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5oa8

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Revision as of 12:19, 26 August 2020

Fe(II)/(alpha)ketoglutarate-dependent dioxygenase AsqJ_V72I mutant in complex with demethylated cyclopeptin (1d)

Structural highlights

5oa8 is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Related:	5dap
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[ASQJ_EMENI] Iron/alpha-ketoglutarate-dependent dioxygenase; part of the gene cluster that mediates the biosynthesis of the aspoquinolone mycotoxins (PubMed:25251934, PubMed:26553478). The first stage is catalyzed by the nonribosomal pepdide synthetase asqK that condenses anthranilic acid and O-methyl-L-tyrosine to produce 4'-methoxycyclopeptin (PubMed:25251934). AsqK is also able to use anthranilic acid and L-phenylalanine as substrates to produce cyclopeptin, but at a tenfold lower rate (PubMed:25251934). 4'-methoxycyclopeptin is then converted to 4'-methoxydehydrocyclopeptin by the ketoglutarate-dependent dioxygenase asqJ through dehydrogenation to form a double bond between C-alpha and C-beta of the O-methyltyrosine side chain (PubMed:25251934, PubMed:26553478). AsqJ also converts its first product 4'-methoxydehydrocyclopeptin to 4'-methoxycyclopenin (PubMed:25251934). AsqJ is a very unique dioxygenase which is capable of catalyzing radical-mediated dehydrogenation and epoxidation reactions sequentially on a 6,7-benzo-diazepinedione substrate in the 4'-methoxyviridicatin biosynthetic pathway (PubMed:25251934). The following conversion of 4'-methoxycyclopenin into 4'-methoxyviridicatin proceeds non-enzymatically (PubMed:25251934). AsqJ is also capable of converting cyclopeptin into dehydrocyclopeptin and cyclopenin in a sequential fashion (PubMed:25251934). Cyclopenin can be converted into viridicatin non-enzymatically (PubMed:25251934). 4'-methoxyviridicatin likely acts as a precursor of quinolone natural products, such as aspoquinolones, peniprequinolones, penigequinolones, and yaequinolones (PubMed:25251934). Further characterization of the remaining genes in the cluster has still to be done to determine the exact identity of quinolone products this cluster is responsible for biosynthesizing (PubMed:25251934).^[1] ^[2]

Publication Abstract from PubMed

The recently discovered Fe(II)/alpha-ketoglutarate-dependent dioxygenase AsqJ from Aspergillus nidulans stereoselectively catalyzes a multistep synthesis of quinolone alkaloids, natural products with significant biomedical applications. To probe molecular mechanisms of this elusive catalytic process, we combine here multi-scale quantum and classical molecular simulations with X-ray crystallography, and in vitro biochemical activity studies. We discover that methylation of the substrate is essential for the activity of AsqJ, establishing molecular strain that fine-tunes pi-stacking interactions within the active site. To rationally engineer AsqJ for modified substrates, we amplify dispersive interactions within the active site. We demonstrate that the engineered enzyme has a drastically enhanced catalytic activity for non-methylated surrogates, confirming our computational data and resolved high-resolution X-ray structures at 1.55 A resolution. Our combined findings provide crucial mechanistic understanding of the function of AsqJ and showcase how combination of computational and experimental data enables to rationally engineer enzymes.

Catalytic mechanism and molecular engineering of quinolone biosynthesis in dioxygenase AsqJ.,Mader SL, Brauer A, Groll M, Kaila VRI Nat Commun. 2018 Mar 21;9(1):1168. doi: 10.1038/s41467-018-03442-2. PMID:29563492^[3]

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

References

↑ Ishikawa N, Tanaka H, Koyama F, Noguchi H, Wang CC, Hotta K, Watanabe K. Non-heme dioxygenase catalyzes atypical oxidations of 6,7-bicyclic systems to form the 6,6-quinolone core of viridicatin-type fungal alkaloids. Angew Chem Int Ed Engl. 2014 Nov 17;53(47):12880-4. doi: 10.1002/anie.201407920. , Epub 2014 Sep 22. PMID:25251934 doi:http://dx.doi.org/10.1002/anie.201407920
↑ Brauer A, Beck P, Hintermann L, Groll M. Structure of the Dioxygenase AsqJ: Mechanistic Insights into a One-Pot Multistep Quinolone Antibiotic Biosynthesis. Angew Chem Int Ed Engl. 2015 Nov 10. doi: 10.1002/anie.201507835. PMID:26553478 doi:http://dx.doi.org/10.1002/anie.201507835
↑ Mader SL, Brauer A, Groll M, Kaila VRI. Catalytic mechanism and molecular engineering of quinolone biosynthesis in dioxygenase AsqJ. Nat Commun. 2018 Mar 21;9(1):1168. doi: 10.1038/s41467-018-03442-2. PMID:29563492 doi:http://dx.doi.org/10.1038/s41467-018-03442-2

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5oa8"

@@ Line 1: / Line 1: @@
 ==Fe(II)/(alpha)ketoglutarate-dependent dioxygenase AsqJ_V72I mutant in complex with demethylated cyclopeptin (1d)==
-<StructureSection load='5oa8' size='340' side='right' caption='[[5oa8]], [[Resolution|resolution]] 1.75&Aring;' scene=''>
+<StructureSection load='5oa8' size='340' side='right'caption='[[5oa8]], [[Resolution|resolution]] 1.75&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5oa8]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5OA8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5OA8 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5oa8]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5OA8 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5OA8 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=58L:DEMETHYLATED+CYCLOPEPTIN'>58L</scene>, <scene name='pdbligand=AKG:2-OXOGLUTARIC+ACID'>AKG</scene>, <scene name='pdbligand=NI:NICKEL+(II)+ION'>NI</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=58L:DEMETHYLATED+CYCLOPEPTIN'>58L</scene>, <scene name='pdbligand=AKG:2-OXOGLUTARIC+ACID'>AKG</scene>, <scene name='pdbligand=NI:NICKEL+(II)+ION'>NI</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5dap|5dap]]</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=5oa8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5oa8 OCA], [http://pdbe.org/5oa8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5oa8 RCSB], [http://www.ebi.ac.uk/pdbsum/5oa8 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5oa8 ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5oa8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5oa8 OCA], [http://pdbe.org/5oa8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5oa8 RCSB], [http://www.ebi.ac.uk/pdbsum/5oa8 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5oa8 ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 19: / Line 19: @@
 </div>
 <div class="pdbe-citations 5oa8" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Dioxygenase 3D structures|Dioxygenase 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Large Structures]]
 [[Category: Braeuer, A]]
 [[Category: Groll, M]]

5oa8

From Proteopedia

Revision as of 12:19, 26 August 2020

Fe(II)/(alpha)ketoglutarate-dependent dioxygenase AsqJ_V72I mutant in complex with demethylated cyclopeptin (1d)

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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