Disruption of de novo adenosine triphosphate (ATP) biosynthesis abolishes virulence in Cryptococcus neoformans

Blundell, Ross D., Williams, Simon J., Arras, Samantha D. M., Chitty, Jessica L., Blake, Kirsten L., Ericsson, Daniel J., Tibrewal, Nidhi, Rohr, Jurgen, Koh, Y. Q. Andre, Kappler, Ulrike, Robertson, Avril A. B., Butler, Mark S., Cooper, Matthew A., Kobe, Bostjan and Fraser, James A. (2016) Disruption of de novo adenosine triphosphate (ATP) biosynthesis abolishes virulence in Cryptococcus neoformans. ACS Infectious Diseases, 2 9: 651-663. doi:10.1021/acsinfecdis.6b00121


Author Blundell, Ross D.
Williams, Simon J.
Arras, Samantha D. M.
Chitty, Jessica L.
Blake, Kirsten L.
Ericsson, Daniel J.
Tibrewal, Nidhi
Rohr, Jurgen
Koh, Y. Q. Andre
Kappler, Ulrike
Robertson, Avril A. B.
Butler, Mark S.
Cooper, Matthew A.
Kobe, Bostjan
Fraser, James A.
Title Disruption of de novo adenosine triphosphate (ATP) biosynthesis abolishes virulence in Cryptococcus neoformans
Formatted title
Disruption of de novo adenosine triphosphate (ATP) biosynthesis abolishes virulence in Cryptococcus neoformans
Journal name ACS Infectious Diseases   Check publisher's open access policy
ISSN 2373-8227
Publication date 2016-09-09
Year available 2016
Sub-type Article (original research)
DOI 10.1021/acsinfecdis.6b00121
Open Access Status Not yet assessed
Volume 2
Issue 9
Start page 651
End page 663
Total pages 13
Place of publication Washington, DC United States
Publisher American Chemical Society
Collection year 2017
Language eng
Formatted abstract
Opportunistic fungal pathogens such as Cryptococcus neoformans are a growing cause of morbidity and mortality among immunocompromised populations worldwide. To address the current paucity of antifungal therapeutic agents, further research into fungal-specific drug targets is required. Adenylosuccinate synthetase (AdSS) is a crucial enzyme in the adeosine triphosphate (ATP) biosynthetic pathway, catalyzing the formation of adenylosuccinate from inosine monophosphate and aspartate. We have investigated the potential of this enzyme as an antifungal drug target, finding that loss of function results in adenine auxotrophy in C. neoformans, as well as complete loss of virulence in a murine model. Cryptococcal AdSS was expressed and purified in Escherichia coli and the enzyme’s crystal structure determined, the first example of a structure of this enzyme from fungi. Together with enzyme kinetic studies, this structural information enabled comparison of the fungal enzyme with the human orthologue and revealed species-specific differences potentially exploitable via rational drug design. These results validate AdSS as a promising antifungal drug target and lay a foundation for future in silico and in vitro screens for novel antifungal compounds.
Keyword Antifungal
Cryptococcus neoformans
Molecular genetics
Target verification
X-ray crystallography
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

 
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Created: Fri, 09 Sep 2016, 01:55:44 EST by Susan Allen on behalf of Institute for Molecular Bioscience