Towards covalent inhibition of phosphoglucomutase in Aspergillus fumigatus

Abstract

Aspergillus fumigatus, an opportunistic fungal pathogen, is a causative agent of life-threatening invasive aspergillosis. Phosphoglucomutase 1 (PGM) is a critical enzyme interconverting glucose-1phosphate and glucose-6-phosphate, participating in both biogenesis of the cell wall and trehalose metabolism. Here, it is demonstrated that recombinantly expressed AfPGM can be covalently inhibited via a cysteine residue (C353) not conserved in the human orthologue. Two mechanistically dissimilar probes were utilised to interrogate the enzyme and its mutein, showing that inhibition is elicited exclusively via cysteine C353. Preliminary data also indicated that labelling cysteine C353 with used inhibitors does not destabilise the enzyme but precludes the motion of key domains resulting in ineffective phosphoryl transfer.

Date of Award	2023
Original language	English
Awarding Institution	University of Dundee
Supervisor	Daan van Aalten (Supervisor) & David Murray (Supervisor)