Cryptococcus neoformans ADS lyase is an enzyme essential for virulence whose crystal structure reveals features exploitable in antifungal drug design

Chitty, Jessica L., Blake, Kirsten L., Blundell, Ross D., Koh, Y. Q. Andre E., Thompson, Merinda, Robertson, Avril A. B., Butler, Mark S., Cooper, Matthew A., Kappler, Ulrike, Williams, Simon J., Kobe, Bostjan and Fraser, James A. (2017) Cryptococcus neoformans ADS lyase is an enzyme essential for virulence whose crystal structure reveals features exploitable in antifungal drug design. Journal of Biological Chemistry, 292 28: 11829-11839. doi:10.1074/jbc.M117.787994


Author Chitty, Jessica L.
Blake, Kirsten L.
Blundell, Ross D.
Koh, Y. Q. Andre E.
Thompson, Merinda
Robertson, Avril A. B.
Butler, Mark S.
Cooper, Matthew A.
Kappler, Ulrike
Williams, Simon J.
Kobe, Bostjan
Fraser, James A.
Title Cryptococcus neoformans ADS lyase is an enzyme essential for virulence whose crystal structure reveals features exploitable in antifungal drug design
Journal name Journal of Biological Chemistry   Check publisher's open access policy
ISSN 1083-351X
0021-9258
Publication date 2017-07-14
Year available 2017
Sub-type Article (original research)
DOI 10.1074/jbc.M117.787994
Open Access Status Not yet assessed
Volume 292
Issue 28
Start page 11829
End page 11839
Total pages 11
Place of publication Bethesda, MD, United States
Publisher American Society for Biochemistry and Molecular Biology
Language eng
Abstract There is significant clinical need for new antifungal agents to manage infections with pathogenic species such as Cryptococcus neoformans. Because the purine biosynthesis pathway is essential for many metabolic processes, such as synthesis of DNA and RNA and energy generation, it may represent a potential target for developing new antifungals. Within this pathway, the bifunctional enzyme adenylosuccinate (ADS) lyase plays a role in the formation of the key intermediates inosine monophosphate and AMP involved in the synthesis of ATP and GTP, prompting us to investigate ADS lyase in C. neoformans. Here, we report that ADE13 encodes ADS lyase in C. neoformans. We found that an ade13 Delta mutant is an adenine auxotroph and is unable to successfully cause infections in a murine model of virulence. Plate assays revealed that production of a number of virulence factors essential for dissemination and survival of C. neoformans in a host environment was compromised even with the addition of exogenous adenine. Purified recombinant C. neoformans ADS lyase shows catalytic activity similar to its human counterpart, and its crystal structure, the first fungal ADS lyase structure determined, shows a high degree of structural similarity to that of human ADS lyase. Two potentially important amino acid differences are identified in the C. neoformans crystal structure, in particular a threonine residue that may serve as an additional point of binding for a fungal enzyme-specific inhibitor. Besides serving as an antimicrobial target, C. neoformans ADS lyase inhibitors may also serve as potential therapeutics for metabolic disease; rather than disrupt ADS lyase, compounds that improve the stability the enzyme may be used to treat ADS lyase deficiency disease.
Keyword Biochemistry & Molecular Biology
Biochemistry & Molecular Biology
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID APP1049716
1003325
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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