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| | <StructureSection load='6tn3' size='340' side='right'caption='[[6tn3]], [[Resolution|resolution]] 2.28Å' scene=''> | | <StructureSection load='6tn3' size='340' side='right'caption='[[6tn3]], [[Resolution|resolution]] 2.28Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6tn3]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Aspfu Aspfu]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6TN3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6TN3 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6tn3]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Aspergillus_fumigatus_Af293 Aspergillus fumigatus Af293]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6TN3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6TN3 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GN1:2-(ACETYLAMINO)-2-DEOXY-1-O-PHOSPHONO-ALPHA-D-GLUCOPYRANOSE'>GN1</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.282Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">AFUA_7G02180 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=330879 ASPFU])</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GN1:2-(ACETYLAMINO)-2-DEOXY-1-O-PHOSPHONO-ALPHA-D-GLUCOPYRANOSE'>GN1</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/UDP-N-acetylglucosamine_diphosphorylase UDP-N-acetylglucosamine diphosphorylase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.7.23 2.7.7.23] </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=6tn3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6tn3 OCA], [https://pdbe.org/6tn3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6tn3 RCSB], [https://www.ebi.ac.uk/pdbsum/6tn3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6tn3 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=6tn3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6tn3 OCA], [https://pdbe.org/6tn3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6tn3 RCSB], [https://www.ebi.ac.uk/pdbsum/6tn3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6tn3 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/Q4WAR0_ASPFU Q4WAR0_ASPFU] |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Aspfu]] | + | [[Category: Aspergillus fumigatus Af293]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: UDP-N-acetylglucosamine diphosphorylase]]
| + | [[Category: Guerrero RH]] |
| - | [[Category: Guerrero, R H]] | + | [[Category: Raimi OG]] |
| - | [[Category: Raimi, O G]] | + | |
| - | [[Category: Anti-fungal]]
| + | |
| - | [[Category: Aspergillus fumigatus]]
| + | |
| - | [[Category: Pyrophosphorylase]]
| + | |
| - | [[Category: Transferase]]
| + | |
| Structural highlights
Function
Q4WAR0_ASPFU
Publication Abstract from PubMed
UDP-N-acetylglucosamine pyrophosphorylase (UAP1) catalyses the last step in eukaryotic biosynthesis of uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc), converting UTP and GlcNAc-1P to the sugar nucleotide. Gene disruption studies have shown that this gene is essential in eukaryotes and a possible antifungal target, yet no inhibitors of fungal UAP1 have so far been reported. Here we describe the crystal structures of substrate/product complexes of UAP1 from Aspergillus fumigatus that together provide snapshots of catalysis. A structure with UDP-GlcNAc, pyrophosphate and Mg(2+) provides the first Michaelis complex trapped for this class of enzyme, revealing the structural basis of the previously reported Mg(2+) dependence and direct observation of pyrophosphorolysis. We also show that a highly conserved lysine mimics the role of a second metal observed in structures of bacterial orthologues. A mechanism-inspired UTP alpha,beta-methylenebisphosphonate analogue (meUTP) was designed and synthesized and was shown to be a micromolar inhibitor of the enzyme. The mechanistic insights and inhibitor described here will facilitate future studies towards the discovery of small molecule inhibitors of this currently unexploited potential antifungal drug target.
A mechanism-inspired UDP-N-acetylglucosamine pyrophosphorylase inhibitor.,Raimi OG, Hurtado-Guerrero R, Borodkin V, Ferenbach A, Urbaniak MD, Ferguson MAJ, van Aalten DMF RSC Chem Biol. 2020 Mar 24;1(1):13-25. doi: 10.1039/c9cb00017h. eCollection 2020 , Apr 16. PMID:34458745[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Raimi OG, Hurtado-Guerrero R, Borodkin V, Ferenbach A, Urbaniak MD, Ferguson MAJ, van Aalten DMF. A mechanism-inspired UDP-N-acetylglucosamine pyrophosphorylase inhibitor. RSC Chem Biol. 2020 Mar 24;1(1):13-25. doi: 10.1039/c9cb00017h. eCollection 2020 , Apr 16. PMID:34458745 doi:http://dx.doi.org/10.1039/c9cb00017h
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