title: GMP Synthase Is Required for Virulence Factor Production and Infection byCryptococcus neoformans.
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 yeastCryptococcus neoformansMost commonly found in the environment in purine-rich bird guano,C. neoformansexperiences 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 characterizedC. neoformansGMP synthase, the second enzyme in the guanylate branch ofde novopurine biosynthesis. We show that in the absence of GMP synthase,C. neoformansbecomes 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 theC. neoformansand 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.
authors.affiliation: From the Australian Infectious Diseases Research Centre, School of Chemistry & Molecular Biosciences.|the Institute for Molecular Bioscience, and.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Chitty
authors.affiliation: From the Australian Infectious Diseases Research Centre, School of Chemistry & Molecular Biosciences.
authors.forename: Tayla L
authors.initials: TL
authors.lastname: Tatzenko
authors.affiliation: From the Australian Infectious Diseases Research Centre, School of Chemistry & Molecular Biosciences.|the ANU Research School of Biology, Australian National University, Acton, ACT 2601, Australia.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Williams
authors.affiliation: From the Australian Infectious Diseases Research Centre, School of Chemistry & Molecular Biosciences.
authors.forename: Y Q Andre E
authors.initials: YQ
authors.lastname: Koh
authors.affiliation: From the Australian Infectious Diseases Research Centre, School of Chemistry & Molecular Biosciences.
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Corfield
authors.affiliation: the Institute for Molecular Bioscience, and.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Butler
authors.affiliation: the Institute for Molecular Bioscience, and.
authors.forename: Avril A B
authors.initials: AA
authors.lastname: Robertson
authors.affiliation: From the Australian Infectious Diseases Research Centre, School of Chemistry & Molecular Biosciences.|the Institute for Molecular Bioscience, and.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Cooper
authors.affiliation: From the Australian Infectious Diseases Research Centre, School of Chemistry & Molecular Biosciences.|the Centre for Metals in Biology, University of Queensland, St. Lucia, Queensland 4072, Australia and.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Kappler
authors.affiliation: From the Australian Infectious Diseases Research Centre, School of Chemistry & Molecular Biosciences.|the Institute for Molecular Bioscience, and.
authors.forename: Bostjan
authors.initials: B
authors.lastname: Kobe
authors.affiliation: From the Australian Infectious Diseases Research Centre, School of Chemistry & Molecular Biosciences, jafraser@uq.edu.au.
authors.forename: James A
authors.initials: JA
authors.lastname: Fraser
mesh_terms: D019731:Carbon-Nitrogen Ligases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D003453:Cryptococcosis / Q000201:enzymology / Q000382:microbiology*; D003455:Cryptococcus neoformans / Q000235:genetics / Q000472:pathogenicity*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005800:Genes, Fungal; D037521:Virulence Factors / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D037521:Virulence Factors; D019731:Carbon-Nitrogen Ligases; C020828:GMP synthase (glutamine-hydrolyzing)
keywords: GMP synthase; enzyme kinetics; fungi; nucleoside/nucleotide biosynthesis; purine; virulence factor