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5lx4

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Revision as of 08:42, 19 December 2018

Cys-Gly dipeptidase GliJ mutant D38H

Structural highlights

5lx4 is a 1 chain structure with sequence from Aspfm. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Related:	5lwz, 5lx0
Gene:	AFUA_6G09650 (ASPFM)
Activity:	Membrane dipeptidase, with EC number 3.4.13.19
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[GLIJ_ASPFU] Dipeptidase; 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). Gliotoxin contributes to pathogenesis during invasive aspergillosis (PubMed:17601876, PubMed:18199036). In macrophages and neutrophils, gliotoxin showed inhibition of various different cell functions including cytokine production, antigen presentation, phagocytosis, and production of reactive oxygen species (PubMed:17601876).^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8] ^[9] ^[10] ^[11]

Publication Abstract from PubMed

The formation of glutathione (GSH) conjugates, best known from the detoxification of xenobiotics, is a widespread strategy to incorporate sulfur into biomolecules. The biosynthesis of gliotoxin, a virulence factor of the human pathogenic fungus Aspergillus fumigatus, involves attachment of two GSH molecules and their sequential decomposition to yield two reactive thiol groups. The degradation of the GSH moieties requires the activity of the Cys-Gly carboxypeptidase GliJ, for which we describe the X-ray structure here. The enzyme forms a homodimer with each monomer comprising one active site. Two metal ions are present per proteolytic center, thus assigning GliJ to the diverse family of dinuclear metallohydrolases. Depending on availability, Zn2+, Fe2+, Fe3+, Mn2+, Cu2+, Co2+, or Ni2+ ions are accepted as cofactors. Despite this high metal promiscuity, a preference for zinc versus iron and manganese was noted. Mutagenesis experiments revealed details of metal coordination, and molecular modeling delivered insights into substrate recognition and processing by GliJ. The latter results suggest a reaction mechanism in which the two scissile peptide bonds of one gliotoxin precursor molecule are hydrolyzed sequentially and in a given order.

Gliotoxin Biosynthesis: Structure, Mechanism, and Metal Promiscuity of Carboxypeptidase GliJ.,Marion A, Groll M, Scharf DH, Scherlach K, Glaser M, Sievers H, Schuster M, Hertweck C, Brakhage AA, Antes I, Huber EM ACS Chem Biol. 2017 Jul 21;12(7):1874-1882. doi: 10.1021/acschembio.6b00847. Epub, 2017 Jun 6. PMID:28525266^[12]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Balibar CJ, Walsh CT. GliP, a multimodular nonribosomal peptide synthetase in Aspergillus fumigatus, makes the diketopiperazine scaffold of gliotoxin. Biochemistry. 2006 Dec 19;45(50):15029-38. PMID:17154540 doi:http://dx.doi.org/10.1021/bi061845b
↑ Spikes S, Xu R, Nguyen CK, Chamilos G, Kontoyiannis DP, Jacobson RH, Ejzykowicz DE, Chiang LY, Filler SG, May GS. Gliotoxin production in Aspergillus fumigatus contributes to host-specific differences in virulence. J Infect Dis. 2008 Feb 1;197(3):479-86. doi: 10.1086/525044. PMID:18199036 doi:http://dx.doi.org/10.1086/525044
↑ Schrettl M, Carberry S, Kavanagh K, Haas H, Jones GW, O'Brien J, Nolan A, Stephens J, Fenelon O, Doyle S. Self-protection against gliotoxin--a component of the gliotoxin biosynthetic cluster, GliT, completely protects Aspergillus fumigatus against exogenous gliotoxin. PLoS Pathog. 2010 Jun 10;6(6):e1000952. doi: 10.1371/journal.ppat.1000952. PMID:20548963 doi:http://dx.doi.org/10.1371/journal.ppat.1000952
↑ Davis C, Carberry S, Schrettl M, Singh I, Stephens JC, Barry SM, Kavanagh K, Challis GL, Brougham D, Doyle S. The role of glutathione S-transferase GliG in gliotoxin biosynthesis in Aspergillus fumigatus. Chem Biol. 2011 Apr 22;18(4):542-52. doi: 10.1016/j.chembiol.2010.12.022. PMID:21513890 doi:http://dx.doi.org/10.1016/j.chembiol.2010.12.022
↑ Forseth RR, Fox EM, Chung D, Howlett BJ, Keller NP, Schroeder FC. Identification of cryptic products of the gliotoxin gene cluster using NMR-based comparative metabolomics and a model for gliotoxin biosynthesis. J Am Chem Soc. 2011 Jun 29;133(25):9678-81. doi: 10.1021/ja2029987. Epub 2011 Jun, 6. PMID:21612254 doi:http://dx.doi.org/10.1021/ja2029987
↑ Scharf DH, Remme N, Habel A, Chankhamjon P, Scherlach K, Heinekamp T, Hortschansky P, Brakhage AA, Hertweck C. A dedicated glutathione S-transferase mediates carbon-sulfur bond formation in gliotoxin biosynthesis. J Am Chem Soc. 2011 Aug 17;133(32):12322-5. doi: 10.1021/ja201311d. Epub 2011 Jul, 22. PMID:21749092 doi:http://dx.doi.org/10.1021/ja201311d
↑ Gallagher L, Owens RA, Dolan SK, O'Keeffe G, Schrettl M, Kavanagh K, Jones GW, Doyle S. The Aspergillus fumigatus protein GliK protects against oxidative stress and is essential for gliotoxin biosynthesis. Eukaryot Cell. 2012 Oct;11(10):1226-38. doi: 10.1128/EC.00113-12. Epub 2012 Aug, 17. PMID:22903976 doi:http://dx.doi.org/10.1128/EC.00113-12
↑ Scharf DH, Chankhamjon P, Scherlach K, Heinekamp T, Roth M, Brakhage AA, Hertweck C. Epidithiol formation by an unprecedented twin carbon-sulfur lyase in the gliotoxin pathway. Angew Chem Int Ed Engl. 2012 Oct 1;51(40):10064-8. doi: 10.1002/anie.201205041., Epub 2012 Aug 31. PMID:22936680 doi:http://dx.doi.org/10.1002/anie.201205041
↑ Chang SL, Chiang YM, Yeh HH, Wu TK, Wang CC. Reconstitution of the early steps of gliotoxin biosynthesis in Aspergillus nidulans reveals the role of the monooxygenase GliC. Bioorg Med Chem Lett. 2013 Apr 1;23(7):2155-7. doi: 10.1016/j.bmcl.2013.01.099., Epub 2013 Feb 4. PMID:23434416 doi:http://dx.doi.org/10.1016/j.bmcl.2013.01.099
↑ Scharf DH, Chankhamjon P, Scherlach K, Heinekamp T, Willing K, Brakhage AA, Hertweck C. Epidithiodiketopiperazine biosynthesis: a four-enzyme cascade converts glutathione conjugates into transannular disulfide bridges. Angew Chem Int Ed Engl. 2013 Oct 11;52(42):11092-5. doi: 10.1002/anie.201305059. , Epub 2013 Aug 26. PMID:24039048 doi:http://dx.doi.org/10.1002/anie.201305059
↑ Scharf DH, Habel A, Heinekamp T, Brakhage AA, Hertweck C. Opposed effects of enzymatic gliotoxin N- and S-methylations. J Am Chem Soc. 2014 Aug 20;136(33):11674-9. doi: 10.1021/ja5033106. Epub 2014 Aug, 7. PMID:25062268 doi:http://dx.doi.org/10.1021/ja5033106
↑ Marion A, Groll M, Scharf DH, Scherlach K, Glaser M, Sievers H, Schuster M, Hertweck C, Brakhage AA, Antes I, Huber EM. Gliotoxin Biosynthesis: Structure, Mechanism, and Metal Promiscuity of Carboxypeptidase GliJ. ACS Chem Biol. 2017 Jul 21;12(7):1874-1882. doi: 10.1021/acschembio.6b00847. Epub, 2017 Jun 6. PMID:28525266 doi:http://dx.doi.org/10.1021/acschembio.6b00847

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5lx4"

@@ Line 3: / Line 3: @@
 <StructureSection load='5lx4' size='340' side='right' caption='[[5lx4]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5lx4]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5LX4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5LX4 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5lx4]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Aspfm Aspfm]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5LX4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5LX4 FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FE:FE+(III)+ION'>FE</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5lwz|5lwz]], [[5lx0|5lx0]]</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">AFUA_6G09650 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=746128 ASPFM])</td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Membrane_dipeptidase Membrane dipeptidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.13.19 3.4.13.19] </span></td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5lx4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5lx4 OCA], [http://pdbe.org/5lx4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5lx4 RCSB], [http://www.ebi.ac.uk/pdbsum/5lx4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5lx4 ProSAT]</span></td></tr>
@@ Line 24: / Line 25: @@
 __TOC__
 </StructureSection>
+[[Category: Aspfm]]
 [[Category: Membrane dipeptidase]]
 [[Category: Groll, M]]

5lx4

From Proteopedia

Revision as of 08:42, 19 December 2018

Cys-Gly dipeptidase GliJ mutant D38H

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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