A mechanism-inspired UDP-<i>N</i>-acetylglucosamine pyrophosphorylase inhibitor.

ABSTRACT: 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 Mg²⁺ provides the first Michaelis complex trapped for this class of enzyme, revealing the structural basis of the previously reported Mg²⁺ dependence and direct observation of

SUBMITTER: Raimi OG 

PROVIDER: S-EPMC8386105 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature