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Targeting a critical step in fungal hexosamine biosynthesis

DOI: 10.1074/jbc.RA120.012985 DOI Help

Authors: Deborah E. A. Lockhart (University of Aberdeen) , Mathew Stanley (University of Dundee) , Olawale G. Raimi (University of Dundee) , David A. Robinson (University of Dundee) , Dominika Boldovjakova (University of Aberdeen) , Daniel R. Squair (University of Dundee) , Andrew T. Ferenbach (University of Dundee) , Wenxia Fang (University of Dundee) , Daan M. F. Van Aalten (University of Dundee)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Biological Chemistry

State: Published (Approved)
Published: April 2020

Abstract: Aspergillus fumigatus is a human opportunistic fungal pathogen whose cell wall protects it from the extracellular environment, including host defense responses. Chitin, an essential component of the fungal cell wall, is synthesized from UDP-GlcNAc produced in the hexosamine biosynthetic pathway. Because this pathway is critical for fungal cell wall integrity, the hexosamine biosynthesis enzymes represent potential targets of antifungal drugs. Here, we provide genetic and chemical evidence that glucosamine 6-phosphate N-acetyltransferase (Gna1), a key enzyme in this pathway, is an exploitable antifungal drug target. GNA1 deletion resulted in loss of fungal viability and disruption of the cell wall, phenotypes that could be rescued by exogenous GlcNAc, the product of the Gna1 enzyme. In a murine model of aspergillosis, the Δgna1 mutant strain exhibited attenuated virulence. Using a fragment-based approach, we discovered a small heterocyclic scaffold that binds proximal to the Gna1 active site and can be optimized to a selective sub-micromolar binder. Taken together, we have provided genetic, structural, and chemical evidence that Gna1 is an antifungal target in A. fumigatus.

Journal Keywords: glucosamine 6-phosphate N-acetyltransferase (Gna1); resistance; fragment; anti fungal drug development; chitin; protein-protein interaction; virulence factor; cell wall; Aspergillus; fungi; X-ray crystallography

Diamond Keywords: Fungi; Enzymes

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 29/04/2020 08:41

Discipline Tags:

Pathogens Health & Wellbeing Biochemistry Genetics Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)