Protein: Cytochrome P450 monooxygenase gliF (EC 1.-.-.-) (Gliotoxin biosynthesis protein F) (Q4WMJ0)
Organism: Aspergillus fumigatus (strain ATCC MYA-4609 / CBS 101355 / FGSC A1100 / Af293) (Neosartorya fumigata)
Function: Cytochrome P450 monooxygenase; 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.
Subcellular location: Membrane {ECO:0000255}; Single-pass membrane protein {ECO:0000255}.
Sequence: MDQVYLPQSVRTAVAVSFGVGLLYWVYRLLLQKTKSLKALDLPVLQSVGDQDIVKTLEEGHAKYPDTPFALGVPGQQLVVLPVSEIDTVKALPENQLSIKKHHYNQFLGEYSYMGTKADEFDDAMRYLLVRNTPAVLASFTAEIDYAMSTVLQVPPNSWTRVKPRSIMPKVATILSGRAFVGLPLSREPDWIESNVNYTQDVSRAWMVLRFYPHWIRPLVAPFLREVKTLEQNKALIGRKIAKLLADQEAQKLSPAQEKIPGGDMIDWFKSRYQAQGKTATAQQLTRDQLLATFASIYNLSNALTYVMFDLAANPAAVDELREELDQVLGPNVGAESIDKTALPRLIKLDSFVRESQRLSPTSLVNIPRIVTDPNGLRLKTGHVIPPGYLVMVRAQPINQSPTLYPNPERFDAFRFARLRQQGGANENRWQHTSTGADNINFGHGIWACPGRFFASAEIKVVVAYVIRHYDLRLIEGRPHPKPKYGGLAIFPDAGAEVELKPRV
InterPro domains: - IPR001128: Cytochrome P450 (family) [194-485]
- IPR036396: Cytochrome P450 superfamily (homologous_superfamily) [42-503]
- IPR002403: Cytochrome P450, E-class, group IV (family) [346-467]
Interaction partners: - O-methyltransferase gliM
- N-methyltransferase gliN
- Thioredoxin reductase gliT
- Glutathione S-transferase gliG
- Nonribosomal peptide synthetase gliP
Gene Ontology annotations:
Molecular Function (MF): GO:0003674 (molecular function), GO:0003824 (catalytic activity), GO:0016491 (oxidoreductase activity), GO:0004497 (monooxygenase activity)
Biological Process (BP): GO:0008150 (biological process), GO:0008152 (metabolic process), GO:0009058 (biosynthetic process), GO:0019748 (secondary metabolic process), GO:0071704 (organic substance metabolic process), GO:0006807 (nitrogen compound metabolic process), GO:0044550 (secondary metabolite biosynthetic process), GO:1901564 (organonitrogen compound metabolic process), GO:1901576 (organic substance biosynthetic process), GO:1900619 (acetate ester metabolic process), GO:1901566 (organonitrogen compound biosynthetic process), GO:1900620 (acetate ester biosynthetic process), GO:0009821 (alkaloid biosynthetic process), GO:0009820 (alkaloid metabolic process), GO:0035835 (indole alkaloid biosynthetic process), GO:0035834 (indole alkaloid metabolic process), GO:0009709 (terpenoid indole alkaloid biosynthetic process), GO:0046447 (terpenoid indole alkaloid metabolic 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:0012505 (endomembrane system), GO:0043229 (intracellular organelle), GO:0005783 (endoplasmic reticulum), GO:0043227 (membrane-bounded organelle), GO:0043231 (intracellular membrane-bounded organelle)