USTH_ASPFN
ID USTH_ASPFN Reviewed; 591 AA.
AC B8NM71;
DT 05-OCT-2016, integrated into UniProtKB/Swiss-Prot.
DT 03-MAR-2009, sequence version 1.
DT 03-AUG-2022, entry version 67.
DE RecName: Full=Glutathione hydrolase;
DE EC=3.4.19.13 {ECO:0000250|UniProtKB:P19440};
DE AltName: Full=Gamma-glutamyltransferase ustH {ECO:0000303|PubMed:24841822};
DE EC=2.3.2.2 {ECO:0000250|UniProtKB:P19440};
DE AltName: Full=Ustiloxin B biosynthesis protein H {ECO:0000303|PubMed:24841822};
DE Flags: Precursor;
GN Name=ustH {ECO:0000303|PubMed:24841822}; ORFNames=AFLA_095030;
OS Aspergillus flavus (strain ATCC 200026 / FGSC A1120 / IAM 13836 / NRRL 3357
OS / JCM 12722 / SRRC 167).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Aspergillus;
OC Aspergillus subgen. Circumdati.
OX NCBI_TaxID=332952;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=ATCC 200026 / FGSC A1120 / IAM 13836 / NRRL 3357 / JCM 12722 / SRRC
RC 167;
RX PubMed=25883274; DOI=10.1128/genomea.00168-15;
RA Nierman W.C., Yu J., Fedorova-Abrams N.D., Losada L., Cleveland T.E.,
RA Bhatnagar D., Bennett J.W., Dean R., Payne G.A.;
RT "Genome sequence of Aspergillus flavus NRRL 3357, a strain that causes
RT aflatoxin contamination of food and feed.";
RL Genome Announc. 3:E0016815-E0016815(2015).
RN [2]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=24841822; DOI=10.1016/j.fgb.2014.04.011;
RA Umemura M., Nagano N., Koike H., Kawano J., Ishii T., Miyamura Y.,
RA Kikuchi M., Tamano K., Yu J., Shin-ya K., Machida M.;
RT "Characterization of the biosynthetic gene cluster for the ribosomally
RT synthesized cyclic peptide ustiloxin B in Aspergillus flavus.";
RL Fungal Genet. Biol. 68:23-30(2014).
RN [3]
RP FUNCTION.
RX PubMed=27166860; DOI=10.1002/anie.201602611;
RA Ye Y., Minami A., Igarashi Y., Izumikawa M., Umemura M., Nagano N.,
RA Machida M., Kawahara T., Shin-Ya K., Gomi K., Oikawa H.;
RT "Unveiling the biosynthetic pathway of the ribosomally synthesized and
RT post-translationally modified peptide ustiloxin B in filamentous fungi.";
RL Angew. Chem. Int. Ed. 55:8072-8075(2016).
RN [4]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=26703898; DOI=10.1016/j.fgb.2015.12.010;
RA Nagano N., Umemura M., Izumikawa M., Kawano J., Ishii T., Kikuchi M.,
RA Tomii K., Kumagai T., Yoshimi A., Machida M., Abe K., Shin-ya K., Asai K.;
RT "Class of cyclic ribosomal peptide synthetic genes in filamentous fungi.";
RL Fungal Genet. Biol. 86:58-70(2016).
CC -!- FUNCTION: Gamma-glutamyltransferase; part of the gene cluster that
CC mediates the biosynthesis of the secondary metabolite ustiloxin B, an
CC antimitotic tetrapeptide (PubMed:24841822, PubMed:27166860,
CC PubMed:26703898). First, ustA is processed by the subtilisin-like
CC endoprotease Kex2 that is outside the ustiloxin B gene cluster, at the
CC C-terminal side of Arg-Lys, after transfer to Golgi apparatus through
CC the endoplasmic reticulum (ER) (PubMed:24841822). Cleavage by KEX2
CC generates 16 peptides YAIG-I to YAIG-XVI (PubMed:24841822). To process
CC the precursor peptide further, at least two peptidases are necessary to
CC cleave the N-terminal and C-terminal sides of the Tyr-Ala-Ile-Gly core
CC peptide which serves as backbone for the synthesis of ustiloxin B,
CC through cyclization and modification of the tyrosine with a non-protein
CC coding amino acid, norvaline (PubMed:24841822). One of the two
CC peptidases must be the serine peptidase ustP; and the other pepdidase
CC is probably ustH (PubMed:24841822). Macrocyclization of the core
CC peptide derived from ustA requires the tyrosinase ustQ, as well as the
CC homologous oxidases ustYa and ustYb, and leads to the production of the
CC first cyclization product N-desmethylustiloxin F (PubMed:27166860,
CC PubMed:26703898). For the formation of N-desmethylustiloxin F, three
CC oxidation steps are required, hydroxylation at the benzylic position,
CC hydroxylation at either the aromatic ring of Tyr or beta-position of
CC Ile, and oxidative cyclization (PubMed:27166860). UstQ may catalyze the
CC oxidation of a phenol moiety, whereas the ustYa and ustYb are most
CC likely responsible for the remaining two-step oxidations
CC (PubMed:27166860). N-desmethylustiloxin F is then methylated by ustM to
CC yield ustiloxin F which in turn substrate of the cytochrome P450
CC monooxygenase ustC which catalyzes the formation of S-deoxyustiloxin H
CC (PubMed:27166860). The flavoprotein monooxygenases ustF1 and ustF2 then
CC participate in the modification of the side chain of S-deoxyustiloxin
CC H, leading to the synthesis of an oxime intermediate, via ustiloxin H
CC (PubMed:27166860). Finally, carboxylative dehydration performed by the
CC cysteine desulfurase-like protein ustD yields ustiloxin B
CC (PubMed:27166860). {ECO:0000269|PubMed:24841822,
CC ECO:0000269|PubMed:26703898, ECO:0000269|PubMed:27166860}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=an alpha-amino acid + an N-terminal (5-L-glutamyl)-[peptide] =
CC 5-L-glutamyl amino acid + N-terminal L-alpha-aminoacyl-[peptide];
CC Xref=Rhea:RHEA:23904, Rhea:RHEA-COMP:9780, Rhea:RHEA-COMP:9795,
CC ChEBI:CHEBI:77644, ChEBI:CHEBI:78597, ChEBI:CHEBI:78599,
CC ChEBI:CHEBI:78608; EC=2.3.2.2;
CC Evidence={ECO:0000250|UniProtKB:P19440};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=glutathione + H2O = L-cysteinylglycine + L-glutamate;
CC Xref=Rhea:RHEA:28807, ChEBI:CHEBI:15377, ChEBI:CHEBI:29985,
CC ChEBI:CHEBI:57925, ChEBI:CHEBI:61694; EC=3.4.19.13;
CC Evidence={ECO:0000250|UniProtKB:P19440};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=an S-substituted glutathione + H2O = an S-substituted L-
CC cysteinylglycine + L-glutamate; Xref=Rhea:RHEA:59468,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:29985, ChEBI:CHEBI:90779,
CC ChEBI:CHEBI:143103; EC=3.4.19.13;
CC Evidence={ECO:0000250|UniProtKB:P19440};
CC -!- PATHWAY: Mycotoxin biosynthesis. {ECO:0000269|PubMed:26703898}.
CC -!- DISRUPTION PHENOTYPE: Does not alter the production of ustiloxin B
CC (PubMed:24841822, PubMed:26703898). {ECO:0000269|PubMed:24841822,
CC ECO:0000269|PubMed:26703898}.
CC -!- SIMILARITY: Belongs to the gamma-glutamyltransferase family.
CC {ECO:0000305}.
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DR EMBL; EQ963480; EED49422.1; -; Genomic_DNA.
DR RefSeq; XP_002381323.1; XM_002381282.1.
DR AlphaFoldDB; B8NM71; -.
DR SMR; B8NM71; -.
DR STRING; 5059.CADAFLAP00009188; -.
DR MEROPS; T03.011; -.
DR EnsemblFungi; EED49422; EED49422; AFLA_095030.
DR VEuPathDB; FungiDB:AFLA_095030; -.
DR eggNOG; KOG2410; Eukaryota.
DR HOGENOM; CLU_014813_4_0_1; -.
DR OMA; SFWPRTW; -.
DR Proteomes; UP000001875; Unassembled WGS sequence.
DR GO; GO:0036374; F:glutathione hydrolase activity; IEA:UniProtKB-EC.
DR GO; GO:0102953; F:hypoglycin A gamma-glutamyl transpeptidase activity; IEA:UniProtKB-EC.
DR GO; GO:0103068; F:leukotriene C4 gamma-glutamyl transferase activity; IEA:UniProtKB-EC.
DR GO; GO:0006751; P:glutathione catabolic process; IEA:InterPro.
DR GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW.
DR Gene3D; 1.10.246.130; -; 1.
DR Gene3D; 3.60.20.40; -; 1.
DR InterPro; IPR043138; GGT_lsub_C.
DR InterPro; IPR000101; GGT_peptidase.
DR InterPro; IPR043137; GGT_ssub.
DR InterPro; IPR029055; Ntn_hydrolases_N.
DR PANTHER; PTHR11686; PTHR11686; 1.
DR SUPFAM; SSF56235; SSF56235; 1.
DR TIGRFAMs; TIGR00066; g_glut_trans; 1.
PE 3: Inferred from homology;
KW Acyltransferase; Glycoprotein; Hydrolase; Protease; Signal; Transferase.
FT SIGNAL 1..41
FT /evidence="ECO:0000255"
FT CHAIN 42..591
FT /note="Glutathione hydrolase"
FT /evidence="ECO:0000255"
FT /id="PRO_0000437297"
FT ACT_SITE 393
FT /note="Nucleophile"
FT /evidence="ECO:0000250|UniProtKB:P19440"
FT BINDING 122
FT /ligand="L-glutamate"
FT /ligand_id="ChEBI:CHEBI:29985"
FT /evidence="ECO:0000250|UniProtKB:P19440"
FT BINDING 411
FT /ligand="L-glutamate"
FT /ligand_id="ChEBI:CHEBI:29985"
FT /evidence="ECO:0000250|UniProtKB:P19440"
FT BINDING 432
FT /ligand="L-glutamate"
FT /ligand_id="ChEBI:CHEBI:29985"
FT /evidence="ECO:0000250|UniProtKB:P19440"
FT BINDING 464..465
FT /ligand="L-glutamate"
FT /ligand_id="ChEBI:CHEBI:29985"
FT /evidence="ECO:0000250|UniProtKB:P19440"
FT CARBOHYD 135
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 270
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 389
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 534
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
SQ SEQUENCE 591 AA; 64306 MW; 0558B3146BCF0A6C CRC64;
MASKWIEEQP LVHRRDIRIS SKSRIAAGLL VLLVLWRYGL PSSIHFGFSS EEPKQLGAVA
SEHALCSRYG ADMLERGGNA ADAMVATMFC IGVVGMYHSG IGGGGFMLIK SPDGDFEFVD
FRETAPAAIV ALGKNTSAGL RSGVPGEVRG LEYLHRKYGV LPWSVVLEPA IRTARDGFLV
QEDLVNYIDM AVEETGEDFL SKHPSWAVDF SPSGSRVRLG DTMTRRRLAA TLERISVDGP
DAFYSGPIAE DMVASLRNVG GIMTLEDLAN YTVVTRDTSH IDYRGYQITS TTAPSSGTIA
MNILKVLDTY DEFFTPGTTE LSTHRMIEAM KFAFGLRTRL GDPSFVHGME EYENHILSAE
MIDHIRQSIS DSHTQDTSAY NPDGLEVVNS TGTAHIATVD HQGLAISATT TINRLFGNQI
MCDRTGIIMN NEMDDFSVPT SSPPTFGHTP SSTNFAEPGK RPLSAISPAI ILHPDGSLFL
IAGSAGSNWI TTTTVQNIIS GIDQNLAAQE ILATPRVHHQ LIPNHAIFET TYDNGTVDFL
SQLGHEVTWY PPAASMAHLI RVNADGGFDP AGDPRLKNSG GVVALQRRKF W
