GMP synthase is required for virulence factor production and infection by cryptococcus neoformans

Chitty, Jessica L., Tatzenko, Tayla L. , Williams, Simon J., Koh, Y. Q. Andre E., Corfield, Elizabeth C., Butler, Mark S., Robertson, Avril A. B., Cooper, Matthew A., Kappler, Ulrike, Kobe, Bostjan and Fraser, James A. (2017) GMP synthase is required for virulence factor production and infection by cryptococcus neoformans. Journal of Biological Chemistry, 292 7: 3049-3059. doi:10.1074/jbc.M116.767533

Author Chitty, Jessica L.
Tatzenko, Tayla L.
Williams, Simon J.
Koh, Y. Q. Andre E.
Corfield, Elizabeth C.
Butler, Mark S.
Robertson, Avril A. B.
Cooper, Matthew A.
Kappler, Ulrike
Kobe, Bostjan
Fraser, James A.
Title GMP synthase is required for virulence factor production and infection by cryptococcus neoformans
Journal name Journal of Biological Chemistry   Check publisher's open access policy
ISSN 1083-351X
Publication date 2017-02-17
Sub-type Article (original research)
DOI 10.1074/jbc.M116.767533
Open Access Status Not yet assessed
Volume 292
Issue 7
Start page 3049
End page 3059
Total pages 11
Place of publication Rockville, MD, United States
Publisher American Society for Biochemistry and Molecular Biology
Collection year 2018
Language eng
Formatted abstract
Over the last four decades the HIV pandemic and advances in medical treatments that also cause immunosuppression have produced an ever-growing cohort of individuals susceptible to opportunistic pathogens. Of these, AIDS patients are particularly vulnerable to infection by the encapsulated yeast Cryptococcus neoformans. Most commonly found in the environment in purine-rich bird guano, C. neoformans experiences a drastic change in nutrient availability during host infection, ultimately disseminating to colonize the purine-poor central nervous system. Investigating the consequences of this challenge, we have characterized C. neoformans GMP synthase, the second enzyme in the guanylate branch of de novo purine biosynthesis. We show that in the absence of GMP synthase, C. neoformans becomes a guanine auxotroph, the production of key virulence factors is compromised, and the ability to infect nematodes and mice is abolished. Activity assays performed using recombinant protein unveiled differences in substrate binding between the C. neoformans and human enzymes, with structural insights into these kinetic differences acquired via homology modeling. Collectively, these data highlight the potential of GMP synthase to be exploited in the development of new therapeutic agents for the treatment of disseminated, life-threatening fungal infections.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
School of Chemistry and Molecular Biosciences
Institute for Molecular Bioscience - Publications
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