7mo6

Publication Abstract from PubMed

Purine biosynthesis is a fundamental cellular process that sustains life by maintaining the intracellular pool of purines for DNA/RNA synthesis and signal transduction. As an integral determinant of fungal survival and virulence, the enzymes in this metabolic pathway have been pursued as potential antifungal targets. Guanosine monophosphate (GMP) synthase has been identified as an attractive target as it is essential for virulence in the clinically prominent fungal pathogens Aspergillus fumigatus, Candida albicans and Cryptococcus neoformans. However, a lack of structural information on GMP synthase has hindered drug-design efforts. Here, the first structure of a GMP synthase of fungal origin, that from A. fumigatus (at 2.3 A resolution), is presented. Structural analysis of GMP synthase shows a distinct absence of the D1 dimerization domain that is present in the human homologue. Interestingly, A. fumigatus GMP synthase adopts a dimeric state, as determined by native mass spectrometry and gel-filtration chromatography, in contrast to the monomeric human homologue. Analysis of the substrate-binding pockets of A. fumigatus GMP synthase reveals key differences in the ATP- and XMP-binding sites that can be exploited for species-specific inhibitor drug design. Furthermore, the inhibitory activities of the glutamine analogues acivicin (IC50 = 16.6 +/- 2.4 microM) and 6-diazo-5-oxo-L-norleucine (IC50 = 29.6 +/- 5.6 microM) against A. fumigatus GMP synthase are demonstrated. Together, these data provide crucial structural information required for specifically targeting A. fumigatus GMP synthase for future antifungal drug-discovery endeavours.

Structural insights into the antifungal drug target guanosine monophosphate synthase from Aspergillus fumigatus.,Nguyen S, Jovcevski B, Pukala TL, Bruning JB Acta Crystallogr D Struct Biol. 2022 Feb 1;78(Pt 2):248-259. doi:, 10.1107/S2059798321012031. Epub 2022 Jan 26. PMID:35102890^[1]

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