Protein: Glutathione S-transferase gliG (EC 2.5.1.18) (Gliotoxin biosynthesis protein G) (A4GYZ0)
Organism: Aspergillus fumigatus (strain ATCC MYA-4609 / CBS 101355 / FGSC A1100 / Af293) (Neosartorya fumigata)
Function: Glutathione S-transferase; part of the gene cluster that mediates the biosynthesis of gliotoxin, a member of the epipolythiodioxopiperazine (ETP) class of toxins characterized by a disulfide bridged cyclic dipeptide. The first step in gliotoxin biosynthesis is the condensation of serine and phenylalanine to form the cyclo-L-phenylalanyl-L-serine diketopiperazine (DKP) by the NRPS gliP. GliP is also able to produce the DKP cyclo-L-tryptophanyl-L-serine, suggesting that the substrate specificity of the first adenylation (A) domain in gliP is sufficiently relaxed to accommodate both L-Phe and L-Trp. The cytochrome P450 monooxygenase gliC has been shown to catalyze the subsequent hydroxylation of the alpha-carbon of L-Phe in cyclo-L-phenylalanyl-L-serine whereas the second cytochrome P450 enzyme, gliF, is presumably involved in the modification of the DKP side chain. The glutathione S-transferase (GST) gliG then forms a bis-glutathionylated biosynthetic intermediate which is responsible for the sulfurization of gliotoxin. This bis-glutathionylated intermediate is subsequently processed by the gamma-glutamyl cyclotransferase gliK to remove both gamma-glutamyl moieties. Subsequent processing via gliI yields a biosynthetic intermediate, which is N-methylated via the N-methyltransferase gliN, before the gliotoxin oxidoreductase gliT-mediated disulfide bridge closure. GliN-mediated amide methylation confers stability to ETP, damping the spontaneous formation of tri- and tetrasulfides. Intracellular dithiol gliotoxin oxidized by gliT is subsequently effluxed by gliA. Gliotoxin contributes to pathogenesis during invasive aspergillosis. In macrophages and neutrophils, gliotoxin showed inhibition of various different cell functions including cytokine production, antigen presentation, phagocytosis, and production of reactive oxygen species.
Sequence: MSERPSDLVVNRLVLFVVKGTATSTHNTVKPLILLEELGVPHDIYVVEKVSAPWFSEINPHKMVPAILDRSPDGRDTLRAWESTSTLMYIADAYDKDGTLGGRNVQERSEINNWLTLHTAALGPTAKYWLYFYKLHPEKLPKTIEKLRSNITVQYDILERRLNEPGQQYLALKDRPTIADIATLPFAMKSTAELFGLEFEKWPKLQEWSVRMGEREAVKRAWQRVAGFGHGEKEYGMLEA
InterPro domains: - IPR036249: Thioredoxin-like superfamily (homologous_superfamily) [26-99]
- IPR036282: Glutathione S-transferase, C-terminal domain superfamily (homologous_superfamily) [104-223]
- IPR004046: Glutathione S-transferase, C-terminal (domain) [127-216]
- IPR010987: Glutathione S-transferase, C-terminal-like (domain) [104-237]
- IPR040079: Glutathione transferase family (family) [27-215]
- IPR004045: Glutathione S-transferase, N-terminal (domain) [15-98]
Interaction partners: - O-methyltransferase gliM
- Cytochrome P450 monooxygenase gliC
- Thioredoxin reductase gliT
- Dipeptidase gliJ
- Nonribosomal peptide synthetase gliP
- Cytochrome P450 monooxygenase gliF
- Gamma-glutamyl cyclotransferase gliK
- N-methyltransferase gliN
Gene Ontology annotations:
Molecular Function (MF): GO:0003674 (molecular function), GO:0098772 (molecular function regulator activity), GO:0140677 (molecular function activator activity)
Biological Process (BP): GO:0008150 (biological process), GO:0008152 (metabolic process), GO:0009987 (cellular process), GO:0009058 (biosynthetic process), GO:0044237 (cellular metabolic process), GO:0044281 (small molecule metabolic process), GO:0006807 (nitrogen compound metabolic process), GO:0019748 (secondary metabolic process), GO:0071704 (organic substance metabolic process), GO:0044550 (secondary metabolite biosynthetic process), GO:0042180 (cellular ketone metabolic process), GO:1901615 (organic hydroxy compound metabolic process), GO:1901360 (organic cyclic compound metabolic process), GO:1901576 (organic substance biosynthetic process), GO:1901564 (organonitrogen compound metabolic process), GO:0044283 (small molecule biosynthetic process), GO:0120254 (olefinic compound metabolic process), GO:0046483 (heterocycle metabolic process), GO:0044249 (cellular biosynthetic process), GO:0009404 (toxin metabolic process), GO:0006725 (cellular aromatic compound metabolic process), GO:0034641 (cellular nitrogen compound metabolic process), GO:0043603 (amide metabolic process), GO:0006790 (sulfur compound metabolic process), GO:1901566 (organonitrogen compound biosynthetic process), GO:1901362 (organic cyclic compound biosynthetic process), GO:0043385 (mycotoxin metabolic process), GO:0120255 (olefinic compound biosynthetic process), GO:0009403 (toxin biosynthetic process), GO:0006518 (peptide metabolic process), GO:0044272 (sulfur compound biosynthetic process), GO:0019438 (aromatic compound biosynthetic process), GO:0019290 (siderophore biosynthetic process), GO:0018130 (heterocycle biosynthetic process), GO:0009820 (alkaloid metabolic process), GO:1901617 (organic hydroxy compound biosynthetic process), GO:0043604 (amide biosynthetic process), GO:0044271 (cellular nitrogen compound biosynthetic process), GO:0042181 (ketone biosynthetic process), GO:0030654 (beta-lactam antibiotic biosynthetic process), GO:0018958 (phenol-containing compound metabolic process), GO:0042435 (indole-containing compound biosynthetic process), GO:0043043 (peptide biosynthetic process), GO:0043386 (mycotoxin biosynthetic process), GO:0046394 (carboxylic acid biosynthetic process), GO:0046189 (phenol-containing compound biosynthetic process), GO:1901378 (organic heteropentacyclic compound biosynthetic process)
Cellular Component (CC): GO:0005575 (cellular component), GO:0110165 (cellular anatomical entity), GO:0005622 (intracellular anatomical structure), GO:0043226 (organelle), GO:0005737 (cytoplasm), GO:0043229 (intracellular organelle), GO:0005739 (mitochondrion), GO:0043227 (membrane-bounded organelle), GO:0043231 (intracellular membrane-bounded organelle)