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

Jessica L. Chitty, Kirsten L. Blake, Ross D. Blundell, Y. Q.Andre E. Koh, Merinda Thompson, Avril A.B. Robertson, Mark S. Butler, Matthew A. Cooper, Ulrike Kappler, Simon J. Williams, Bostjan Kobe, James A. Fraser*

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

    15 Citations (Scopus)

    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 ade13Δ 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 enzymespecific 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.

    Original languageEnglish
    Pages (from-to)11829-11839
    Number of pages11
    JournalJournal of Biological Chemistry
    Volume292
    Issue number28
    DOIs
    Publication statusPublished - 14 Jul 2017

    Fingerprint

    Dive into the research topics of 'Cryptococcus neoformans ADS lyase is an enzyme essential for virulence whose crystal structure reveals features exploitable in antifungal drug design'. Together they form a unique fingerprint.

    Cite this