6tn3

Crystal Structure of Aspergillus fumigatus UDP-N-acetylglucosamine pyrophosphorylase in complex with GlcNAc-1P

spinqualitylabelsall models 6tn3, resolution 2.28Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6tn3 is a 2 chain structure with sequence from Aspergillus fumigatus Af293. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.282Å Ligands: GN1, PO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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