4ntc

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== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[4ntc]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Aspergillus_fumigatus Aspergillus fumigatus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4NTC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4NTC FirstGlance]. <br>
<table><tr><td colspan='2'>[[4ntc]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Aspergillus_fumigatus Aspergillus fumigatus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4NTC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4NTC FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.9&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4ntc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ntc OCA], [https://pdbe.org/4ntc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ntc RCSB], [https://www.ebi.ac.uk/pdbsum/4ntc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ntc ProSAT]</span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4ntc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ntc OCA], [https://pdbe.org/4ntc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ntc RCSB], [https://www.ebi.ac.uk/pdbsum/4ntc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ntc ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
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[https://www.uniprot.org/uniprot/GLIT_ASPFU GLIT_ASPFU] Thioredoxin reductase; 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 (PubMed:15979823, PubMed:21612254). 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 (PubMed:17154540, PubMed:21612254). 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 (PubMed:23434416). 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 (PubMed:24039048, PubMed:23434416). The glutathione S-transferase (GST) gliG then forms a bis-glutathionylated biosynthetic intermediate which is responsible for the sulfurization of gliotoxin (PubMed:21513890, PubMed:21749092). This bis-glutathionylated intermediate is subsequently processed by the gamma-glutamyl cyclotransferase gliK to remove both gamma-glutamyl moieties (PubMed:22903976, PubMed:24039048). 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 (PubMed:20548963, PubMed:22936680, PubMed:24039048, PubMed:25062268). GliN-mediated amide methylation confers stability to ETP, damping the spontaneous formation of tri- and tetrasulfides (PubMed:25062268). Intracellular dithiol gliotoxin oxidized by gliT is subsequently effluxed by gliA (PubMed:26150413). GliT is required for self-protection against gliotoxin (PubMed:20548963, PubMed:26150413). GliT plays a role in preventing dysregulation of the methyl/methionine cycle to control intracellular S-adenosylmethionine (SAM) depletion and S-adenosylhomocysteine (SAH) homeostasis during gliotoxin biosynthesis and exposure (PubMed:26150413).<ref>PMID:17154540</ref> <ref>PMID:20548963</ref> <ref>PMID:21513890</ref> <ref>PMID:21612254</ref> <ref>PMID:21749092</ref> <ref>PMID:22903976</ref> <ref>PMID:22936680</ref> <ref>PMID:23434416</ref> <ref>PMID:24039048</ref> <ref>PMID:25062268</ref> <ref>PMID:26150413</ref>
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[https://www.uniprot.org/uniprot/GLIT_ASPFU GLIT_ASPFU] Thioredoxin reductase; 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 (PubMed:15979823, PubMed:21612254). 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 (PubMed:17154540, PubMed:21612254). 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 (PubMed:23434416). 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 (PubMed:23434416, PubMed:24039048). The glutathione S-transferase (GST) gliG then forms a bis-glutathionylated biosynthetic intermediate which is responsible for the sulfurization of gliotoxin (PubMed:21513890, PubMed:21749092). This bis-glutathionylated intermediate is subsequently processed by the gamma-glutamyl cyclotransferase gliK to remove both gamma-glutamyl moieties (PubMed:22903976, PubMed:24039048). 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 (PubMed:20548963, PubMed:22936680, PubMed:24039048, PubMed:25062268). GliN-mediated amide methylation confers stability to ETP, damping the spontaneous formation of tri- and tetrasulfides (PubMed:25062268). Intracellular dithiol gliotoxin oxidized by gliT is subsequently effluxed by gliA (PubMed:26150413). GliT is required for self-protection against gliotoxin (PubMed:20548963, PubMed:26150413). GliT plays a role in preventing dysregulation of the methyl/methionine cycle to control intracellular S-adenosylmethionine (SAM) depletion and S-adenosylhomocysteine (SAH) homeostasis during gliotoxin biosynthesis and exposure (PubMed:26150413).<ref>PMID:17154540</ref> <ref>PMID:20548963</ref> <ref>PMID:21513890</ref> <ref>PMID:21612254</ref> <ref>PMID:21749092</ref> <ref>PMID:22903976</ref> <ref>PMID:22936680</ref> <ref>PMID:23434416</ref> <ref>PMID:24039048</ref> <ref>PMID:25062268</ref> <ref>PMID:26150413</ref>
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== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==

Current revision

Crystal structure of GliT

PDB ID 4ntc

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