The following text describes a protein:
Function:
Nonribosomal peptide synthetase; 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.
Domain:
NRP synthetases are composed of discrete domains (adenylation (A), thiolation (T) or peptidyl carrier protein (PCP) and condensation (C) domains) which when grouped together are referred to as a single module. Each module is responsible for the recognition (via the A domain) and incorporation of a single amino acid into the growing peptide product. Thus, an NRP synthetase is generally composed of one or more modules and can terminate in a thioesterase domain (TE) that releases the newly synthesized peptide from the enzyme. Occasionally, epimerase (E) domains (responsible for L- to D-amino acid conversion) are present within the NRP synthetase. GliP has the following architecture: A-T-C-A-T-C-T.
Sequence:
MPSVVALDLCQLFDRSVARTPHQLAVDHESGSLTYTELDVASSNLARKLKQEGVVPGEAVLLLTEHGTRNVVALLAILKAHACYVPLDRSSWSSERIQAVLDGTDSRILINTTVEPFESPRHKVIHLTSADVTTLSTDRSTTKVIPDIAPEDLACLIFTSGSTGVPKGVMIPHRAVANYAQTSPFNMDVQPGDRVLHILSVSFDASTGMLFSILGNSGIVVPATMDTLFDKAQSCSILASTPSILATLPLPTALPDSYPYVHTILLGGESPPAPLLSSWLQFGVRILNAYGPTETTCASLMQEVEVCQETGMINRSIIGRPMPNGPVYLLQPDTLLPVEEEGEEGEIAIAGVGLAHGYYRNAALTAEKFIEWHGKRVYRTGDQGRWTRRNDGQRVVEFRGRSDRTVKNRGFLVNLPADVEEPLRQMGFGVTDVYASLINGLLVALVTPATADLDGLQSEADRRLSSFHRPGRYLAVDQFPLSANGKIDTKAIENMLKEYQARLCEGTDDEETTGGERPTEREQVIAECMYTALGLDLPSASASKDFNFFAMGGNSLAALRFTSLCRERGILLTTRDLYLHPTVRGILPYARDLAHSGLPLPDKEEQIDHRLSLKAEVAAALHLLGDIDVAPLTPLQLQLSAPIFQSDGTNTNQLRQSYPLASAEHICNAWRQVVLSEPVFRTQIALDIGPGVQIVHAQPRCQPQEITFHRREDYNAALSDPSRLPVGLGMRLEFMKFMPNDDDDDEGEVTVVWTAHHSLIDGYSLGLILARVQQASQGVASSRVSSFVDAAWNLLSVQKQRDTEARRFWEQYLQPVRSLTKAEATTTPVARPYLAQEVLFKHVGGVDELHRLASSCSVTLAAVYYTAWAMTIARTTKSTLVTLGVVFSGREILPDDAQAVGPLMATLPLVCRIDGEASIERQLQTTFEGLATISTYAWSAPDQIGYRVDSLLATQYDFPTYDQPIPPQKEQFFENTTFALSLLVEADARFRLVYNPSVHGEQTVQQYADTFQQALQALVGDSTMEAWLTGPTKAPLAVDQASDIQHVNVPNVASAFYASVDLHKDLIAVDGPGGTLPYRELDQKSNAVASHIAKHFSRAQVIAIHADGTLNWVVGILGILKAGCAYCPLDPAYPIARRVAVYEQSGASALLIPNACSSSAALLPITDLRVFTIQETETSDTSRQPSLLANANEDALIVFTSGTTGRPKGVPISHRGLLALQSNPEATMFSRPGRRIAQFMSPAFDYCANEIFSALLHGGTLVLRDPSDPLAHLAKVDVSTITPSVLSVLNPDDYPNLDMVYATGEPVTPGLLARWGEGRAFYNAYGPAECSICTSFTRLEPGQQVTIGNAVRTARMYILDPDLQPVSDGQTGEIFLAGQQVMRGYVGDDAKTAYSVLPDPWHPGERMYRTGDYGYWNADRQIVYIGRLDRQVKIRGFRVELAAVEQKMYQEEPRLTQAAALVVNDTLVAFVMPLDVDVSRLEQRLRESLQPSWVPQVITALEEFPWTANRKVDYRKLAERATLTRPEDSLPQQKTPAGMTAKDASIADGIATLWKNVLRLQAGGGSRKLCEDDDFRALGGHSVLQMMLAARLGSTFGISVSMRDVIEHSTLAEQVELVRRKRQASTAKPRTICDAFPDHCLSPLERQTWFQYLIAADVRTFNIPVLLHLGGTFDRDRLVQSFNAVLASRKIFRTNFVETSLGPCRIFRDTPPRVLVCDGALDTTKEIDRSFDLARDELIRVFLDRRTLLVVTSHAVADLNSVQNLLQDVSGVYAGRTTPTPDRWHYPRAPAWSRQATEQERKFWSKYLEGAPQRLDIPRYPGQMAFEGRSRVSEFKGDLVRRAVTLGQEHGLSQHQLVCAAVAQTLQWLAGSNDVVLGSPWANRGHTVEQESMGLFLDRLPLRFKTPVNADCATILQSTRAASQAAVCNSIPFEQVLNLLHLPRTIRQHPLFEAMVTFHLKGAVEDCLAIEGLEVKREMCFASGAKFLLMFEWTEIEADHWTLRIEYDDHQLDDATVTTIEDSIRCVLEGLADRLSRAAIHERLNAMHKTARTKVDWNFYRRLVGILQREMATCLGVSLDEFPCSVSFFEAGGDSIQAWRLSRQLKRVGLEVPICNIFDHPTAQDLAQRLYRQVL