Science Bite (3 min Oral Presentation) Lorne Infection and Immunity 2019

Bifunctional purine biosynthesis enzyme GAR synthetase/AIR synthetase as an antifungal target (#66)

Sheena Chua 1 , James Fraser 1
  1. Australian Infectious Disease Research Centre, School of Chemistry and Molecular Bioscience, Brisbane, Queensland, Australia

Cryptococcus neoformans is a major fungal pathogen that causes life-threatening systemic mycoses. The current antifungals employed to treat this disease have not changed significantly for the past 25 years despite the high mortality and morbidity. Therefore, there is an urgent need to develop new antifungal drugs. An area of interest for finding new antifungal targets is the purine biosynthesis pathway. Many effective drugs have been developed based on the purine metabolic pathway, however there are limited studies that utilise this pathway as a source of targets for antifungal discovery. The purine biosynthesis pathway consists of eleven sequential enzymatic steps to form IMP, an intermediate for formation of ATP and GTP. Over the course of evolution of the eukaryotes, several gene fusion events have occurred resulting in the formation of bifunctional or trifunctional enzymes in higher order organisms. An example of this is bifunctional GAR synthetase/AIR synthetase, which catalyses steps two and five of the purine biosynthesis pathway. In humans, this has undergone has an additional gene fusion to create a trifunctional enzyme that includes GAR transformylase. The gross differences between the fungal and human enzymes could potentially be exploited in the development of fungal specific inhibitors. The enzyme has been characterised using molecular genetic, enzymology and structural biology techniques. Our work proves that the enzyme is required for de novo adenine and guanine production and is essential for virulence in a mouse inhalation model, showing its potential as an antifungal target. Each domain of the protein has been heterologously expressed and crystallised. The GARS domain crystal had a preliminary diffraction of 3 Å and the AIRS domain crystal had a preliminary diffraction of 2 Å, and reveals differences from the human enzyme that could be exploited in antifungal drug development.