4ntc | pdb_00004ntc

Crystal structure of GliT

spinqualitylabelsall models 4ntc, resolution 1.90Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4ntc is a 2 chain structure with sequence from Aspergillus fumigatus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.9Å Ligands: FAD Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function 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). Publication Abstract from PubMed Nature provides a rich source of compounds with diverse chemical structures and biological activities, among them, sulfur-containing metabolites from bacteria and fungi. Some of these compounds bear a disulfide moiety that is indispensable for their bioactivity. Specialized oxidoreductases such as GliT, HlmI, and DepH catalyze the formation of this disulfide bridge in the virulence factor gliotoxin, the antibiotic holomycin, and the anticancer drug romidepsin, respectively. We have examined all three enzymes by X-ray crystallography and activity assays. Despite their differently sized substrate binding clefts and hence, their diverse substrate preferences, a unifying reaction mechanism is proposed based on the obtained crystal structures and further supported by mutagenesis experiments. Flavoenzyme-catalyzed formation of disulfide bonds in natural products.,Scharf DH, Groll M, Habel A, Heinekamp T, Hertweck C, Brakhage AA, Huber EM Angew Chem Int Ed Engl. 2014 Feb 17;53(8):2221-4. doi: 10.1002/anie.201309302., Epub 2014 Jan 20. PMID:24446392 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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