
FT STRAND 289..291
FT /evidence="ECO:0007829|PDB:5NRY"
FT STRAND 297..300
FT /evidence="ECO:0007829|PDB:5NRY"
FT HELIX 308..310
FT /evidence="ECO:0007829|PDB:5NRY"
FT HELIX 311..320
FT /evidence="ECO:0007829|PDB:5NRY"
FT HELIX 325..332
FT /evidence="ECO:0007829|PDB:5NRY"
FT HELIX 334..353
FT /evidence="ECO:0007829|PDB:5NRY"
FT HELIX 368..383
FT /evidence="ECO:0007829|PDB:5NRY"
SQ SEQUENCE 388 AA; 43525 MW; 2133C17F37E5A07C CRC64;
MSPSPIEEQA TRLLKEVPLI DGHNDFPYMI RGWFRNDING QDAHLYDMPI GQTDLQRLQK
GLLGGQFWSA FVPCPKNPDK EVGSLEALRQ TLQQLDVIHR LIERHPTILQ FADSAASIWS
SFRAGRVASL IGIEGLHQIA DSVSALRMLH RLGVRYVTLT HNCHNAFADA ATVSPELHGG
LSRKGERLIR ELNRMGMMID LSHTSHEAQT QALRLSRAPV IYSHSSIYSL RAHARNVTDE
NLHLLHRNRG VVMICFLREL LASEADQATL AHVIDHIIYA GTRIGYEHVG IGSDFDGMLR
GPDGLHDVSC YPALVAGLLE RGVSEEDVKR VMGLNVIRVL EEVERVAAEL QGAGEECLCD
ELDEVWNEDI KEQLTRERER VRKLGPQK
